Cerebral Hemorrhage Risk in Hereditary Hemorrhagic Telangiectasia (BVMN6203)

• ClinicalTrials.gov Identifier: NCT01158807
• Recruitment Status: Recruiting
• First Posted: July 8, 2010
• Last Update Posted: December 12, 2022
• Sponsor: Unity Health Toronto
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Unity Health Toronto

Study Description

Brief Summary:

This study is one of the three projects of an NIH Rare Disease Clinical Research Consortium. A "consortium" is a group of centres sharing information and resources to perform research. The consortium research focuses on brain blood vessel malformations in three different rare diseases.

The focus of this specific study is on Hemorrhagic Telangiectasia (HHT).

HHT is a condition characterized by blood vessel malformations, called telangiectasia and arteriovenous malformations (AVMs), occurring in the brain, nose, lungs, stomach, bowels and liver. Brain AVMs (BAVMs) in HHT are difficult to study because they are rare, affecting approximately 10% of people with HHT. While other types of BAVMs have been studied in depth, studies in the HHT population have been very small. Here, we propose the first large-scale collaboration by joining with 12 HHT Centers of Excellence in North America to perform a large study of risk factors for bleeding from BAVMs, called intracranial hemorrhage (ICH) in HHT patients.

The current standard of clinical practice across North America, is to screen all HHT patients for BAVMs with magnetic resonance imaging (MRI). If BAVMs are detected, patients are referred to a multidisciplinary neurovascular team for consideration for treatment. Treatment decisions are made on a case by case basis, balancing risks of complications from the BAVM with risks of therapy, but are limited by the few studies available in HHT. We hope that the knowledge we obtain about the risk factors for intracranial bleeding in these patients from this larger study will help us to improve the care of HHT patients.

We plan to study risk factors for rupture of BAVMs, including primarily genetics and imaging characteristics of the BAVMs. Knowledge about risk factors will help in the care and management of HHT patients. This will be achieved through the collection of health information to construct a HHT database, blood sampling and banking (through the National Institute of Neurological Disorders and Stroke [NINDS]), and through genetic analysis at the University of California San Francisco.

Condition or disease
Hereditary Hemorrhagic Telangiectasia

Detailed Description:

4. Study Design and Methods In conjunction with the DMCC, we will construct a relational database and web-based data collection instrument; see Table 1 showing the sites that will contribute to this effort. Data will include demographics, symptomology, cerebral angioarchitecture, other organ involvement and HHT gene mutation results.

The database will be used to serve Aim 2 and Aim 3 but will also serve as a platform to foster further HHT research. The recruitment of HHT BAVM cases will be emphasized by use of a 3:1 ratio for enrolling non-BAVM to BAVM HHT cases, i.e., for each brain AVM recruited, 3 patients without a brain AVM will be recruited. This will provide the largest RDCRN 6203 Cerebral Hemorrhage Risk in single sample available that will also have centralized expert neuroradiological adjudication of the brain phenotype.

The study design is detailed, by aim, in Section 6. The data to be collected is detailed in Sections 4.5 and 4.5.1 and the study schedule is detailed in Section 4.6.

4.1. Study Population: The study population will include patients with HHT, with inclusion and exclusion criteria as detailed in section 4.3. Cases will be recruited from two sources: (a) the network of HHT Centers of Excellence (Table 1); and (b) patients who contact study personnel or the HHT Foundation International after learning about the study through the HHT Foundation International social networks, the RDCRN public website, friends, physicians, relatives, etc.

Inclusion and exclusion criteria are detailed in section 4.3. 4.2. Case Ascertainment and Enrollment As shown in Table 2, we estimate conservatively that 875 cases will be available for recruitment over five years. Cases will be derived from two sources. First, we will recruit from the HHT Centers of Excellence cases that are currently being followed and new cases as they pass through the individual clinics. Ascertainment and enrollment will use IRB approved, HIPAA-compliant procedures. Each center will submit cases using web-based forms. Second, we will recruit new cases through the HHT Foundation. The HHT Foundation has a mailing list of 5646 families; there is approximately 1000 new families added per year. HHT Patients who contact the HHT Foundation with an interest in participating in the study will be directed to the closest participating HHT Center of Excellence. The HHT Foundation will recruit patients who contact the HHT Foundation who are interested in participating in the BAVM arm of the study but who are not affiliated with a participating center or do not wish to visit a center to participate in the study. We will also enroll non-BAVM HHT cases to facilitate long-term involvement of the HHT community in systematic, organized rare disease research. We have structured the database to be scalable to accommodate all types of HHT. Under the supervision of the site PI, each local PI and research staff will identify and obtain informed consent from patients and their clinical information is entered into a master registry. At enrollment, arrangements for a blood specimen will also be made. Approximately 20 ml (about 4 teaspoons) of blood will be drawn (two ACD tubes of 8.5 ml each). If a blood draw is not possible, the UCSF core will provide bar-coded saliva DNA collection kits. Representative standard clinical imaging studies (MR and angiography) of enrolled cases will be provided to Dr. Karel TerBrugge at Toronto Western Hospital for adjudication and coding of angioarchitecture. We have conservatively estimated that we will be able to collect DNA from 500 of the 875 project cases that will be enrolled over the course of the study.

4.3 Patient Selection

Inclusion Criteria:

1. (a) Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis of HHT Curacao criteria: (a) spontaneous recurrent nosebleeds; (b) mucocutaneous telangiectasia at characteristic sites (lips, oral cavity, fingers or the nose); (c) visceral involvement such as pulmonary, hepatic or CNS BAVM; and (d) an affected first degree relative by same criteria.(65) OR (b) Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis of HHT Curacao criteria: (a) spontaneous recurrent nosebleeds; (b) mucocutaneous telangiectasia at characteristic sites (lips, oral cavity, fingers or the nose); (c) visceral involvement such as pulmonary, hepatic or CNS BAVM; and (d) an affected first degree relative by same criteria.(65) AND Presence of BAVM For the purpose of the study, we will focus on BAVM that directly shunts blood from arterial to venous circulations without an intervening capillary bed, including Toronto classifications(23) of A-V fistulas, "micro" BAVMs (<1 cm) and 8 "small" (1-3 cm) BAVMs, and if present, larger lesions. We will not include intracranial telangiectasias in isolation.
2. Able to provide informed consent Exclusion Criteria: None 4.4 Recruitment and Informed Consent The prospective HHT population will consist of patients seen for evaluation and treatment of HHT. Health status for all patients will encompass a spectrum of disabilities encountered with the disease processes being studied. The Human Subjects Committee/Institutional Review Board of each clinical center will approve the informed consent form. A copy of the letter of approval from the IRB/REB and a copy of the consent form will be filed with the DMCC before a clinical center will be allowed to initiate enrollment. The informed consent will include the objectives of the study, a description of the screening process, the potential risks and benefits, the cost to the patient, alternatives to participation and liabilities of the particular participating center. All patients who are diagnosed with HHT, regardless of gender, race or ethnicity, are potential candidates for the RDCRC. To the best of our knowledge, there is no race-ethnicity predilection for HHT or sporadic BAVMs.

4.5 Data and Sample Collection Development A detailed table of relevant fields and their data types and ranges were constructed by combining elements that are in use by the HHT community and those fields that are collected in our ongoing study of sporadic BAVM. We used these data tables as a departure point to work with the DMCC in constructing both the relational database for the project as well as the data web entry forms. Database issues are also addressed in the GSAC and AU sections.

All recruited participants will be assigned a Database study ID. The link between patient identifying information and database study ID will only be maintained at the recruiting center. Data will be entered through a web-based system into a central Database developed at the DMCC. Only de-identified information will be entered in the central Database.

4.5.1 Detailed Clinical and Radiographic Information to be Collected Information collected will include both attributes of the systemic manifestations of HHT with a focus on the brain vascular phenotype. Detailed tables of data fields and data web entry forms are available from the Site PI, Project Leader, and DMCC. The Clinical data elements include demographic information as well as specific clinical information about clinical features and complications of BAVMs, as well as other organ AVMs and complications related to HHT. The Neuroradiological elements include information about angiographic features, clinical presentation, complications and treatment of BAVMs. This data will be collect at baseline. Every year after recruitment, , participants will be contacted by the recruiting Center to collect a limited follow-up data set, regarding treatment and complications of BAVMs and mortal status.

The diagnosis of BAVM will be made by referring centers and adjudicated by Dr. TerBrugge based on the submitted imaging studies. All imaging studies will be abstracted under the supervision of the consultant neuroradiologist, Dr. TerBrugge. The imaging source and date of CT, MRI, MR angiography, and any diagnostic cerebral angiography furnish primary descriptors including side, nidus size, anatomic location, "eloquence," feeding arteries, arterial aneurysms, number of lesions, and venous drainage pattern. Additional factors include location, the presence of intra- and extranidal aneurysms, and the presence of venous stenoses, as described in the Writing Group paper. New AVM hemorrhage is bleeding into the brain or its surrounding spaces likely to be associated with AVM (age and location of hemorrhage are also estimated). The time from diagnosis to any new hemorrhage will be used in the survival analyses. We will also record other potential sources of co-morbidity, including hypertension, diabetes mellitus, smoking history, hyperlipidemia, i.e., factors that may non-specifically increase the risk of hemorrhage. Although functional status is not part of the primary aims, we will record Modified Rankin Score (mRS)(66-68) (adapted from the ISAT trial patient questions(69)) coded as : 0 = no symptoms and cope well with life; 1 = few symptoms which do not interfere with everyday life; 2 = symptoms which have changed my life but I am still able to look after myself; 3 = symptoms which significantly changed my life, and I need some help looking after myself; 4 = quite severe symptoms, I need help from other people; 5 = major symptoms which severely handicap me and I need constant attention day and night; deaths are coded as 6.

The mRS will be recorded at least for patient status at the time of BAVM discovery and the last available date. For retrospective cases, these will be estimated using available clinical records; for prospective cases, the last available status during the project period will be assessed. New ICH during follow-up will also be recorded. Working with the DMCC, we will institute a web-based system to facilitate data entry. The main follow-up will be targeted to be completed during the fifth year of the RDCRC project and will include: (a) date and nature of any treatment; (b) any new hemorrhagic events; and (c) modified Rankin score.

4.5.2 Sample Collection, Processing and Banking Each site will arrange to obtain a blood sample from BAVM cases, but we will accommodate banking of samples from HHT patients without BAVM for exploratory analyses. Blood samples will be collected and sent directly to the Coriell/NINDS Human Genetics DNA and Cell Line Repository using their published instructions (http://ccr.coriell.org). Coriell with retain DNA and also release a DNA sample to the study investigators UCSF, where it will be stored as well. The advantages of using Coriell/NINDS are (1) 20 μg of genomic DNA will be made available to the researchers at no additional charge, and (2) lymphocytes will be immortalized, ensuring a durable renewable supply of DNA for future studies. The PI has worked with NINDS/Coriell before; we have sent approximately 100 sporadic brain AVM cases to the NINDS DNA bank.

For cases unable to have blood drawn, we will use commercially available saliva mailing kits (Oragene). The kit is sent by the Study Coordinator with instructions for use, consent form, and a return mailing box with pre-printed postage and shipping label. The specimen will be labeled with a study ID number, and sent directly to UCSF for processing and DNA extraction. We have used these with excellent DNA yields and genotyping results. Such samples would be handled directly by the UCSF Genetics and Statistical Analysis Core (GSAC). The Specimen study ID number will be assigned separately from the Database study ID number. Samples will be retained until all DNA has been used up. If there is sample remaining when the study is complete, the study investigators may use the sample for future research studies into genetic factors of and brain AVMs or other aspects of HHT.

Study Design

• Study Type: Observational
• Estimated Enrollment: 1800 participants
• Observational Model: Case-Control
• Time Perspective: Other
• Official Title: Cerebral Hemorrhage Risk in Hereditary Hemorrhagic Telangiectasia (RDCRN# 6203, Protocol Version Date 07Jan10)
• Actual Study Start Date: April 8, 2010
• Estimated Primary Completion Date: September 2024
• Estimated Study Completion Date: September 2024

Groups and Cohorts

Group/Cohort
HHT- Brain Arteriovenous Malformation; Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis of HHT and; Presence of Brain Arteriovenous Malformation
HHT -NO BAVM; 1. Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis of HHT

Outcome Measures

Primary Outcome Measures :

1. Aim 1: The identification of predictors of brain outcomes in HHT patients [ Time Frame: Through study completion, an average of 5 years ]
   This study will investigate predictors of brain outcomes in HHT patients. The investigators hypothesize that the presence of brain arteriovenous malformation (BAVM) in HHT patients versus HHT patients without BAVM and multiplicity of BAVMs will be associated with worsening functional outcome. Therefore, the comprehensive brain outcomes in HHT for future HHT clinical trials will be characterized.

Secondary Outcome Measures :

1. Aim 2: A severe bleeding phenotype in HHT will be defined for clinical trial readiness [ Time Frame: Through study completion, an average of 5 years ]
   The investigators hypothesize that weekly nasal bleeding duration in HHT will predict the need for invasive or life-sustaining therapies. HHT participant reported bleeding duration will be measured longitudinally and correlate with the need for invasive or life-sustaining therapies, as well as with ICH risk from BAVMs and with bleeding in other HHT organ phenotypes.
2. Aim 3: The genetic predictors and circulating biomarkers of severe bleeding and brain outcomes in HHT will be characterized [ Time Frame: Through study completion, an average of 5 years ]
   The investigators hypothesize that there are shared predictors of severe bleeding from the nose and brain in HHT patients, and that identifying these predictors will allow for selection of "at-risk" patients for clinical trials. Specifically, potential genetic, plasma protein biomarker and circulating miRNA biomarker predictors of bleeding will be evaluated. Markers associated with bleeding will then be tested for association with ICH, and with other brain outcomes and HHT severity phenotypes.

Biospecimen Retention:   Samples With DNA

blood and/or saliva

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

HHT individuals with a history of brain arteriovenous malformation. HHT individuals without a history of brain arteriovenous malformation.

Criteria

Inclusion criteria:

• Definite clinical HHT diagnosis (at least 3 Curacao criteria)or genetic diagnosis of HHT or
• Definite clinical HHT diagnosis (at least 3 Curacao criteria) or genetic diagnosis of HHT and Presence of Brain Arteriovenous Malformation
• Able to provide informed consent

Curacao criteria:

1. spontaneous recurrent nosebleeds;
2. mucocutaneous telangiectasia at characteristic sites (lips, oral cavity or the nose);
3. visceral involvement such as pulmonary, hepatic or CNS BAVM; and (d) an affected first degree relative by same criteria.

Willingness

• Willingness to participate in the study and ability to give informed consent

Exclusion Criteria:

• Patients not complying with Inclusion criteria

Contacts and Locations

Contacts

Contact: Marie Faughnan, MD; 416-864-6060 ext 5412; marie.faughnan@unityhealth.to

Contact: Dewi Clark, MHSc; 416-864-6060 ext 42887; dewi.clark@unityhealth.to

Locations

United States, Arizona

Barrow Neurological Institute; Recruiting

Phoenix, Arizona, United States, 85013

Contact: Michael Lawton, MD michael.lawton@barrowbrainandspine.com

Contact: Daniel Belton Daniel.Belton@DignityHealth.org

United States, Arkansas

University of Arkansas for Medical Sciences; Recruiting

Little Rock, Arkansas, United States, 72205

Contact: Mary Meek, MD AthertonMaryE@uams.edu

Contact: Lindsey Wyerick LEWyerick@uams.edu

United States, California

David Geffen School of Medicine at University of California, Los Angeles; Recruiting

Los Angeles, California, United States, 90095

Contact: Victoria Rueda, MPH 310-794-0376 vrueda@mednet.ucla.edu

Principal Investigator: Justin McWilliams, MD

University of California, San Francisco; Recruiting

San Francisco, California, United States, 94110

Contact: Avery Lui avery.lui@ucsf.edu

Contact: Yuanbo Holley Yuanbo.holley@ucsf.edu

Principal Investigator: Steven Hetts, MD

United States, Colorado

UCHealth Pulmonary Vascular Disease Clinic - Anschutz Medical; Recruiting

Aurora, Colorado, United States, 80045

Contact: Peter Hountras, MD PETER.HOUNTRAS@CUANSCHUTZ.EDU

Contact: Cheryl Abbott CHERYL.ABBOTT@CUANSCHUTZ.EDU

United States, Connecticut

Yale University; Active, not recruiting

New Haven, Connecticut, United States, 06520-8042

United States, Georgia

Georgia Regents University; Recruiting

Augusta, Georgia, United States, 30912-3135

Contact: Melissa James, RN 706-721-8391 mejames@gru.edu

Principal Investigator: James R Gossage, MD

United States, Maryland

Johns Hopkins University School of Medicine; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Gina Robinson 410-502-3628 grobin11@jhmi.edu

Principal Investigator: Doris Lin, MD, PhD

HHT Foundation International, Inc.; Recruiting

Monkton, Maryland, United States, 21111

Contact: Marianne S Clancy, RHD, MPA 410-357-9932 research@curehht.org

Contact: Nicole Schaefer 410-357-9932 research@curehht.org

United States, Minnesota

Mayo Clinic; Recruiting

Rochester, Minnesota, United States, 55905

Contact: Sue Ann Donlinger 507-284-9259 donlinger.sueann@mayo.edu

Principal Investigator: Vivek Iyer, MD

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Sharon Heuerman, RN 314-747-8174 sheuerman@dom.wustl.edu

Principal Investigator: Murali Chakinala, Dr.

United States, North Carolina

University of North Carolina at Chapel Hill; Recruiting

Chapel Hill, North Carolina, United States, 27599

Contact: Karen Smith 919-966-0817 karens@med.unc.edu

Principal Investigator: Raj Kasthuri, MD

United States, Ohio

Cincinnati Children's Hospital Medical Center; Recruiting

Cincinnati, Ohio, United States, 45229

Contact: Adrienne Hammill, MD Adrienne.Hammill@cchmc.org

Contact: NIcholas Jakubowski Nicholas.Jakubowski@cchmc.org

United States, Pennsylvania

University of Pennsylvania School of Medicine; Withdrawn

Philadelphia, Pennsylvania, United States, 19104

United States, Utah

University of Utah; Recruiting

Salt Lake City, Utah, United States, 84132

Contact: Renee Neuharth 801-587-4877 renee.neuharth@hsc.utah.edu

Principal Investigator: Jamie McDonald, M.S

Sub-Investigator: Kevin Whitehead, MD

Canada, Alberta

University of Alberta; Active, not recruiting

Edmonton, Alberta, Canada, T6G 2B7

Canada, British Columbia

St. Paul's Hospital, University of British Columbia; Active, not recruiting

Vancouver, British Columbia, Canada, V6Z 1Y6

Canada, Ontario

St. Michael's Hospital; Recruiting

Toronto, Ontario, Canada, M5B 1W8

Contact: Marie E Faughnan, MD MSc FRCPC 416 864 6060 ext 5412 marie.faughnan@unityhealth.to

Contact: Dewi Clark 416-864-6060 ext 42887 dewi.clark@unityhealth.to

Principal Investigator: Marie Faughnan, MD MSc FRCPC

Hospital for Sick Children; Recruiting

Toronto, Ontario, Canada, M5G 1X8

Contact: Stephanie J Manning (416) 813 - 4903 stephanie.jeanneretmanning@sickkids.ca

Contact (416) 813 6167

Principal Investigator: Felix Ratjen, MD PhD FRCPC

Netherlands

St. Antonius Hospital; Recruiting

Nieuwegein, Netherlands, 3435

Contact: Marleen Peterse-vanSchip 030 - 609 34 59 m.peterse@antoniusziekenhuis.nl

Principal Investigator: Hans-Jurgen Mager, MD, PhD

Sponsors and Collaborators

Unity Health Toronto

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Marie Faughnan, MD MSc FRCPC; Unity Health Toronto

More Information

Additional Information:

This is the Rare Diseases Clinical Research Networkweb site which lists the BVMC 6203 HHT study 

• Responsible Party: Unity Health Toronto
• ClinicalTrials.gov Identifier: NCT01158807
• Other Study ID Numbers: RDCRN# 6203; 1U54NS065705 ( U.S. NIH Grant/Contract )
• First Posted: July 8, 2010
• Last Update Posted: December 12, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Unity Health Toronto:

Hereditary Hemorrhagic Telangiectasia; Cerebral arteriovenous malformations

Additional relevant MeSH terms:

Cerebral Hemorrhage; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Hemorrhage; Pathologic Processes; Vascular Diseases; Cardiovascular Diseases; Hemostatic Disorders; Hemorrhagic Disorders; Hematologic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases