CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness

Brain Cavernous Angiomas with Symptomatic Hemorrhage (CASH) are rare, but they exact a heavy burden of neurologic disability from recurrent bleeding, for which there is no proven therapy. This trial readiness project aims to address current critical obstacles in identifying cases at multiple sites, characterizing their relevant features, and measuring their outcome. The timing cannot be more opportune, with therapeutic targets already identified, exceptional collaboration among researchers and with the patient community, and several drugs ready to benefit from a track to clinical testing in the next five years.

Study Overview

• Status: Completed
• Conditions: Cerebral Cavernous Malformation; Cavernous Angioma; Cavernoma; CCM; Cerebral Cavernous Malformations 1; Cerebral Cavernous Malformations 2; Cerebral Cavernous Malformations 3

Detailed Description

The Trial Readiness grant mechanism, funded by NINDS, proposes to address knowledge gaps and establish a research network as infrastructure for future research. This project includes an observational cohort study of 181 patients with an operational goal of demonstrating the feasibility of screening, enrollment rates, baseline disease categorization and follow-up of CASH using common data elements at multiple sites, and to assess the following endpoints for 123 participants enrolled at centers prespecified to do prospective follow-up: (1) the rates of recurrent hemorrhage; (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures which have been shown to correlate with lesion activity, and (3) change in functional status during prospective follow-up.

• Study Type: Observational
• Enrollment (Actual): 181

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with Brain Cavernous Angiomas with Symptomatic Hemmhorage (CASH) that have occurred within the last year.

Description

Inclusion Criteria

1. 18 years of age and older
2. Diagnosed with a brain CA (single or multiple)
3. Had a SH within the past year (with demonstrated new lesional bleeding or hemorrhagic growth on diagnostic studies AND attributable new symptoms)
4. Subject is able to provide informed consent

Exclusion Criteria

1. Spinal CA as source of SH
2. Prior brain irradiation
3. Cases where verification of SH with clinical and imaging review cannot be accomplished
4. Prior or planned treatment of the symptomatic lesion (after neurosurgical consultation)

To be eligible for Aims 2 and 3, CASH cases enrolled in Aim 1 will be further excluded from follow-up and baseline validation (FUBV) for the following reasons:

1. Contraindication for administration of contrast agent or otherwise unwilling or unable to undergo research MRI studies
2. Pregnant or breastfeeding women
3. Homeless or incarcerated persons, or other reason a subject will be unable/unlikely to return for follow-up visits

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
CASH (Cavernous Angiomas with Symptomatic Hemorrhage); The adjudicated definition of CASH (Cavernous Angiomas with Symptomatic Hemorrhage) requires diagnostic evidence of new lesional bleeding or hemorrhagic growth, in association with directly attributable symptoms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of recurrent symptomatic hemorrhage during the two year follow-up period in patients with CASH.	Number of new bleeds reported during the two year follow-up period in the cohort with CASH. We will assess the change in the number of bleeds from baseline to year 1, baseline to year 2, and year 1 to year 2 year follow-up.	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Quantitative susceptibility mapping (QSM) change during the 2 year follow-up period.	Change in QSM value will be assessed from baseline to year 1 and year 1 to year 2 follow-up MRIs.	2 years of follow-up
Mean dynamic contrast-enhanced quantitative perfusion (DCEQP) change during the 2 year follow-up period.	Change in DCEQP value from the MRIs will be assessed from baseline to year 1 and year 1 to year 2 of follow-up	2 years of follow-up
Change in the the proportion of patients with mRS score 0 to 1 during the 2 year follow-up period.	Change in the proportion of patients with mRS score 0 to will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. The mRS is a simple global measure of functional disability. Scores range from 0 (no symptoms) to 6 (death). An mRS score of 0 to 1 is considered a minimal clinical disability, and 0 to 2 is independent.	2 years of follow-up
Change in the median National Institutes of Health Stroke Scale (NIHSS) during the 2 year follow-up period.	Change in median NIHSS value will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. NIHSS values range from 0 to 42, with stroke severity categorized as mild (0 to 4), moderate (5 to 14), severe (15 to 24), and very severe (≥25). 4-point decline in ischemic stroke clinical trials typically measures functional decline.	2 years of follow-up
Change in the median score of European Quality of Life Visual Analogue Scale (EQ-VAS) during the 2 year follow-up period.	Change in the median score of EQ-VAS will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. The EQ-VAS is a vertical visual analogue scale that takes values between 100 (best imaginable health) and 0 (worst imaginable health), on which patients provide a global assessment of their health.	2 years of follow-up
Change in proportion of patients with no problems, mild, or severe problems in the "Mobility" domain of European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3 L) during the 2 year follow-up period.	Change in proportion of patients with no problems, mild, or severe problems in the "Mobility" domain of EQ-5D-3 L will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. EQ-5D-3 L is a generic tool for Patient Reported Outcomes (PRO) measurement that can assess patients' quality of life, irrespective of the disease and includes 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. There are 3 questions per domain where patients respond if they have no problems, mild, or severe problems.	2 years of follow-up
Change in proportion of patients with no problems, mild, or severe problems in the "Self-care" domain of European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3 L) during the 2 year follow-up period.	Change in proportion of patients with no problems, mild, or severe problems in the "Self-care" domain of EQ-5D-3 L will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. EQ-5D-3 L is a generic tool for Patient Reported Outcomes (PRO) measurement that can assess patients' quality of life, irrespective of the disease and includes 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. There are 3 questions per domain where patients respond if they have no problems, mild, or severe problems.	2 years of follow-up
Change in proportion of patients with no problems, mild, or severe problems in the "Usual activities" domain of European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3 L) during the 2 year follow-up period.	Change in proportion of patients with no problems, mild, or severe problems in the "Usual activities" domain of EQ-5D-3 L will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. EQ-5D-3 L is a generic tool for Patient Reported Outcomes (PRO) measurement that can assess patients' quality of life, irrespective of the disease and includes 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. There are 3 questions per domain where patients respond if they have no problems, mild, or severe problems.	2 years of follow-up
Change in proportion of patients with no problems, mild, or severe problems in the "Pain / Discomfort" domain of European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3 L) during the 2 year follow-up period.	Change in proportion of patients with no problems, mild, or severe problems in the "Pain / Discomfort" domain of EQ-5D-3 L will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. EQ-5D-3 L is a generic tool for Patient Reported Outcomes (PRO) measurement that can assess patients' quality of life, irrespective of the disease and includes 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. There are 3 questions per domain where patients respond if they have no problems, mild, or severe problems.	2 years of follow-up
Change in proportion of patients with no problems, mild, or severe problems in the "Anxiety / Depression" domain of European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3 L) during the 2 year follow-up period.	Change in proportion of patients with no problems, mild, or severe problems in the "Anxiety / Depression" domain of EQ-5D-3 L will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. EQ-5D-3 L is a generic tool for Patient Reported Outcomes (PRO) measurement that can assess patients' quality of life, irrespective of the disease and includes 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. There are 3 questions per domain where patients respond if they have no problems, mild, or severe problems.	2 years of follow-up
Change in the median T-score for "Anxiety" domain of Patient-Reported Outcome Measurement Information System (PROMIS-29) during the 2 year follow-up period.	Change in the median T-score for "Anxiety" domain of PROMIS-29 will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. PROMIS-29 (Version 2.0) is a generic health-related quality of life measure including 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities).12 Each domain contains questions ranked using a 5-point Likert scale. PROMIS-29 domain scores are converted to T scores and have been standardized to a reference population (mean, 50; SD, 10). Clinically meaningful change is considered to be at least half the SD (5 points).	2 years of follow-up
Change in the median T-score for "Depression" domain of Patient-Reported Outcome Measurement Information System (PROMIS-29) during the 2 year follow-up period.	Change in the median T-score for "Depression" domain of PROMIS-29 will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. PROMIS-29 (Version 2.0) is a generic health-related quality of life measure including 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities).12 Each domain contains questions ranked using a 5-point Likert scale. PROMIS-29 domain scores are converted to T scores and have been standardized to a reference population (mean, 50; SD, 10). Clinically meaningful change is considered to be at least half the SD (5 points).	2 years of follow-up
Change in the median T-score for "Fatigue" domain of Patient-Reported Outcome Measurement Information System (PROMIS-29) during the 2 year follow-up period.	Change in the median T-score for "Fatigue" domain of PROMIS-29 will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. PROMIS-29 (Version 2.0) is a generic health-related quality of life measure including 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities).12 Each domain contains questions ranked using a 5-point Likert scale. PROMIS-29 domain scores are converted to T scores and have been standardized to a reference population (mean, 50; SD, 10). Clinically meaningful change is considered to be at least half the SD (5 points).	2 years of follow-up
Change in the median T-score for "Pain" domain of Patient-Reported Outcome Measurement Information System (PROMIS-29) during the 2 year follow-up period.	Change in the median T-score for "Pain" domain of PROMIS-29 will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. PROMIS-29 (Version 2.0) is a generic health-related quality of life measure including 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities).12 Each domain contains questions ranked using a 5-point Likert scale. PROMIS-29 domain scores are converted to T scores and have been standardized to a reference population (mean, 50; SD, 10). Clinically meaningful change is considered to be at least half the SD (5 points).	2 years of follow-up
Change in the median T-score for "Sleep Disturbance" domain of Patient-Reported Outcome Measurement Information System (PROMIS-29) during the 2 year follow-up period.	Change in the median T-score for "Sleep Disturbance" domain of PROMIS-29 will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. PROMIS-29 (Version 2.0) is a generic health-related quality of life measure including 7 domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities).12 Each domain contains questions ranked using a 5-point Likert scale. PROMIS-29 domain scores are converted to T scores and have been standardized to a reference population (mean, 50; SD, 10). Clinically meaningful change is considered to be at least half the SD (5 points).	2 years of follow-up
Change in the median T-score for "Social" domain of Patient-Reported Outcome Measurement Information System (PROMIS-29) during the 2 year follow-up period.	Change in the median T-score for "Social" domain of PROMIS-29 will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. PROMIS-29 (Version 2.0) is a generic health-related quality of life measure including 7 domains (anxiety, depression, fatigue, pain interference, sleep disturbance, and ability to participate in social roles and activities, and physical function).12 Each domain contains questions ranked using a 5-point Likert scale. PROMIS-29 domain scores are converted to T scores and have been standardized to a reference population (mean, 50; SD, 10). Clinically meaningful change is considered to be at least half the SD (5 points).	2 years of follow-up
Change in the median T-score for "Physical Function" domain of Patient-Reported Outcome Measurement Information System (PROMIS-29) during the 2 year follow-up period.	Change in the median T-score for "Physical Function" domain of PROMIS-29 will be assessed from baseline to year 1 and year 1 to year 2 follow-up periods. PROMIS-29 (Version 2.0) is a generic health-related quality of life measure including 7 domains (anxiety, depression, fatigue, pain interference, sleep disturbance, and ability to participate in social roles and activities, and physical function).12 Each domain contains questions ranked using a 5-point Likert scale. PROMIS-29 domain scores are converted to T scores and have been standardized to a reference population (mean, 50; SD, 10). Clinically meaningful change is considered to be at least half the SD (5 points).	2 years of follow-up

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: Johns Hopkins University; Mayo Clinic; National Institute of Neurological Disorders and Stroke (NINDS); University of California, San Francisco; University of Utah; University of New Mexico; Barrow Neurological Institute
• Investigators: Principal Investigator: Issam A Awad, MD, University of Chicago; Principal Investigator: Daniel Hanley, MD, Johns Hopkins University; Principal Investigator: Kelly Flemming, MD, Mayo Clinic; Principal Investigator: Helen Kim, MPH, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2018
• Primary Completion (Actual): November 3, 2022
• Study Completion (Actual): November 3, 2022

Study Registration Dates

• First Submitted: July 18, 2018
• First Submitted That Met QC Criteria: August 27, 2018
• First Posted (Actual): August 29, 2018

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Cerebral Cavernous Malformation; Quantitative Susceptibility Mapping (QSM); CCM (Cerebral Cavernous Malformations); Dynamic Contrast Enhanced Quantitative Perfusion (DCEQP); Cavernoma; Cavernous Angioma
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Cardiovascular Abnormalities; Neoplasms, Vascular Tissue; Nervous System Malformations; Vascular Malformations; Central Nervous System Vascular Malformations; Cavernous Sinus Syndromes; Hemorrhage; Congenital Abnormalities; Hemangioma; Hemangioma, Cavernous, Central Nervous System; Hemangioma, Cavernous
• Other Study ID Numbers: U01NS104157 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study Protocol has been published in Neurosurgery
• IPD Sharing Time Frame: Protocol paper was published November 2018 in Neurosurgery
• IPD Sharing Access Criteria: can be accessed through Neurosurgery or Pubmed. Primary study contacts can also provide a copy upon request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No