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Familial Cerebral Cavernous Malformation

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.

Issam A Awad, MD

Daniel Hanley, MD

Kelly Flemming, MD

Helen Kim, MPH, PhD

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.

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.

CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness

Study Protocol has been published in Neurosurgery

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.

Change in QSM value will be assessed from baseline to year 1 and year 1 to year 2 follow-up MRIs.

Change in DCEQP value from the MRIs will be assessed from baseline to year 1 and year 1 to year 2 of follow-up

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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).

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).

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).

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).

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).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness	NCT03652181	CCM Cavernoma Cerebral Cavern... Cerebral Cavern... Cerebral Cavern... Cerebral Cavern... Cavernous Angio...		18 Years -	University of Chicago
CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness	NCT03652181	CCM Cavernoma Cerebral Cavern... Cerebral Cavern... Cerebral Cavern... Cerebral Cavern... Cavernous Angio...		18 Years -	University of Chicago

Spots Global Cancer Trial Database for cerebral cavernous malformations 3