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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).

Mayo Clinic

Johns Hopkins University

University of California, San Francisco

National Institute of Neurological Disorders and Stroke (NINDS)

University of Utah

University of New Mexico

Barrow Neurological Institute

University of Chicago

Epilepsy

Seizures

Neurologic Manifestations

Disease Attributes

Patients with cerebral cavernous malformation and associated with epilepsy will undergo MR imaging and be followed-up annually as our protocol defined.

Patients with cerebral cavernous malformation but without epilepsy will undergo MR imaging and be followed-up annually as our protocol defined.

Li Ma, MD, PhD

Yuanli Zhao, MD

Chunxue Wu, MD

Zongze Li, MD

Cerebral cavernous malformation (CCM)-related epilepsy (CRE) impairs the quality of life in patients with CCM. Patients could not always achieve seizure freedom after surgical resection of the lesion, suggesting an inadequate treatment and evaluation of the epileptogenic zone or network. Iron deposition in cerebral cavernous malformations has been postulated to play an important role in triggering CRE. Quantitative susceptibility mapping (QSM), as an optimal in vivo imaging technique to quantify iron deposition, is employed to analyze the iron quantity in CCM patients with epilepsy and further combined with brain structural and connectome analysis, to describe the difference between CCMs with and without epilepsy. In vivo biomarkers predicting CRE risk in CCM natural history and CRE control outcome after CCM surgical resection will be further identified to improve management strategy.

The CRESS study is a prospective observational study of imaging biomarker for cerebral cavernous malformation (CCM) related epilepsy (CRE) risk in natural history or after surgical resection. This project, funded by the National Nature Science Foundation of China, will be performed in two sites: Bejing Tiantan Hospital, Capital Medical University and Peking University International Hospital, which cover the south and north part of Beijing. Bejing Tiantan Hospital is also the China National Clinical Research Center for Neurological Diseases and the largest neurological center with high volume of patients all over the nation.

Study overview: Each participants will be followed for 5 year since enrollment. Epilepsy will be tracked with serial video EEG recordings and clinical investigations performed annually. Besides medical history of the patients, data from seizure diary and MR imaging studies (including quantitative susceptibility mapping, diffusion tensor imaging and three dimension-T1 weighted imaging), will be collected. Blood samples and tissue samples of surgical resected lesion for biomarkers studies will also be collected in all participants of the project. The data obtained in participants of CCM with or without epilepsy will be compared.

Sample size: Investigators plan to enroll 200 CCM patients in 24 months and follow up for 5 years. Based upon the preliminary results and extensive literature review, investigators predict that about 50% of participants will undergo surgical treatment, while 25% of participants remain suffering from seizure after treatment.

Study endpoints: The primary clinical endpoint of this study is a collection of a set of clinical, molecular, and MRI data in all participants.

Surgical resected lesion and 20 ml blood sample before surgery

Quantitative Susceptibility Biomarker and Brain Structural Property for Cerebral Cavernous Malformation Related Epilepsy

Quantitative Susceptibility Mapping Biomarker, Brain Structure and Connectome Associated With Cerebral Cavernous Malformation Related Epilepsy and Outcome After Surgery

Study Protocol to be published in peer-reviewed journal

Each patient contributes five outcome measurements (at annual image of 5-year follow-up). Perilesional QSM measurements will be performed at baseline and at annual epoch of image. Perilesional mean QSM (in parts per million, ppm) in each study group will be evaluated using univariate comparison and a repeated measures analysis implemented as an unadjusted linear mixed model.

Each patient contributes three outcome measurements (at year 1 and 2 and 3 after surgery). Perilesional QSM measurements will be performed at annual imaging follow-up after surgery. Mean QSM (in parts per million, ppm) in patients with or without postoperative seizure will be evaluated using univariate comparison and a repeated measures analysis implemented as an unadjusted linear mixed model.

Seizure freedom, defined as Engel Classification of Post-treatment Outcome Class I, will be assessed annually during follow-up period. For patients with medical treatment or conservative observation, the follow-up period begins since enrollment. For patients with surgical resection, the follow-up period begins after surgery.

The presurgical grey matter volume will be calculated from three dimension T1 weighted imaging. Data of CCM with or without epilepsy will be compared and to detect the correlation between grey matter volume and seizure severity (Liverpool Seizure Severity Scale) and frequency.

Whole-brain connectome will be reconstructed from whole-brain diffusion tensor imaging before surgical treatment. Data of CCM with or without epilepsy will be compared.

Study title	NCT ID	Conditions	Eligibility	Organization
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
Quantitative Susceptibility Biomarker and Brain Structural Property for Cerebral Cavernous Malformation Related Epilepsy	NCT04076449	Cavernous Malfo... Cavernous Angio... Cavernous Heman... Cavernous Heman... Seizures Seizures, Epile... Epilepsy	18 Years - 70 Years	Beijing Tiantan Hospital
Quantitative Susceptibility Biomarker and Brain Structural Property for Cerebral Cavernous Malformation Related Epilepsy	NCT04076449	Cavernous Malfo... Cavernous Angio... Cavernous Heman... Cavernous Heman... Seizures Seizures, Epile... Epilepsy	18 Years - 70 Years	Beijing Tiantan Hospital

Spots Global Cancer Trial Database for quantitative susceptibility mapping (qsm)