CCM Blood Biomarker Validation Study

CCMs Among Hispanic Population Study Group (CHIPS)

Cerebral cavernous malformations (CCMs), one of the most common microvascular malformations in the capillary beds of the brain, are susceptible to hemorrhagic stroke. As an autosomal dominant disorder with incomplete penetrance, the majority of CCM gene mutation carriers are largely asymptomatic but when symptoms occur, the disease has typically reached the stage of focal hemorrhage with irreversible brain damage. Currently, the invasive neurosurgery removal of CCM lesions is the only treatment option, despite the recurrence of the symptoms after surgery. Therefore, there is a grave need for prognostic/monitoring biomarkers as risk predictors for stroke prevention. The objective of the proposal is to develop a set of blood prognostic/monitoring biomarkers as precise risk indicators for stroke prevention. In this project, the plan is to validate the novel serum biomarkers identified in Ccms animal models and human CCMs patients, and utilize these biomarkers with statistical algorithms for risk prediction of hemorrhagic CCMs. This proposal has been formulated based on recent findings of five serum etiological biomarkers associated with disruption of the Blood-Brain Barrier (BBB), the first step for hemorrhagic CCMs in Ccm mice models. This work will lay the groundwork for larger human trials for final validation and revolutionary potential clinical applications.

Study Overview

• Status: Terminated
• Conditions: Cerebral Cavernous Malformation; Hemorrhagic Stroke, Intracerebral
• Intervention / Treatment: Diagnostic test: CCM Hemorrhagic Panel

Detailed Description

Cerebral cavernous malformations (CCMs), one of the most common vascular malformations, are characterized by abnormally dilated intracranial capillaries resulting in increased susceptibility to hemorrhagic stroke. As an autosomal dominant disorder with incomplete penetrance, the majority of CCMs gene mutation carriers are largely asymptomatic but when symptoms occur, the disease has typically reached the stage of focal hemorrhage with irreversible brain damage. Currently, the invasive neurosurgery removal of CCM lesions is the only treatment option, despite the recurrence of symptoms after surgery. Therefore, there is a grave need for prognostic/monitoring biomarkers as risk predictors for stroke prevention. The goal is to develop a set of blood prognostic biomarkers as risk predictors for stroke prevention. The objective of this project is to validate novel serum biomarkers identified in Ccm animal models in human blood that could predict the risk of hemorrhagic events. The central hypothesis is that quantitative detection of certain serum biomarkers can be utilized to predict the timing of hemorrhagic events. The hypothesis has been formulated based on the recent findings of five serum etiological biomarkers associated with disruption of the Blood-Brain Barrier (BBB), which could lead to hemorrhagic events. Taking advantage of the research team's expertise in Ccm pathology and serum biomarkers, the central hypothesis will be tested to achieve the study goal by pursuing the following three revolutionary aims in two phases, starting from the phase 1 with the first two biomarker discovery aims (1, 2):

1. Validate blood prognostic/monitoring biomarkers with the optimized detection platform for hemorrhagic stroke prevention. The working hypothesis is that expression levels of certain blood molecules are correlated with the progression of a disrupted BBB. In this aim, serum biomarkers identified in Ccms mice will be validated in the blood samples of CCM patients to evaluate their feasibility and reliability. The correlation functions between the serum/plasma levels of biomarkers and the progression of a disrupted BBB identified in Ccms mice will be tested using the "gold standard", enzyme-linked immunosorbent assay (ELISA) platform in CCM patients for 1a). Clinical preparation for large cohort CCM analysis; 1b). Validating serum progesterone (PRG) as a biomarker, and 1c). Validating 4 etiological serum peptide biomarkers with the optimized ELISA platform in CCM patients.
2. To optimize the sensitivity, specificity, dynamic range, and reliability of biomarkers using the cutting-edge multiplex platform to predict risks of hemorrhagic stroke. The working hypothesis is that the measurement parameters of blood biomarkers, such as sensitivity, specificity, dynamic working range, and inter/intra variability, can be drastically improved with a larger sample size, improved clinical definitions, and better detection platforms. High-performance ELISAs will be continuously utilized for validating etiological biomarkers. To ensure the highest sensitivity and specificity, a robust automatic multiplex platform for the repetitive analysis of large cohorts is essential to validate biomarkers for hemorrhagic strokes. Linear or logistic regression analysis will be performed to delineate the correlation between validated biomarkers and those of clinical criteria. In this aim, the will 2a). Improve sensitivity and specificity of candidate blood biomarkers through correlation equations were optimized with increased CCM blood sample sizes and updated clinical information; 2b). Define new biomarkers using high-throughput omic approaches, and 2c). Improve sensitivity and increase dynamic working range of blood biomarkers with a multiplex bead array assay (MBAA) platform and optimized protocols.

Phase-2 Aim: 3) Improve clinical utility of validated prognostic/monitoring biomarkers with optimized algorithms in larger cohorts in preparation for human clinical trials. The working hypothesis is that clinical sensitivity and specificity of blood biomarkers can be further improved through a blindly test-retest approach in larger independent human cohorts. This aim will provide sufficient proof that the clinical utility of blood biomarkers can be improved and utilized to predict the risk of hemorrhagic stroke, laying the groundwork for future clinical trials and possible future revolutionary clinical applications. The research team will continue to 3a). Improve clinical utility by optimizing the precision of prognostic/monitoring algorithms of validated biomarker(s)/panel(s) using larger cohorts; 3b). Further improve clinical utility by confirming reliability of validated biomarker(s)/panel(s) in a larger cohort; and 3c). Confirm validated prognostic/monitoring biomarker(s)/panel(s) are ready for future clinical trials.

• Study Type: Observational
• Enrollment (Actual): 12

Contacts and Locations

Study Locations

• United States
  • Texas
    • El Paso, Texas, United States, 79902
      • TTUHSC El Paso

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 78 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Mexican Hispanic population

Description

Inclusion Criteria:

1. 10 to 78 years of age.
2. Medical history meets the criteria for the International Classification of Diseases diagnosis codes 10 (ICD-10) for cerebral cavernous malformations (CCMs) (Q28.3) or stroke/epilepsy.
3. Has a family member whose medical history meets the criteria for the International Classification of Diseases diagnosis codes for cerebral cavernous malformations (CCMs) (Q28.3) or stroke/epilepsy.
4. Has a relatively complete medical history that can be accurately confirmed by an interview or electronic and/or paper medical records.
5. Hispanic and non-Hispanic Americans.

Exclusion Criteria:

N/A

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
blood drawing and hemorrhagic events in CCM patients; planned for three blood drawing before surgery	Diagnostic test: CCM Hemorrhagic Panel; Biomarker
blood drawing for age/gender/ethnicity matched controls; Blood draw from Control patients with no inflammation	Diagnostic test: CCM Hemorrhagic Panel; Biomarker

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification and validation of at least (>1) biomarker(s) with a significant p-value (p≤ 0.001) to correlate with the progression of hemorrhagic events in CCM patients using our optimized ELISAs.	Confirmation of at least (>1) biomarker(s) is essential for the feasibility assessment of this project after three years investigation and validation in the mid-sized cohorts (~300 each cases/controls). Thus, to assess the consistency of the measurement between different CCM cohorts at the end of the 1st phase, the blinded test-retest reliability (r2) will be calculated with a relatively strong outcome range (~0.65-0.70, p=0.005) on at least (>1) positively/negatively correlated biomarker(s).	the first two years

Collaborators and Investigators

• Sponsor: Texas Tech University Health Sciences Center, El Paso
• Investigators: Principal Investigator: Jun Zhang, TTUHSC

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2021
• Primary Completion (Actual): August 29, 2023
• Study Completion (Actual): August 29, 2023

Study Registration Dates

• First Submitted: July 27, 2021
• First Submitted That Met QC Criteria: December 2, 2021
• First Posted (Actual): December 8, 2021

Study Record Updates

• Last Update Posted (Actual): September 1, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Stroke; Cardiovascular Abnormalities; Hemangioma; Neoplasms, Vascular Tissue; Nervous System Malformations; Vascular Malformations; Central Nervous System Vascular Malformations; Hemangioma, Cavernous; Hemorrhagic Stroke; Hemangioma, Cavernous, Central Nervous System
• Other Study ID Numbers: E21010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No