Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT05148663 |
| Other study ID # |
E21010 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2021 |
| Est. completion date |
August 29, 2023 |
Study information
| Verified date |
August 2023 |
| Source |
Texas Tech University Health Sciences Center, El Paso |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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.
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.
