PROMISE-BD-100: PRecisiOn Medicine In StrokE: Evolution of Plasma Brain-Derived Tau in Acute Stroke

Sponsor

Ludwig-Maximilians - University of Munich (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT06121336

Collaborator

(none)

100

Enrollment

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The investigators recently identified Brain-derived tau (BD-tau) as a sensitive blood-based biomarker for brain injury in acute ischemic stroke: in patients with acute ischemic stroke, plasma BD-tau was associated with imaging-based metrics of brain injury upon admission, increased within the first 24 hours in correlation with infarct progression, and at 24 hours was superior to final infarct volume in predicting 90-day functional outcome. While informing on the relation of BD-tau with imaging-based metrics of brain injury, this cross-sectional study was restricted to BD-tau assessments upon admission and at day 2 and could not inform on key characteristics of the evolution of plasma BD-tau, including when exactly it starts to rise, how long it continues to rise, and how it is determined by infarct characteristics as well as comorbidities. Here, the investigators aim to assess plasma BD-tau every hour from admission to 48 hours after onset to evaluate the hypothesis that BD-tau rises immediately after onset and plateaus between three and 48 hours after onset.

Condition or Disease	Intervention/Treatment	Phase
Stroke Stroke, Acute Stroke, Ischemic Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Brain Ischemia Nervous System Diseases	Diagnostic Test: Plasma levels of BD-tau

Detailed Description

Ischemic stroke remains a leading cause of death and long-term disability worldwide,1 despite major advancements in reperfusion therapies.2,3 While neuroimaging modalities have expanded patient eligibility for reperfusion therapies by estimating ischemic core and salvageable tissue,4-7 their assessments are mostly single-timed. Currently available clinical algorithms lack the capacity to continuously track the dynamic evolution of how the primary core progresses to a final infarct, which, however, is a major determinant of functional outcome.8-10 Monitoring infarct trajectories could support therapeutic decision-making in patients with large-vessel occlusion stroke and unveil determinants of stroke progression, aiding in patient selection for trials evaluating cytoprotection11 and targeting clinically ineffective reperfusion.12 Previously studied blood-based biomarkers such as Neurofilament Light Chain (NfL),13 neuron-specific enolase (NSE),14 glial fibrillary acidic protein (GFAP),15,16 and S 100 calcium-binding protein B (S100B)17 either failed to capture the extent of brain injury within the acute phase of stroke or lack specificity. Plasma levels of brain-derived tau (BD-tau) were recently found to show high value for monitoring brain injury in patients with acute ischemic stroke: In 502 patients with acute IS, plasma BD-tau was associated with imaging-based metrics of brain injury upon admission, increased within the first 24 hours in correlation with infarct progression, and at 24 hours was superior to final infarct volume in predicting 90-day functional outcome.18 While informing on the relation of BD-tau with imaging-based metrics of brain injury, this large cross-sectional study was restricted to BD-tau assessments upon admission (median time from onset: 4.4 hours) and at day 2 (median time from onset: 22.7 hours) and could not inform on key characteristics of the evolution of plasma BD-tau, including when exactly it starts to rise, how long it continues to rise, and how it is determined by infarct characteristics as well as comorbidities. That knowledge would be of great value to determine the responsiveness of plasma BD-tau to brain injury after onset and to evaluate whether BD-tau plateaus at different time points after onset indicating no further infarct progression. Here, the investigators hypothesize that BD-tau rises immediately after onset and plateaus between three and 48 hours after onset. PROMISE-BD-100 will thus assess BD-tau levels every hour from admission to 48 hours from stroke onset in patients that present with the clinical diagnosis of an acute ischemic stroke due to a large- or medium-vessel occlusion within 9 hours from symptom onset.

Study Design

Study Type:

Observational

Anticipated Enrollment :

100 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

PRecisiOn Medicine In StrokE Study on the Evolution of Plasma Brain-Derived Tau in 100 Patients With Acute Ischemic Stroke

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

May 31, 2025

Anticipated Study Completion Date :

Aug 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Ischemic Stroke 100 patients admitted to a specialized stroke service because of an acute ischemic stroke due to large- or medium-vessel occlusion within 9 hours of stroke onset. BD-tau levels and other suggested markers of brain injury (e.g.. NfL) will be assessed every hour from admission to 48 hours after onset. Routinely collected clinical data including from neuroimaging will be collected throughout hospitalization. Clinical follow-up will be performed at 3 months.	Diagnostic Test: Plasma levels of BD-tau Plasma levels of BD-tau will be assessed using a single-molecule array assay.

Arm

Intervention/Treatment

Ischemic Stroke

100 patients admitted to a specialized stroke service because of an acute ischemic stroke due to large- or medium-vessel occlusion within 9 hours of stroke onset. BD-tau levels and other suggested markers of brain injury (e.g.. NfL) will be assessed every hour from admission to 48 hours after onset. Routinely collected clinical data including from neuroimaging will be collected throughout hospitalization. Clinical follow-up will be performed at 3 months.

Diagnostic Test: Plasma levels of BD-tau

Plasma levels of BD-tau will be assessed using a single-molecule array assay.

Outcome Measures

Primary Outcome Measures

The primary outcome are plasma BD-tau levels in acute ischemic stroke. [Every hour from admission to 48 hours after onset.]
The evolution of BD-tau levels will be characterized by: the time point when plasma BD-tau levels start to rise after onset (defined as the earliest time point [in relation to onset] that showed higher BD-tau levels compared with the previous assessment and lower levels compared with the next assessment), the type of rise (e.g. linear, exponential, or logarithmic), and until when plasma BD-tau levels continue to rise (defined as the time point [in relation to onset] compared to which BD-tau levels do not increase by ≥ 5 % compared to 1h, 2h, and 3h afterwards). 5 % were chosen without prior knowledge and in an attempt to account for assay-dependent variations of BD-tau quantifications (coefficient of variation 8-9 %)18 while keeping a biologically and clinically plausible value (rather than e.g. 10 %).

Secondary Outcome Measures

ASPECTS on non-contrast CT [Upon admission]
Ischemic core volume on CT perfusion [Upon admission]
Regional leptomeningeal collateral score on CT angiography [Upon admission]
Final infarct volume [Between 48 hours after symptom onset and discharge (latest 10 days after onset)]
Final infarct volume will be assessed on delayed neuroimaging (CT or MRI), at least 48 after symptom onset.
Infarct progression [Between admission and discharge (latest 10 days after onset)]
Infarct progression is defined as the difference between ischemic core volume quantified on admission CT perfusion scans and infarct volume quantified on delayed neuroimaging.
90-day functional outcome [90 days (± 14 days) after onset]
Functional outcome at 90 days (± 14 days) will be assessed using the modified Rankin Scale (mRS). The mRS is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.
7-day functional outcome [7 days after onset]
Functional outcome at 7 days (or discharge if earlier) will be assessed using the modified Rankin Scale (mRS). The mRS is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.
Early recurrent ischemic stroke [Between admission and discharge (latest 10 days after onset)]
The diagnosis of an early recurrent ischemic stroke will be based on i) sudden onset of a new focal neurological deficit within the first seven days after the index stroke that can not be explained by other non-ischemic causes such as seizure, metabolic derangement, or other systemic conditions, and ii) the presence of a new DWI-positive lesion on MRI or a new ischemic lesion on a delayed CT scan that is distinct from the index stroke lesion and that is consistent with the new clinical symptoms.
Secondary intracerebral hemorrhage [Between admission and discharge (latest 10 days after onset)]
Secondary intracerebral hemorrhage is defined as a new intracerebral hemorrhage independent of the primary ischemic lesion that is observed between the initial hemorrhage-free neuroimaging scan and discharge
Hemorrhagic transformation [Between admission and discharge (latest 10 days after onset)]
The occurrence of hemorrhagic transformation will be evaluated based on the morphological ECASS criteria.20

Other Outcome Measures

Plasma levels of NfL [Hourly from admission to 48 hours after onset]
Plasma levels of NfL will be assessed at an hourly basis using a single-molecule array assay.
Plasma levels of GFAP [Hourly from admission to 48 hours after onset]
Plasma levels of GFAP will be assessed at an hourly basis using a single-molecule array assay.
Plasma proteome and metabolome composition [Hourly from admission to 48 hours after onset]
Plasma proteome and metabolome composition will be assessed using mass spectrometry or alternatives.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

clinical diagnosis of acute ischemic stroke
presentation within 9 hours of symptom onset
large- or medium-vessel occlusion (i.e. an occlusion of the ICA, MCA [segments M1-M4], ACA [segments A1-A3], basilar artery, or PCA [segments P1 to P3]) confirmed by CT or MRI angiography
at least 18 years of age
written informed consent

Exclusion Criteria:

CT or MRI showing intracranial hemorrhage upon admission
A history of ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, subdural hematoma, epidural hematoma, CNS tumor, meningitis, or encephalitis within the last three months
severe renal dysfunction (eGFR < 30ml/min/1.73m2)
dementia
pre-stroke disability defined as a premorbid modified Rankin Scale score > 1