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

Stroke Clinical Trial

— PROMISE-BD-100  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06121336
• Other study ID #: LMU_ISD_2023_PROMISE-BD-100
• Status: Recruiting
• Start date: March 1, 2023
• Est. completion date: August 31, 2025

Study information

• Verified date: March 2024
• Source: Ludwig-Maximilians - University of Munich
• Contact: Steffen Tiedt, MD PhD
• Phone: +4989440046046
• Email: steffen.tiedt[@]med.uni-muenchen.de
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: August 31, 2025
• Est. primary completion date: May 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Brain Diseases
• Brain Ischemia
• Central Nervous System Diseases
• Cerebrovascular Disorders
• Ischemia
• Ischemic Stroke
• Nervous System Diseases
• Stroke
• Stroke, Acute
• Stroke, Ischemic

Intervention

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

Locations

Country	Name	City	State
Germany	LMU University hospital, LMU Munich	Munich	Bavaria

Sponsors (1)

Lead Sponsor	Collaborator
Ludwig-Maximilians - University of Munich

Country where clinical trial is conducted

Germany, 

References & Publications (25)

18. Vlegels N, Gonzalez-Ortiz F, Knuth NL, et al. Brain-derived Tau for Monitoring Brain Injury in Acute Ischemic Stroke. Under review.

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Menon BK, Smith EE, Modi J, Patel SK, Bhatia R, Watson TW, Hill MD, Demchuk AM, Goyal M. Regional leptomeningeal score on CT angiography predicts clinical and imaging outcomes in patients with acute anterior circulation occlusions. AJNR Am J Neuroradiol. 2011 Oct;32(9):1640-5. doi: 10.3174/ajnr.A2564. Epub 2011 Jul 28. — View Citation

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Olivot JM, Mlynash M, Inoue M, Marks MP, Wheeler HM, Kemp S, Straka M, Zaharchuk G, Bammer R, Lansberg MG, Albers GW; DEFUSE 2 Investigators. Hypoperfusion intensity ratio predicts infarct progression and functional outcome in the DEFUSE 2 Cohort. Stroke. 2014 Apr;45(4):1018-23. doi: 10.1161/STROKEAHA.113.003857. Epub 2014 Mar 4. Erratum In: Stroke. 2014 May;45(5):e92. — View Citation

Ospel JM, McDonough R, Demchuk AM, Menon BK, Almekhlafi MA, Nogueira RG, McTaggart RA, Poppe AY, Buck BH, Roy D, Haussen DC, Chapot R, Field TS, Jayaraman MV, Tymianski M, Hill MD, Goyal M; ESCAPE-NA1 investigators. Predictors and clinical impact of infarct progression rate in the ESCAPE-NA1 trial. J Neurointerv Surg. 2022 Sep;14(9):886-891. doi: 10.1136/neurintsurg-2021-017994. Epub 2021 Sep 7. — View Citation

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Tiedt S, Duering M, Barro C, Kaya AG, Boeck J, Bode FJ, Klein M, Dorn F, Gesierich B, Kellert L, Ertl-Wagner B, Goertler MW, Petzold GC, Kuhle J, Wollenweber FA, Peters N, Dichgans M. Serum neurofilament light: A biomarker of neuroaxonal injury after ischemic stroke. Neurology. 2018 Oct 2;91(14):e1338-e1347. doi: 10.1212/WNL.0000000000006282. Epub 2018 Sep 14. — View Citation

Turc G, Bhogal P, Fischer U, Khatri P, Lobotesis K, Mazighi M, Schellinger PD, Toni D, de Vries J, White P, Fiehler J. European Stroke Organisation (ESO) - European Society for Minimally Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical Thrombectomy in Acute Ischaemic StrokeEndorsed by Stroke Alliance for Europe (SAFE). Eur Stroke J. 2019 Mar;4(1):6-12. doi: 10.1177/2396987319832140. Epub 2019 Feb 26. — View Citation

Turc G, Tsivgoulis G, Audebert HJ, Boogaarts H, Bhogal P, De Marchis GM, Fonseca AC, Khatri P, Mazighi M, Perez de la Ossa N, Schellinger PD, Strbian D, Toni D, White P, Whiteley W, Zini A, van Zwam W, Fiehler J. European Stroke Organisation - European Society for Minimally Invasive Neurological Therapy expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischaemic stroke and anterior circulation large vessel occlusion. Eur Stroke J. 2022 Mar;7(1):I-XXVI. doi: 10.1177/23969873221076968. Epub 2022 Feb 17. Erratum In: Eur Stroke J. 2023 Mar;8(1):403. — View Citation

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Plasma levels of NfL	Plasma levels of NfL will be assessed at an hourly basis using a single-molecule array assay.	Hourly from admission to 48 hours after onset
Other	Plasma levels of GFAP	Plasma levels of GFAP will be assessed at an hourly basis using a single-molecule array assay.	Hourly from admission to 48 hours after onset
Other	Plasma proteome and metabolome composition	Plasma proteome and metabolome composition will be assessed using mass spectrometry or alternatives.	Hourly from admission to 48 hours after onset
Primary	The primary outcome are plasma BD-tau levels in acute ischemic stroke.	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 %).	Every hour from admission to 48 hours after onset.
Secondary	ASPECTS on non-contrast CT		Upon admission
Secondary	Ischemic core volume on CT perfusion		Upon admission
Secondary	Regional leptomeningeal collateral score on CT angiography		Upon admission
Secondary	Final infarct volume	Final infarct volume will be assessed on delayed neuroimaging (CT or MRI), at least 48 after symptom onset.	Between 48 hours after symptom onset and discharge (latest 10 days after onset)
Secondary	Infarct progression	Infarct progression is defined as the difference between ischemic core volume quantified on admission CT perfusion scans and infarct volume quantified on delayed neuroimaging.	Between admission and discharge (latest 10 days after onset)
Secondary	90-day functional outcome	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.	90 days (± 14 days) after onset
Secondary	7-day functional outcome	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.	7 days after onset
Secondary	Early recurrent ischemic stroke	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.	Between admission and discharge (latest 10 days after onset)
Secondary	Secondary intracerebral hemorrhage	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	Between admission and discharge (latest 10 days after onset)
Secondary	Hemorrhagic transformation	The occurrence of hemorrhagic transformation will be evaluated based on the morphological ECASS criteria.20	Between admission and discharge (latest 10 days after onset)