PROMISE: Precision Medicine in Stroke

Sponsor

Ludwig-Maximilians - University of Munich (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT05815836

Collaborator

(none)

787

Enrollment

122

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

PROMISE aims at identifying novel diagnostic and prognostic circulating biomarkers for patients with acute stroke and at informing on crucial yet undetected pathophysiological mechanisms driving outcome after stroke by enriching all phenotypic information available from clinical routine with in-depth quantification of the circulating proteome and metabolome as well as other entities.

Condition or Disease	Intervention/Treatment	Phase
Stroke Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Brain Ischemia Nervous System Diseases

Detailed Description

The heterogeneity of ischemic stroke (IS) poses a challenge for assigning patients to optimal treatment strategies and is a major reason for the large number of failed clinical trials. Current diagnostic algorithms are insufficient to explain clinical outcomes arguing for crucial yet undetected pathophysiological mechanisms. Diagnostic tests further leave stroke etiology undetermined in 40 % of IS patients thus impeding the allocation of these patients to optimal secondary prevention regimens. Heterogeneity is also seen at the level of neuronal injury, which greatly varies between IS patients, but can neither be assessed in the pre-hospital setting nor serially in the acute phase to monitor stroke progression and to develop individual trajectories of neuronal loss over time. The circulating proteome and metabolome capture pathophysiological events from multiple organs including local and systemic events (e.g. stress) related to acute stroke and might thus inform on neuronal injury and the mechanisms causing stroke. The circulating proteome and metabolome may further inform on i) the systemic effects of stroke, which contribute significantly to stroke outcome but are under-researched, and ii) how concepts from preclinical stroke research such as reperfusion injury translate to human stroke. The investigators hypothesize that the combination of detailed clinical phenotyping with advanced profiling technologies (genomics, proteomics, and metabolomics) will enable the identification of key molecular signatures of IS that inform on pathophysiological mechanisms and might also be utilized as diagnostic instruments.

Study Design

Study Type:

Observational

Actual Enrollment :

787 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Precision Medicine in Stroke

Actual Study Start Date :

Oct 1, 2013

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Acute Ischemic Stroke 504 patients admitted to a specialized stroke service because of an acute ischemic stroke. The circulating proteome and metabolome as well as specific molecular targets of interest (i.e. NfL) will be assessed upon admission (day 1), the next morning (day 2), day 3, day 7 (or day of discharge if earlier), and day 90. Routinely collected clinical data including from neuroimaging will be collected throughout hospitalization. Clinical follow-up will be performed at 3 months.
Acute Intracerebral hemorrhage 130 patients admitted to a specialized stroke service because of an acute intracerebral hemorrhage. The circulating proteome and metabolome as well as specific molecular targets of interest (i.e. NfL) will be assessed upon admission (day 1). Routinely collected clinical data including from neuroimaging will be collected throughout hospitalization.
Stroke Mimics 51 patients admitted to the emergency department because of acute stroke-like symptoms caused by epileptic seizures, migraine attacks, or other stroke-mimicking diseases. The circulating proteome and metabolome as well as specific molecular targets of interest (i.e. NfL) will be assessed upon admission (day 1), the next morning (day 2), day 3, day 7, and day 90. Routinely collected clinical data including from neuroimaging will be collected throughout hospitalization.
Healthy subjects 102 subjects without acute neurological symptoms. The circulating proteome and metabolome as well as specific molecular targets of interest (i.e. NfL) will be assessed.

Outcome Measures

Primary Outcome Measures

Prediction of clinical outcome as defined by the modified Rankin Scale (mRS) score [3 months]
The modified Rankin Scale (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. We will assess associations of clinical outcome with: Global, class, pathway, and individual metabolite levels upon admission (day 1), day 2, day 3, day7, and day 90 [raw values, referenced to HC, or referenced to SM] Global, pathway, and individual protein levels upon admission (day 1), day 2, day 3, day7, and day 90 [raw values, referenced to HC, or referenced to SM]
Prediction of clinical outcome as defined by the modified Rankin Scale (mRS) score [7 days or day of discharge if earlier (on average 5 days)]
The modified Rankin Scale (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. We will assess associations of clinical outcome with: Global, class, pathway, and individual metabolite levels upon admission (day 1), day 2, day 3, and day 7 [raw values, referenced to HC, or referenced to SM] Global, pathway, and individual protein levels upon admission (day 1), day 2, day 3, and day 7 [raw values, referenced to HC, or referenced to SM]

Secondary Outcome Measures

Acute brain injury as assessed by neuroimaging [day 1]
The extent of acute brain injury (in ml) will be assessed on admission NCCT and CT perfusion scans.
Subacute brain injury as assessed by neuroimaging [day 3 to day 10]
The extent of subacute brain injury will be manually segmented on images from delayed routine CT or MRI scans.
Neck and cerebral vessel morphology [day 1 to day 10]
We will assess the number of different plaque types on routine CT/MRI angiography scans.
Heart morphology and function as assessed by echocardiography and ECG [day 1 to day 10]
We will assess the likelihood of cardiac embolism by a score that integrates PTFV1, left ventricular strain and left atrial area.
Stroke etiology [7 days or day of discharge if earlier (on average 5 days)]
Stroke etiology will be assessed using the TOAST classification systems.
Sensitivity and specificity to separet diagnostic groups [day 1 to day 10]
Groups (Ischemic stroke, hemorrhagic stroke, stroke mimics, healthy subjects) will be compared.
Systemic sequelae of stroke [day 1 to day 10]
Systemic sequelae will be assessed by clinical laboratory tests.
Treatment efficacy of mechanical thrombectomy [day 1 to day 90]
Treatment efficacy will be assessed by comparing mRS scores between treated and non-treated groups.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Patients with acute ischemic stroke:
Age 18 years or older
Diagnosis of an acute ischemic stroke defined by an acute focal neurological deficit in combination with a diffusion-weighted imaging-positive lesion on magnetic resonance imaging or a new lesion on a delayed CT scan.
Time from last seen well to admission and first blood sampling < 24 hours
Blood samples collected upon admission (day 1), the next morning (day 2), day 3, and day 7 (or day of discharge if earlier)
Informed consent in accord with ethical approval
Patients with acute intracerebral hemorrhage:
Age 18 years or older
Diagnosis of an acute intracerebral hemorrhage defined by an acute focal neurological deficit in combination with imaging-based evidence of intracerebral hemorrhage.
Time from last seen well to admission and first blood sampling < 24 hours
Blood samples collected upon admission (day 1)
Informed consent in accord with ethical approval
Patients with stroke mimics:
Age 18 years or older
Diagnosis of a stroke-mimicking disease defined by an acute focal neurological deficit in combination with a lack of infarction on neuroimaging.
Time from last seen well to admission and first blood sampling < 24 hours
Blood samples collected upon admission (day 1), the next morning (day 2), day 3, and day 7
Informed consent in accord with ethical approval
Healthy subjects:
Age 18 years or older
Informed consent in accord with ethical approval

Exclusion Criteria:

Patients with acute ischemic stroke:
Lack of follow-up CT or MRI imaging
Major surgery within the last four weeks
In-house stroke
Myocardial infarction, ischemic stroke, transient ischemic attacks, traumatic brain injury, cerebral venous sinus thrombosis, any intracranial hemorrhage, thrombosis, or pulmonary embolism within the last four weeks
Chronic inflammatory bowel disease or percutaneous endoscopic gastrostomy
Patients with acute intracerebral hemorrhage:
Major surgery within the last four weeks
In-house stroke
Myocardial infarction, ischemic stroke, transient ischemic attacks, traumatic brain injury, cerebral venous sinus thrombosis, any intracranial hemorrhage, thrombosis, or pulmonary embolism within the last four weeks
Chronic inflammatory bowel disease or percutaneous endoscopic gastrostomy
Patients with stroke mimics:
Major surgery within the last four weeks
Myocardial infarction, ischemic stroke, transient ischemic attacks, traumatic brain injury, cerebral venous sinus thrombosis, any intracranial hemorrhage, thrombosis, or pulmonary embolism within the last four weeks
Chronic inflammatory bowel disease or percutaneous endoscopic gastrostomy
Healthy subjects:
Major surgery within the last four weeks
Myocardial infarction, ischemic stroke, transient ischemic attacks, traumatic brain injury, cerebral venous sinus thrombosis, any intracranial hemorrhage, thrombosis, or pulmonary embolism within the last four weeks
Chronic inflammatory bowel disease or percutaneous endoscopic gastrostomy