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CERebrolysine Effect on Blood-brain Barrier in acUte Ischemic Stroke (CERBERUS)

Primary Purpose

Acute Ischemic Stroke

Status
Recruiting
Phase
Phase 4
Locations
Poland
Study Type
Interventional
Intervention
Cerebrolysin
Sponsored by
Poznan University of Medical Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Ischemic Stroke focused on measuring Acute Ischemic Stroke, blood-brain barrier, cerebrolysin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: acute ischemic stroke patients informed consent Exclusion Criteria: no informed consent primary or metastatic brain tumor brain abscess encephalitis localized inflammation sepsis autoimmune diseases of central or peripheral nervous system Cerebrolysin hypersensitivity / allergy epilepsy severe kidney disease

Sites / Locations

  • University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

No Intervention

Experimental

No Intervention

Arm Label

Thrombolysis and/or mechanical thrombectomy

Cerebrolysin

No reperfusion therapy / no cerebrolysin

Arm Description

patients included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy - comparator

patients included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy and treated with Cerebrolysin

patients not referred to reperfusion therapy nor Cerebrolysin

Outcomes

Primary Outcome Measures

National Institute of Health Stroke Scale
National Institute of Health Stroke Scale; score range: 1-42; 1-4 - Minor stroke; 5-15 - Moderate stroke; 16-20 - Moderate to severe stroke; 21-42 - Severe stroke
National Institute of Health Stroke Scale
National Institute of Health Stroke Scale; score range: 1-42; 1-4 - Minor stroke; 5-15 - Moderate stroke; 16-20 - Moderate to severe stroke; 21-42 - Severe stroke
Detection of hemorrhagic transformation [range o:1]
hemorrhagic transformation on head computerized tomography
Concentration of plasma occludin [ng/mL]
Occludin is an enzyme (EC 1.6) that oxidizes NADH (Nicotinamide adenine dinucleotide)
Concentration of plasma occludin [ng/mL]
Occludin is an enzyme (EC 1.6) that oxidizes NADH (Nicotinamide adenine dinucleotide)
Concentration of plasma claudin 5 [ng/mL]
Claudins are small (20-24/27 kilodalton (kDa)) transmembrane proteins.
Concentration of plasma claudin 5 [ng/mL]
Claudins are small (20-24/27 kilodalton (kDa)) transmembrane proteins.
Concentration of plasma ZO1 [ng/mL]
Zonula occludens-1 ZO-1, also known as Tight junction protein-1
Concentration of plasma ZO1 [ng/mL]
Zonula occludens-1 ZO-1, also known as Tight junction protein-1

Secondary Outcome Measures

Modified Rankin scale [range 0:6]
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Modified Rankin scale [range 0:6]
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Modified Rankin scale [range 0:6]
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Modified Rankin scale [range 0:6]
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Barthel Index for Activities of Daily Living (ADL) [range 0:100]
measures the degree of assistance required by an individual; 0-20 - total dependency, 21-60 - severe dependency, 61-90 - moderate dependency, 91-100 - slight dependency
Barthel Index for Activities of Daily Living (ADL) [range 0:100]
measures the degree of assistance required by an individual; 0-20 - total dependency, 21-60 - severe dependency, 61-90 - moderate dependency, 91-100 - slight dependency
Death [range 0:1]
survival measure
Montreal Cognitive Assessment Test [range 0:30]
the assessment of cognitive functions; 26-30 - normal cognition, 18-25 - mild cognitive impairment, 10-17 - moderate cognitive impairment, <10 - severe cognitive impairment

Full Information

First Posted
October 5, 2023
Last Updated
October 11, 2023
Sponsor
Poznan University of Medical Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT06078215
Brief Title
CERebrolysine Effect on Blood-brain Barrier in acUte Ischemic Stroke
Acronym
CERBERUS
Official Title
CERebrolysine Effect on Blood-brain Barrier / Endothelium Integrity During Reperfusion Therapy of acUte Ischemic Stroke (CERBERUS Study)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 10, 2023 (Actual)
Primary Completion Date
January 31, 2025 (Anticipated)
Study Completion Date
March 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Poznan University of Medical Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The study investigates whether Cerebrolysin stabilizes blood-brain barrier integrity in a manner that can be monitored using serum levels of the principal tight junction proteins, e.g., occludin (OCL), claudin-5 (CLN), and zonula occludens-1 (ZO-1), or other molecules known to be involved in BBB degradation, e.g., S100B and whether it protects against hemorrhagic transformation in ischemic stroke patients after reperfusion therapy (i.e. thrombolysis and/or mechanical thrombectomy).
Detailed Description
Hemorrhagic transformation (HT) of ischemic stroke can be identified in 3-40% of patients. The incidence varies depending on the definition used and the studied population. The severity of HT can be described using clinical and radiological tools and classified as asymptomatic/symptomatic, according to European Cooperative Acute Stroke Study classification and Heidelberg Bleeding Classification. Breakdown of the blood-brain barrier (BBB) is associated with an increased risk of developing a hemorrhagic transformation (HT) of ischemic stroke. In patients who received reperfusion therapy (thrombolysis, mechanical thrombectomy), secondary HT had a negative influence on the clinical course and outcome. Tight junction (TJ) proteins are important cell adhesion components that stabilize endothelium cells lining and are responsible for maintaining the BBB integrity. Biomarkers of BBB damage that can be evaluated during the early phases of stroke might be useful for predicting the risk of HT. Such biomarkers could also facilitate the decision of whether to begin thrombolytic therapy in acute ischemic stroke patients. Experimental data support the evidence for protective effect of Cerebrolysin on BBB integrity. Moreover, it diminished and reversed negative effect of recombinant tissue plasminogen activator (rtPA) used as thrombolytic agent on endothelial cells integrity. Cerebrolysin stabilized tight junction proteins expression: occludin, claudin-5 and zona occludens 1 (ZO1). In our previous study we have found that circulating TJs predict HT in ischemic stroke patients. Clinically evident HTs were associated with increased concentrations of occludin and S100B, an increase in the claudin-5/ZO-1 ratio, and a decreased level of vascular endothelial growth factor (VEGF). Claudin-5 levels also correlated with HT occurrence when estimated within 3 hours of stroke onset. The protective effects of Cerebrolysin were already clinically evidenced, however there are no available studies using biomarkers of BBB. Aim of the study We aim to investigate whether Cerebrolysin stabilizes BBB integrity in a manner that can be monitored using serum levels of the principal TJ proteins, e.g., occludin (OCL), claudin-5 (CLN), and zonula occludens-1 (ZO-1), or other molecules known to be involved in BBB degradation, e.g., S100B and whether it protects against HT in ischemic stroke patients after reperfusion therapy. Study design A prospective longitudinal study will be performed in ischemic stroke patients who: are included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy - control (group A), are included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy plus Cerebrolysin (group B) are not referred to reperfusion therapy nor Cerebrolysin (group C). All patients with NIHSS score > 8 will receive 30 ml Cerebrolysin in 500 ml of buffered crystalloid solution intravenously initiated within 12 hours from symptoms onset. Whole blood samples will be withdrawn at the admission, then within 1 to 3 days after stroke onset and at 7th day after stroke onset or when the endpoint will be reached by the patient. Occludin, claudin 5 and ZO-1 concentrations will be analyzed by means of home-made enzyme-linked immunosorbent assay. Endpoint will include clinical worsening (increase in the NIHSS by > 4 points), radiologically evident hemorrhage or radiologically evident brain edema at control CT performed within 1 to 3 days after stroke onset. Standard head CT will be performed in all patients at the admission, within 1 to 3 days after stroke onset, after worsening of clinical status and additionally when the differentiation between hemorrhage and contrast staining will be required in thrombectomy patients. Hemorrhagic transformation of ischemic stroke will be classified according to Table 1. Clinimetric evaluation of all patients will include NIHSS every day for 7 days and at day 30. Modified Rankin scale (mRS) will be evaluated at visit 1,2,3,4 and 5; Barthel index at visit 4 and 5 and Montreal Cognitive Assessment Test at visit 5. All patents will undergo current American Heart Association Guidelines for the Early Management of Patients with Acute Ischemic Stroke. Expected results It is expected that Cerebrolysin can stabilize blood-brain barrier in ischemic stroke patients treated with reperfusion therapies via remodelling of tight junction proteins between endothelial cells. Such an effect measured by the levels of circulating tight junction proteins can translate into prevention of hemorrhagic transformation. To summarize, Cerebrolysine can guard blood-brain barrier integrity in ischemic stroke (Cerberus effect).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Ischemic Stroke
Keywords
Acute Ischemic Stroke, blood-brain barrier, cerebrolysin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
A prospective longitudinal study will be performed in ischemic stroke patients who: are included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy - control (group A), are included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy plus Cerebrolysin (group B) are not referred to reperfusion therapy nor Cerebrolysin (group C).
Masking
None (Open Label)
Allocation
Randomized
Enrollment
350 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Thrombolysis and/or mechanical thrombectomy
Arm Type
No Intervention
Arm Description
patients included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy - comparator
Arm Title
Cerebrolysin
Arm Type
Experimental
Arm Description
patients included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy and treated with Cerebrolysin
Arm Title
No reperfusion therapy / no cerebrolysin
Arm Type
No Intervention
Arm Description
patients not referred to reperfusion therapy nor Cerebrolysin
Intervention Type
Combination Product
Intervention Name(s)
Cerebrolysin
Other Intervention Name(s)
FPF (Fine Particle Fraction)-1070
Intervention Description
Intravenous infusion of 30 ml Cerebrolysine in 500 ml of buffered crystalloid solution intravenously initiated within 12 hours from symptoms onset
Primary Outcome Measure Information:
Title
National Institute of Health Stroke Scale
Description
National Institute of Health Stroke Scale; score range: 1-42; 1-4 - Minor stroke; 5-15 - Moderate stroke; 16-20 - Moderate to severe stroke; 21-42 - Severe stroke
Time Frame
every day for 7 days after stroke onset
Title
National Institute of Health Stroke Scale
Description
National Institute of Health Stroke Scale; score range: 1-42; 1-4 - Minor stroke; 5-15 - Moderate stroke; 16-20 - Moderate to severe stroke; 21-42 - Severe stroke
Time Frame
at day 30 after stroke onset
Title
Detection of hemorrhagic transformation [range o:1]
Description
hemorrhagic transformation on head computerized tomography
Time Frame
within 1 to 3 days after stroke onset, after worsening of clinical status by more than 4 points in NIHSS
Title
Concentration of plasma occludin [ng/mL]
Description
Occludin is an enzyme (EC 1.6) that oxidizes NADH (Nicotinamide adenine dinucleotide)
Time Frame
at the admission, within 1 to 3 days after stroke onset
Title
Concentration of plasma occludin [ng/mL]
Description
Occludin is an enzyme (EC 1.6) that oxidizes NADH (Nicotinamide adenine dinucleotide)
Time Frame
at 7th day after stroke onset
Title
Concentration of plasma claudin 5 [ng/mL]
Description
Claudins are small (20-24/27 kilodalton (kDa)) transmembrane proteins.
Time Frame
at the admission, within 1 to 3 days after stroke onset
Title
Concentration of plasma claudin 5 [ng/mL]
Description
Claudins are small (20-24/27 kilodalton (kDa)) transmembrane proteins.
Time Frame
at 7th day after stroke onset
Title
Concentration of plasma ZO1 [ng/mL]
Description
Zonula occludens-1 ZO-1, also known as Tight junction protein-1
Time Frame
at the admission, within 1 to 3 days after stroke onset
Title
Concentration of plasma ZO1 [ng/mL]
Description
Zonula occludens-1 ZO-1, also known as Tight junction protein-1
Time Frame
at 7th day after stroke onset
Secondary Outcome Measure Information:
Title
Modified Rankin scale [range 0:6]
Description
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Time Frame
at the admission, within 1 to 3 days after stroke onset
Title
Modified Rankin scale [range 0:6]
Description
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Time Frame
at 7th day after stroke onset
Title
Modified Rankin scale [range 0:6]
Description
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Time Frame
at the 30th +/- 5 day after stroke onset
Title
Modified Rankin scale [range 0:6]
Description
Modified Rankin scale; 0-2 - good functional outcome; 3-6 - poor functional outcome
Time Frame
at 90th +/- 5 day after stroke onset
Title
Barthel Index for Activities of Daily Living (ADL) [range 0:100]
Description
measures the degree of assistance required by an individual; 0-20 - total dependency, 21-60 - severe dependency, 61-90 - moderate dependency, 91-100 - slight dependency
Time Frame
30th +/- 5 day after stroke onset
Title
Barthel Index for Activities of Daily Living (ADL) [range 0:100]
Description
measures the degree of assistance required by an individual; 0-20 - total dependency, 21-60 - severe dependency, 61-90 - moderate dependency, 91-100 - slight dependency
Time Frame
at the 90th +/- 5 day after stroke onset
Title
Death [range 0:1]
Description
survival measure
Time Frame
within 90 days after stroke onset
Title
Montreal Cognitive Assessment Test [range 0:30]
Description
the assessment of cognitive functions; 26-30 - normal cognition, 18-25 - mild cognitive impairment, 10-17 - moderate cognitive impairment, <10 - severe cognitive impairment
Time Frame
at the 90th +/-5 day after stroke onset

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: acute ischemic stroke patients informed consent Exclusion Criteria: no informed consent primary or metastatic brain tumor brain abscess encephalitis localized inflammation sepsis autoimmune diseases of central or peripheral nervous system Cerebrolysin hypersensitivity / allergy epilepsy severe kidney disease
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Slawomir Michalak, Prof.
Phone
+48 61 8691 535
Email
swami@ump.edu.pl
First Name & Middle Initial & Last Name or Official Title & Degree
Joanna Rybacka-Mossakowska, MD, PhD
Phone
+48 61 8691 459
Email
joannarybacka@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Slawomir Michalak, Prof.
Organizational Affiliation
Poznan University of Medical Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital
City
Poznań
ZIP/Postal Code
60-355
Country
Poland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Slawomir Michalak, Prof.
Phone
+4861 8691 535
Email
swami@ump.edu.pl
First Name & Middle Initial & Last Name & Degree
Joanna Rybacka-Mossakowska, MD, PhD
Phone
+4861 8691 458
Email
joannarybacka@gmail.com
First Name & Middle Initial & Last Name & Degree
Jacek Namysl, MD
First Name & Middle Initial & Last Name & Degree
Joanna Rybacka-Mossakowska, MD, PhD
First Name & Middle Initial & Last Name & Degree
Slawomir Michalak, Prof.

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
22993287
Citation
Kazmierski R, Michalak S, Wencel-Warot A, Nowinski WL. Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients. Neurology. 2012 Oct 16;79(16):1677-85. doi: 10.1212/WNL.0b013e31826e9a83. Epub 2012 Sep 19.
Results Reference
background
PubMed Identifier
34214867
Citation
Poljakovic Z, Supe S, Ljevak J, Starcevic K, Peric I, Blazevic N, Krbot-Skoric M, Jovanovic I, Ozretic D. Efficacy and safety of Cerebrolysin after futile recanalisation therapy in patients with severe stroke. Clin Neurol Neurosurg. 2021 Aug;207:106767. doi: 10.1016/j.clineuro.2021.106767. Epub 2021 Jun 18.
Results Reference
background
PubMed Identifier
33661804
Citation
Teng H, Li C, Zhang Y, Lu M, Chopp M, Zhang ZG, Melcher-Mourgas M, Fleckenstein B. Therapeutic effect of Cerebrolysin on reducing impaired cerebral endothelial cell permeability. Neuroreport. 2021 Mar 24;32(5):359-366. doi: 10.1097/WNR.0000000000001598.
Results Reference
background
PubMed Identifier
16219824
Citation
Kassner A, Roberts T, Taylor K, Silver F, Mikulis D. Prediction of hemorrhage in acute ischemic stroke using permeability MR imaging. AJNR Am J Neuroradiol. 2005 Oct;26(9):2213-7.
Results Reference
background
PubMed Identifier
30499355
Citation
Zhang Y, Chopp M, Zhang ZG, Zhang Y, Zhang L, Lu M, Zhang T, Winter S, Doppler E, Brandstaetter H, Mahmood A, Xiong Y. Cerebrolysin Reduces Astrogliosis and Axonal Injury and Enhances Neurogenesis in Rats After Closed Head Injury. Neurorehabil Neural Repair. 2019 Jan;33(1):15-26. doi: 10.1177/1545968318809916. Epub 2018 Nov 30.
Results Reference
background
PubMed Identifier
23009193
Citation
Lang W, Stadler CH, Poljakovic Z, Fleet D; Lyse Study Group. A prospective, randomized, placebo-controlled, double-blind trial about safety and efficacy of combined treatment with alteplase (rt-PA) and Cerebrolysin in acute ischaemic hemispheric stroke. Int J Stroke. 2013 Feb;8(2):95-104. doi: 10.1111/j.1747-4949.2012.00901.x. Epub 2012 Sep 26.
Results Reference
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CERebrolysine Effect on Blood-brain Barrier in acUte Ischemic Stroke

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