CERebrolysine Effect on Blood-brain Barrier in acUte Ischemic Stroke

NCT ID: NCT06078215

Last Updated: 2023-10-13

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 350 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-01-10
• Study Completion Date: 2025-03-31

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:

1. are included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy - control (group A),

2. are included for reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy plus Cerebrolysin (group B)

3. 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).

Conditions

Acute Ischemic Stroke

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Thrombolysis and/or mechanical thrombectomy

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Cerebrolysin

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

Group Type: EXPERIMENTAL

Cerebrolysin

Intervention Type: COMBINATION_PRODUCT

Intravenous infusion of 30 ml Cerebrolysine in 500 ml of buffered crystalloid solution intravenously initiated within 12 hours from symptoms onset

No reperfusion therapy / no cerebrolysin

patients not referred to reperfusion therapy nor Cerebrolysin

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Cerebrolysin

Intravenous infusion of 30 ml Cerebrolysine in 500 ml of buffered crystalloid solution intravenously initiated within 12 hours from symptoms onset

Intervention Type: COMBINATION_PRODUCT

Other Intervention Names

FPF (Fine Particle Fraction)-1070

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Poznan University of Medical Sciences

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Slawomir Michalak, Prof.

Role: PRINCIPAL_INVESTIGATOR

Poznan University of Medical Sciences

Locations

University Hospital

Poznan, , Poland

Site Status: RECRUITING

Countries

Poland

Central Contacts

Slawomir Michalak, Prof.

Role: CONTACT

swami@ump.edu.pl

+48 61 8691 535

Joanna Rybacka-Mossakowska, MD, PhD

Role: CONTACT

joannarybacka@gmail.com

+48 61 8691 459

Facility Contacts

Slawomir Michalak, Prof.

Role: primary

swami@ump.edu.pl

+4861 8691 535

Joanna Rybacka-Mossakowska, MD, PhD

Role: backup

joannarybacka@gmail.com

+4861 8691 458

References

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.

Reference Type: BACKGROUND

PMID: 22993287 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34214867 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33661804 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16219824 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30499355 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23009193 (View on PubMed)

Other Identifiers

392/2023

Identifier Type: -

Identifier Source: org_study_id