Can adding cerebrolysin early to clot-dissolving stroke treatment reduce the risk of brain bleeding?

ISRCTN	ISRCTN87656744
DOI	https://doi.org/10.1186/ISRCTN87656744
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	С2XX1A-2018
Sponsor	State Autonomous Institution of Health Interregional Clinical Diagnostic Center
Funder	Investigator initiated and funded

Submission date: 01/02/2021
Registration date: 16/02/2021
Last edited: 30/06/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Circulatory System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Ischemic stroke is a type of stroke caused by a blockage in an artery that supplies blood to the brain. This blockage reduces blood flow and oxygen, leading to damage or death of brain cells. It is also known as brain ischemia or cerebral ischemia. Intravenous thrombolysis (IVT) is the standard treatment for patients with acute ischemic stroke. It works by dissolving blood clots, improving blood flow, and reducing the risk of damage to tissues and organs. IVT can significantly improve recovery after a stroke. However, some patients may experience complications in the damaged brain tissue after receiving thrombolysis, which can worsen outcomes. Cerebrolysin, a neuroprotective medication, has shown potential benefits in protecting brain cells and supporting recovery. It is approved in Russia and some other countries as an additional treatment for acute ischemic stroke. This study aims to test whether Cerebrolysin, when used alongside IVT, can reduce the risk of complications and improve outcomes for patients with ischemic stroke.

Who can participate?
Adult patients with acute ischemic stroke who arrive at participating hospitals within 4.5 hours after the stroke onset and who are eligible for intravenous thrombolytic therapy.

What does the study involve?
After signing an informed consent form, participants are randomly assigned to either the treatment group (case group) or the control group.
• Both groups: All participants will receive standard care, including IVT.
• Case group: Participants will also receive daily intravenous infusions of Cerebrolysin for 14 consecutive days.
All other treatments and diagnostic procedures will follow current clinical guidelines. In some hospitals, participants from both groups may undergo advanced brain imaging if the technology is available.

What are the possible benefits and risks of participating?
Possible benefits:
• You may receive a potentially more effective treatment before it becomes widely available.
• In some hospitals, you may have access to advanced brain imaging during your care.
• You could play a more active role in managing your health.
• Your participation may help improve stroke treatments for others in the future.
Possible risks:
• The new treatment may cause side effects or discomfort.
• It may not be more effective than the standard treatment.
• If you are assigned to the control group, you will only receive the standard treatment.

Where is the study run from?
The study is being conducted at participating hospitals. For more details, please refer to the full list of locations or contact the main investigator.

When is the study starting and how long is it expected to run for?
April 2018 to November 2020

Who is funding the study?
Investigator initiated and funded

Who is the main contact?
Mikhail Kalinin, ninilak@gmail.com

Contact information

Prof Dina Khasanova
Scientific

Interregional Clinical Diagnostic Center
12A Karbyshev St
Kazan
420101
Russian Federation

ORCID ID	0000-0002-8825-2346
Phone	+7 (843) 291 10 16
Email	dhasanova@mail.ru

Dr Mikhail Kalinin
Public

Interregional Clinical Diagnostic Center
12A Karbyshev St
Kazan
420101
Russian Federation

ORCID ID	0000-0002-3664-6888
Phone	+79172959770
Email	ninilak@gmail.com

Study information

Primary study design	Interventional
Study design	Prospective randomized active-control multicenter trial in parallel groups
Secondary study design	Randomised parallel trial
Study type	Participant information sheet
Scientific title	Cerebrolysin as an Early add-on to Reperfusion therapy: risk of hemorrhagic transformation after ischemic stroke (CEREHETIS). A prospective, randomized, multicenter pilot study
Study acronym	CEREHETIS
Study objectives	Cerebrolysin reduces risk of hemorrhagic transformation when introduced as early add-on to reperfusion therapy for ischemic stroke.
Ethics approval(s)	Approved 24/04/2018, Ethics Committee of the Interregional Clinical Diagnostic Center (12A, Karbyshev str., Kazan, 420101, Russian Federation; +7 (843) 291-10-16; icdc@icdc.ru), ref: protocol #81
Health condition(s) or problem(s) studied	Ischemic stroke
Intervention	Current interventions as of 25/11/2024: Participants will be randomized in a 1:2 ratio into either the case or control group using a computer-generated randomization process. • Control group: Participants will receive intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (alteplase, 0.9 mg/kg). • Case group: Participants will receive IVT with alteplase (0.9 mg/kg) in addition to 30 mL of Cerebrolysin diluted in 100 mL of normal saline, administered simultaneously via a separate intravenous cubital line over 20 minutes. Daily infusions of Cerebrolysin will continue for 14 consecutive days. Standard care, as per current clinical guidelines, will be permitted for both groups. Previous interventions: Randomization in a 1:2 ratio into case or control group by using a random number generating software. Сontrol group: Intravenous thrombolytic therapy (IV TLT) with recombinant tissue plasminogen activator (alteplase, 0.9 mg/kg). Сase group: IV TLT + at the same time Сerebrolysin 30 mL diluted in 100 mL of normal saline over 20 min via another IV cubital line. Then, infusions of Cerebrolysin daily for 14 consecutive days. The standard care is allowed for both groups.
Intervention type	Drug
Phase	Phase III
Drug / device / biological / vaccine name(s)	Cerebrolysin
Primary outcome measure(s)	Current primary outcome measure as of 25/11/2024: The rate of hemorrhagic transformation (both any and symptomatic) will be assessed using follow-up non-contrast brain computed tomography (CT) scans. CT scans will be performed 24 hours after IVT (visit 1), on day 7 (visit 2), day 14 (visit 3), and additionally if requested by the treating neurologist. Symptomatic intracranial hemorrhage will be defined according to the ECASS III criteria as any visible extravascular blood in the brain or cranium associated with clinical deterioration (an increase of ≥4 points on the NIH Stroke Scale [NIHSS]) or resulting in death. Previous primary outcome measure: Rate of hemorrhagic transformation (any and symptomatic) on any of follow-up non-contrast brain computed tomography (CT) scan. CT is performed 24 h after the IV TLT (visit 1), on day 7 (visit 2), 14 (visit 3) and if required by a treating neurologist. Symptomatic intracranial hemorrhage was defined according the ECASS III study as any apparently extravascular blood in the brain or within the cranium that is associated with clinical deterioration (an increase of ≥4 points on the NIHSS), or led to death.
Key secondary outcome measure(s)	Current secondary outcome measure as of 25/11/2024: 1. Functional outcome measured using the National Institutes of Health Stroke Scale (NIHSS) at 24 hours (visit 1), and on days 3 (visit 2) and 14 (visit 3) 2. Functional outcome measured using the modified Rankin Scale on day 90 (visit 4) 3. Permeability-surface area product measured using diffusion-tensor imaging (including fractional anisotropy, axial, radial, and mean diffusivity) and CT-perfusion imaging (measuring the ) at 24 hours after intravenous thrombolysis (DTI only) and on day 14 (DTI and CTP) 4. Adverse events measured using interviews during follow-up at 24 hours, days 3, and 14, along with the evaluation of vital signs (blood pressure, heart rate), standard biochemical panel, and complete blood count at admission and on day 14 Previous secondary outcome measure: 1. Functional outcome measured using National Institutes of Health Stroke Scale (NIHSS) score at (visits 1, 2, 3 and on day 90 (visit 4) 2. Functional outcome measured using modified Rankin scale score at day 14 and 90 3. Blood-brain barrier permeability measures: fractional anisotropy, axial and radial diffusivity, permeability-surface area product measured using axial diffusion-tensor imaging at 24 h after the IV TLT, on day 14 and brain CT perfusion on day 14 and 90 4. Adverse events are assessed by interview during the follow-up 5. Vital signs (blood pressure, heart rate), standard biochemical panel and complete blood count (blood test) are evaluated at admission and on day 14 6. C-reactive protein is measured by blood test at visit 1
Completion date	30/11/2020

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Sex	All
Target sample size at registration	263
Total final enrolment	341
Key inclusion criteria	Current participant inclusion criteria as of 25/11/2024: 1. Patients with a confirmed diagnosis of acute ischemic stroke (AIS) 2. Male or female participants 3. Age ≥18 years 4. Admission to one of the study sites within 4.5 hours of AIS onset 5. Indications for IVT Previous participant inclusion criteria: 1. Patients with confirmed diagnosis of acute ischemic stroke (AIS) 2. Male or female gender 3. Age ≥18 years 4. Admission to one of the sites within 4.5 h after the AIS onset 5. Indications for intravenous thrombolytic therapy
Key exclusion criteria	Current participant exclusion criteria as of 25/11/2024: 1. Contraindications for IVT 2. Contraindications for Cerebrolysin 3. Evidence of hemorrhagic transformation or intracranial hemorrhage on the screening CT scan 4. Any other concurrent life-threatening medical conditions Previous participant exclusion criteria: 1. Contraindications for intravenous thrombolytic therapy 2. Contraindications for Cerebrolysin 3. Signs of hemorrhagic transformation or intracranial hemorrhage on the screening CT scan 4. Any other concurrent life-threatening medical condition
Date of first enrolment	29/04/2018
Date of final enrolment	31/08/2020

Locations

Countries of recruitment

Russian Federation

Study participating centres

Interregional Clinical Diagnostic Center

12a Karbysheva str.
Kazan
420101
Russian Federation

Municipal Clinical Hospital No. 7 of Kazan

54, M. Chuykova str.
Kazan
420103
Russian Federation

Medical clinic of Kazan Federal University

1A, Chehova str.
Kazan
420043
Russian Federation

Perm Territorial Clinical Hospital

85, Pushkina str.
Perm
614045
Russian Federation

Emergency Medical Center of Naberezhnye Chelny

18, Naberezhnochelninskiy av.
Naberezhnye Chelny, Republic of Tatarstan
423803
Russian Federation

Leninogorsk District Hospital

20, Sadrieva str.
Leninogorsk, Republic of Tatarstan
423250
Russian Federation

Nizhnekamsk District Hospital

11, Ahtubinskaya str.
Nizhnekamsk, Republic of Tatarstan
423577
Russian Federation

Arsk District Hospital

32, Komsomolskaya str.
Arsk, Republic of Tatarstan
422000
Russian Federation

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request, Published as a supplement to the results publication
IPD sharing plan	The anonymised dataset generated and analysed during the current study is available upon reasonable request from the corresponding author, Dr. Mikhail Kalinin, ninilak@gmail.com. The raw data of the post hoc analysis have been published as a supplement to the results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	27/03/2023	28/03/2023	Yes	No
Results article		08/09/2023	11/09/2023	Yes	No
Abstract results	Results abstract European Stroke Organisation Conference 2021	03/09/2021	29/03/2023	No	No
Abstract results		30/11/2023	23/01/2024	No	No
Abstract results	Post hoc analysis results: abstract EP025/#2725 - 16th World Stroke Congress	26/10/2024	25/10/2024	No	No
Other publications	Post hoc analysis	05/01/2024	22/01/2024	Yes	No
Other publications	Post hoc analysis	21/03/2024	02/04/2024	Yes	No
Other publications		22/03/2025	24/03/2025	Yes	No
Other publications	Cerebrolysin with reperfusion therapy in ischemic stroke: a prospective analysis of multimodal brain imaging data from the CEREHETIS trial	25/06/2025	30/06/2025	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Preprint results		18/10/2024	21/10/2024	No	No
Protocol file	Russian language	30/04/2018	01/03/2021	No	No
Protocol file	English language	30/04/2018	28/03/2023	No	No
Statistical Analysis Plan		25/04/2024	20/11/2024	No	No

Additional files

ISRCTN87656744_PROTOCOL_30April2018.pdf: Russian language
ISRCTN87656744_PROTOCOL_[English]_30April2018.pdf: English language
ISRCTN87656744_Abstract_26Oct2024.pdf: Post hoc analysis results: abstract EP025/#2725 - 16th World Stroke Congress
ISRCTN87656744_SAP_25April2024.pdf: Statistical Analysis Plan

Editorial Notes

30/06/2025: Publication reference added.
24/03/2025: Publication reference added.
25/11/2024: The following changes were made:
1. The public title was changed from "Cerebrolysin to prevent intracranial bleeding after intravenous thrombolysis (blood clot) in patients with ischemic stroke".
2. The scientific title was changed from "Cerebrolysin as Early add-on to REperfusion therapy and risk of HEmorrhagic Transformation after Ischemic Stroke (CEREHETIS). A prospective randomized active-control multicenter pilot study".
3. The primary and secondary outcome measures were amended.
4. The participant inclusion and exclusion criteria were amended.
20/11/2024: SAP uploaded.
25/10/2024: Abstract added.
21/10/2024: Preprint added.
04/04/2024: Internal review.
02/04/2024: Publication reference added.
23/01/2024: Abstract, publication reference and IPD sharing plan added.
22/01/2024: Publication reference added.
11/09/2023: Publication reference added.
30/03/2023: A public contact was updated.
29/03/2023: Abstract added.
28/03/2023: The following changes have been made:
1. The public contact was added and the plain English summary was changed accordingly.
2. Uploaded protocol [English language] (not peer reviewed).
3. The study phase has been changed from phase IV to phase IIIb.
4. Publication reference added.
01/03/2021: Uploaded protocol version 1.0, 30 April 2018 (not peer reviewed).
11/02/2021: Trial’s existence confirmed by Local ethics board of Interregional Clinical Diagnostic Center (Russia).