STUDY PROTOCOL

published: 04 July 2022

doi: 10.3389/fneur.2022.910697

Efficacy of Cerebrolysin Treatment as

an Add-On Therapy to Mechanical
Thrombectomy in Patients With
Acute Ischemic Stroke Due to Large
Vessel Occlusion: Study Protocol for
a Prospective, Open Label,
Single-Center Study With 12 Months
Edited by:
of Follow-Up
Osama O. Zaidat,
Northeast Ohio Medical University, Jacek Staszewski 1*, Adam Stȩpień 1 , Renata Piusińska-Macoch 1 , Aleksander Dȩbiec 1 ,
United States Katarzyna Gniadek-Olejniczak 2 , Emilia Frankowska 3 , Artur Maliborski 3 , Zoltan Chadaide 4 ,
Reviewed by: David Balo 4 , Beata Król 4 , Rafael Namias 4 , George Harston 4 , Józef Mróz 2 and
Sergi Amaro, Piotr Piasecki 3
Hospital Clínic de Barcelona, Spain
1
Felix Ng, Clinic of Neurology, Military Institute of Medicine, Warsaw, Poland, 2 Neurorehabilitation Clinic, Military Institute of Medicine,
University of Melbourne, Australia Warsaw, Poland, 3 Department of Radiology, Military Institute of Medicine, Warsaw, Poland, 4 Brainomix Ltd., and Oxford
University Hospitals NHSFT, Oxford, United Kingdom
*Correspondence:
Jacek Staszewski
jstaszewski@wim.mil.pl This study is designed to determine the efficacy of Cerebrolysin treatment as an add-
on therapy to mechanical thrombectomy (MT) in reducing global disability in subjects
Specialty section:
This article was submitted to with acute ischemic stroke (AIS). We have planned a single center, prospective, open-
Endovascular and Interventional label, single-arm study with a 12-month follow-up of 50 patients with moderate to
Neurology,
severe AIS, with a small established infarct core and with good collateral circulation
a section of the journal
Frontiers in Neurology who achieve significant reperfusion following MT and who receive additional Cerebrolysin
Received: 01 April 2022 within 8 h of stroke onset compared to 50 historical controls treated with MT alone,
Accepted: 30 May 2022 matched for age, clinical severity, occlusion location, baseline perfusion lesion volume,
Published: 04 July 2022
onset to reperfusion time, and use of iv thrombolytic therapy. The primary outcome
Citation:
Staszewski J, Stȩpień A,
measure will be the overall proportion of subjects receiving Cerebrolysin compared to
Piusińska-Macoch R, Dȩbiec A, the control group experiencing a favorable functional outcome (by modified Rankin Scale
Gniadek-Olejniczak K, Frankowska E,
0–2) at 90 days, following stroke onset. The secondary objectives are to determine
Maliborski A, Chadaide Z, Balo D,
Król B, Namias R, Harston G, Mróz J the efficacy of Cerebrolysin as compared to the control group in reducing the risk of
and Piasecki P (2022) Efficacy of symptomatic secondary hemorrhagic transformation, improving neurological outcomes
Cerebrolysin Treatment as an Add-On
Therapy to Mechanical
(NIHSS 0–2 at day 7, day 30, and 90), reducing mortality rates (over the 90-day and
Thrombectomy in Patients With Acute 12 months study period), and improving: activities of daily living (by Barthel Index),
Ischemic Stroke Due to Large Vessel
health-related quality of life (EQ-5D-5L) assessed at day 30, 90, and at 12 months.
Occlusion: Study Protocol for a
Prospective, Open Label, The other measures of efficacy in the Cerebrolysin group will include: assessment of
Single-Center Study With 12 Months final stroke volume and penumbral salvage (measured by CT/CTP at 30 days) and its
of Follow-Up.
Front. Neurol. 13:910697.
change compared to baseline volume, changes over time in language function (by the
doi: 10.3389/fneur.2022.910697 15-item Boston Naming Test), hemispatial neglect (by line bisection test), global cognitive

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Staszewski et al. Cerebrolysin Add-On Treatment to Thrombectomy

function (by The Montreal Cognitive Assessment), and depression (by Hamilton
Depression Rating Scale) between day 30 and day 90 assessments). The patients will
receive 30 ml of Cerebrolysin within 8 h of AIS stroke onset and continue treatment once
daily until day 21 (first cycle) and they will receive a second cycle of treatment (30 ml/d
for 21 days given in the Outpatient Department or Neurorehabilitation Clinic) from day 69
to 90.
Keywords: Cerebrolysin, add-on therapy, mechanical thrombectomy, ischemic stroke, cytoprotection

INTRODUCTION translate into lower long-term mortality and disability (with

about 31–36% of functionally disabled patients 5 years post-
The recent endovascular stroke trials have established a new stroke), but these group-level data by no means guarantee
paradigm for acute ischemic stroke (AIS) treatment showing maintenance of 3-month positive outcome for individual patients
that mechanical thrombectomy (MT) within 6 h of stroke due to (9). Several critical factors operate in the post-stroke period that
large vessel occlusion (LVO) significantly reduces the mortality can influence long-term recovery of the patient, and the benefits
rate and improves clinical outcomes (1). These positive results depend on continuing and optimizing stroke prevention, access
were not only driven by technical advances and improved to rehabilitation, and post-stroke depression care.
endovascular devices, but also by a refinement of patient selection The concepts of cytoprotection and neurorecovery have been
criteria, including the use of perfusion and collaterals status researched in many preclinical and clinical settings in acute or
(2). Perfusion imaging can be used in late-window patients chronic stroke in the past decades. Despite promising experience
with LVO presenting 6–24 h after symptom onset or with with different agents, suggesting that they can impede the
unknown stroke onset in select patients with a small ischemic evolution of penumbra into core, reduce reperfusion injury,
core and a large penumbral zone, which is a predictor of good improve tissue reperfusion, brain plasticity, or neurogenesis,
neurologic outcome after recanalization (3). The assessment these strategies have not been recommended in humans so
of collateral flow may also be necessary in the extended far (10). Number of reasons could explain this outcome
window to distinguish ischemia with fast or slow progression to e.g., lack of persistent recanalization or reperfusion, too late
irreversibility. Advanced imaging is currently not recommended intervention, suboptimal dosage, single mechanisms of action
to select patients presenting from 0 to 6 h from the time last targeting only one mechanism in ischemic cascade, or one type
known well; however it may help predict the early outcome of of cells in neurovascular unit (NVU), mismatch between animals
MT in individual patients, e.g., higher collateral grades have been and humans, and/or unrobust methodological approaches that
associated with better recanalization rates, while patients with resulted in inconsistent evidence (11, 12). Therefore, the
poor collaterals tend to have worse outcome even with complete focus of modern stroke treatment should be shifted from a
recanalization of parent occlusion (4). neuroprotection to neurovascular protection approach because
Despite these advances, the rates of functional independence elements of NVU show differential vulnerability evolving over
at 3 months following MT performed in both the early and differing time scales and their roles are crucial in blood-
late time window, in clinical trials, or in clinical practice brain-barrier (BBB) regulation, cell preservation, inflammatory
are far from satisfactory (14–58%) compared with the high immune response during or after AIS (13, 14).
rates of recanalization (60–90%) (5, 6). Efficacy of MT is It can be anticipated that cytoprotection in patients who
related to multiple reasons e.g., time from stroke onset achieve early successful recanalization may promote reperfusion,
to reperfusion (OTR), secondary intracerebral hemorrhages protect or reduce the consequences of reperfusion damage,
(ICH) due to reperfusion injury, and the lack of successful and improve early outcome (15, 16). Additionally, effective
recanalization or reflow. The mechanism underlying no-reflow management should target enhancing collateral circulation
phenomenon has not been fully established, but there is now and preventing the no-reflow phenomena and hemorrhagic
class II evidence of no-reflow in human stroke (7). However, transformation after AIS. Recent results of ESCAPE-NA1 study
this phenomenon is probably independent of MT technique, on nerinetide, a novel neuroprotection agent which promotes
can persist despite proximal recanalization, and results from cell survival and disrupts toxic cell signals following ischemia,
altered microvascular circulation, proinflammatory state, and revealed that early treatment in patients without large infarct core
thrombosis, and represents a potential therapeutic target (8). and with effective collateral circulation undergoing reperfusion
Another important aspect that may result in increased morbidity therapy was feasible (17). Although the results showed no
is related to periprocedural complications of MT and include significant differences between the nerinetide and the placebo
arterial wall damage and dissections, ICH, distal embolism, groups, a significant positive effect of nerinetide (improved
and vasospasm. Beside of early outcomes, MT also results in functional outcome, reduced mortality, decreased infarction
favorable outcomes at long-term follow-up compared to standard volumes) was observed in patients not receiving bridging
medical treatment alone. However, prospective follow-up data recombinant tissue plasminogen activator (r-tPA). These findings
from MT trials indicate that 3-month MT benefits will likely suggested a probable drug–drug interaction and nerinetide as an

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Staszewski et al. Cerebrolysin Add-On Treatment to Thrombectomy

add-on therapy to MT is currently being investigated in another (mRS 0-3) at month 12 in the Cerebrolysin group compared
randomized clinical trial (RCT) (18). with controls (respectively, 70 vs. 48% of the subjects; p =
Motor rehabilitation in acute and post-acute stroke is a 0.1) and a statistically significant reduction of hemorrhagic
standard of care because it allows for functional improvements; transformation rates in patients receiving Cerebrolysin (13 vs.
however, it may lack the potential of full recovery for patients 38%, p < 0.05) (32). No safety issues were found. In a large (n =
with large infarcts and there remain significant concerns for 1070) randomized, placebo-controlled study in AIS patients not
long-standing disability and neurological deficits in these patients receiving reperfusion therapy, there was no significant difference
(19). Although stroke neurorestorative strategies combined in confirmatory end-point (combined global directional test
with rehabilitation may improve the long-term neurological of mRS, Barthel Index [BI], NIHSS at 90 days) between the
outcome and quality of life, however clarification of their Cerebrolysin (30 ml/daily for 10 days, started within 12 h after
roles in mediating post-stroke neurorecovery warrants further stroke onset) and control groups; however the subjects did not
investigations (20, 21). Preclinical stroke models demonstrate receive a similar level of rehabilitation care (33). A post hoc
positive responses to different cytoprotective agents with analysis showed a trend in favor of Cerebrolysin in patients
improved cognitive and motor function, therefore, as stated in with severe stroke (NIHSS >12) with a significant difference in
the Action Plan for Stroke in Europe 2018–2030, continuing favorable NIHSS change from baseline (OR 1.27; CI lower bound,
to bridge the translational gap between basic and clinical 0.97, p = 0.04). In this subgroup, the cumulative mortality by
stroke research is vital for the development of effective 90 days was 20.2% in the placebo and 10.5% in the Cerebrolysin
treatment (22, 23). group (HR 1.9661; CI lower bound, 1.0013, p = 0.02). The
Cerebrolysin is a neurotrophic peptidergic preparation results of several other studies also showed positive treatment
with broad pharmacological properties (24). It displays effects in the severely affected ischemic stroke population and
multifactorial cytoprotective properties, improves cellular in some patients with dementia and traumatic brain injury
survival, inhibits glutamate excitotoxicity, free radical formation, (34–37). Meta-analysis of 9 RCT and two phase-IV studies have
and proinflammatory mediators (e.g., TNF-α, IL-1β, IL-6, and recently highlighted the efficacy of the multimodal strategy
NF-κB) (25). It mimics the action of endogenous neurotrophic combining Cerebrolysin with standardized rehabilitation
factors in brain protection and recovery (26). Cerebrolysin therapy for motor and neurological function recovery following
has been the subject of many animal and in vitro studies, the AIS (38, 39). Also, the latest safety meta-analysis comprising
majority of which have yielded encouraging results in terms of a total of 12 randomized double-blind trials showed a very
pleiotropic and multimodal activity (27). However, only a few good safety profile for patients treated with Cerebrolysin (40).
preclinical and clinical studies tested the efficacy of Cerebrolysin Based on the abovementioned results, Cerebrolysin has been
as an add-on therapy to MT and/or r-tPA in AIS so far. Recent recommended by the European Academy of Neurology and
in vitro study showed that Cerebrolysin protects BBB and European Federation of Neurorehabilitation Societies and in
has a therapeutic effect on r-tPA and fibrin-impaired cerebral other practice guidelines as a pharmacological intervention
endothelial cell permeability by reducing proinflammatory and for ischemic stroke, for both the acute- and post-stroke
procoagulation proteins and by elevating tight junction proteins, rehabilitation (41–45).
therefore reducing hemorrhagic transformation, a major safety We have hypothesized that adding Cerebrolysin ≤8 h
concern especially for patients at the end of r-tPA time-window following stroke onset in selected patients based on the
(28). In the rat transient middle cerebral artery occlusion model, clinical and radiological criteria (moderate to severe stroke,
administration of Cerebrolysin at 3 h post-ischemia reduced baseline small ischemic core, good collateral status, significant
infarct volume and promoted long-term functional recovery by recanalization following MT) may increase the effectiveness
reducing neuroinflammation via the activation of CREB/PGC-1α of MT by initiating cytoprotective effects and preventing
pathway and by inhibiting free radical formation (29, 30). In the reperfusion injury and delayed cell death. The multimodal
CERE-LYSE study, the combination of Cerebrolysin (30 mL/day, treatment concept of Cerebrolysin combined with MT in AIS
for 10 days) with r-tPA in humans was safe although it did not and with rehabilitation in post-acute period might also promote
significantly improve functional outcome in the modified Rankin and maintain the most effective recovery from stroke. We
Scale (mRS) at 3 months, but in the National Institutes of Health have chosen Cerebrolysin because of its known pharmacological
Stroke Scale (NIHSS) responder analysis (secondary outcome properties, BBB penetration, good safety profile, parenteral
measure) significantly more patients had an improvement of 6 or administration, promising preclinical data, and results of
more points after two-, five-, 10, and 30 days in the Cerebrolysin RCTs. These factors, together with a multiple-action, multiple-
group (31). This advantage was most pronounced in the most target approach for ischemic stroke could result in a higher
severely affected patients (NIHSS 15-25). In a recently published likelihood of success in patients with stroke in cerebroprotective
pilot trial, 44 severe stroke patients (NIHSS>8) were randomized studies according to the recommendations of STAIR XI (Stroke
to receive Cerebrolysin (30 ml/day, for 14–21 days, n = 23) or Treatment Academic Industry Roundtable) conferences (46).
standard therapy (n = 21) following futile reperfusion therapy (r- Therefore, we aimed to evaluate the efficacy and safety of
tPA and/or MT). There was no statistically significant difference Cerebrolysin treatment as an add-on therapy to MT in patients
in the distribution of clinical outcomes between groups at 90 with AIS in the early recovery phase in AIS (90 days) and
days. There was, however, a trend for a more favorable outcome long-term follow-up (12 months).

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Staszewski et al. Cerebrolysin Add-On Treatment to Thrombectomy

METHODS AND DESIGN followed by 50 ml of saline to assess the extension of the core
and the ischemic penumbra, which is defined as the mismatch
Study Design and Setting between “mean transit time” and “cerebral blood volume” maps.
The study protocol was developed in accordance with the Collaterals are measured with a multiphase CTA covering the first
Standard Protocol Items: Recommendations for Interventional phase from the carina until the vertex and the second and third
Trials (SPIRIT) Statement and the trial was registered on phases from the foramen magnum to the vertex. Acquisition is
ClinicalTrials.gov on May 27, 2021, with reference number triggered using a bolus tracking (100 HU) in the aortic arch
NCT04904341 (47). This academic investigator-initiated study is after intravenous injection contrast, and then the second and
managed by a group of collaborative clinical researchers and has third phases started 4 s after the previous phase. Collaterals
been planned to investigate health research questions relevant are measured by comparing backfilling arteries beyond the
to everyday practice (48, 49). Our main goal was to determine occluded artery to similar arteries in the opposite unaffected
the efficacy and safety of Cerebrolysin treatment as an add-on hemisphere in three different phases. Intracranial hemorrhages
therapy to MT in reducing global disability in subjects with AIS. are diagnosed according to the control NCCT scan at 24 h or
We have planned a single center, prospective, open-label, later in case of neurologic deterioration (an increase of NIHSS
single-arm study with a 12-month follow-up of consecutive score ≥4 points from baseline and parenchymal hematoma
50 patients referred to the reference stroke center (Military type 2 within 36 h of MT). Asymptomatic and symptomatic
Institute of Medicine, Warsaw, Poland) due to moderate to hemorrhagic transformations and the presence of brain edema
severe AIS, with a small established infarct core, with good with midline shift at 24 h NCCT will also be assessed in study
collateral circulation, significant recanalization following MT, groups because they are a complication of reperfusion therapy,
and who received additional Cerebrolysin (Cerebrolysin group) and currently they are regarded as markers of BBB disruption,
compared to 50 historical controls treated with MT alone. The which may be protected by Cerebrolysin (28, 51, 52). Midline
treatment with Cerebrolysin will begin as soon as possible after shift defined as any deviation of midline structures (e.g. the
MT and no later than 8 h following stroke onset. Clinical and septum pellucidum) will be assessed as a dichotomous variable
radiological evaluation will be performed by blinded assessors. (present or absent).
The participants for the historical cohort (control group)
will be selected retrospectively from a larger and ongoing,
prospectively maintained investigator database from patients Post-processing Software
who were previously treated in the study center. Database Automated processing of NCCT, CTA, and CTP will be
contains imaging, demographic, and outcome data of patients performed using the latest CE-marked version of e-Stroke
treated with MT by the same team of experienced 3 operators software (Brainomix, Oxford, UK) at baseline, and follow-up
since January 2018. Control patients will be matched one-to-one imaging will be processed using algorithms in development
to patients receiving Cerebrolysin based on the occlusion location by Brainomix. This will provide objective and consistent
(ICA or MCA-M1 or MCA-M2) and then further matched for quantification of imaging biomarkers to ensure robust matching
age (±5 years), baseline mRS (0–2 or 3–5), TICI score (2b or to historical controls, as well as the evaluation of imaging
3), baseline perfusion lesion volume, onset to reperfusion time, endpoints, and will help to reduce the risk of bias when analyzing
and the use of bridging r-tPA using probabilistic matching. If data. NCCT, CTA and CTP will be processed using e-ASPECTS,
no matched control is identified, we will exclude that case from e-CTA, and e-CTP modules within e-Stroke respectively (53–
the primary outcome analysis. Historical controls will receive a 58). e-Stroke imaging software is intended to be used as a
similar standard of care with the same diagnostic, endovascular, decision support tool and will be used to facilitate adjudication of
and perioperative management as Cerebrolysin group and patient inclusion criteria for prospective patients and historical
will be excluded if they had an incomplete medical record. controls, where the results are intended for this purpose. MCA
All the patients will fulfill the same clinical and radiological vascular enhancement distal to occlusion is rated by using CTA
inclusion/exclusion criteria. collateral score (CTA-CS, also known as Tan score) (59, 60).
On a scale of 0 to 3, higher grades are associated with a
Neuroimaging Protocol better collateral flow (0: absent collateral supply to the occluded
According to our neuroradiological acute stroke protocol, all MCA territory; 1: collateral supply filling ≤50% but >0% of
patients qualified for MT receive a noncontrast CT (NCCT) the occluded MCA territory; 2: collateral supply filling >50%
to rule out hemorrhage, CT angiography (CTA), and perfusion but <100% of the occluded MCA territory; 3: 100% collateral
CT (CTP) to determine large-vessel occlusion and perfusion supply of the occluded MCA territory). The imaging values that
status. Follow-up NCCT are acquired at 24 h (all patients) and 30 will be derived for each patient using e-Stroke are presented in
days (Cerebrolysin group only). NCCT images will be assessed Table 1.
by assessors who are unaware of clinical data. All CT scans Analysis of baseline imaging, including patient selection and
are obtained with the patient in a supine position by using a analysis of historical controls is delivered using a deployed
64-slice GE CT scanner. Early and late ischemic signs will be installation of the Brainomix e-Stroke software. Analysis
determined using the Alberta Stroke Program Early CT Score involving follow-up imaging will be undertaken by the Brainomix
(ASPECTS) scale on baseline and follow-up NCCT (50). CTP is team in the imaging lab and will be performed at the end of the
performed after the injection of 50 ml of contrast mean 5 ml/s study to ensure consistent biomarkers are derived.

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Staszewski et al. Cerebrolysin Add-On Treatment to Thrombectomy

TABLE 1 | Summary of imaging values assessed during the study. artery ischemic territory (e.g., in two major divisions of the
MCA and their territories); 3-complete antegrade reperfusion
Baseline Follow-up
of the previously occluded target artery ischemic territory, with
NCCT NCCT at 24 h absence of visualized occlusion in all distal branches). Successful
e-ASPECTS Final infarct volume (FIV) reperfusion is defined by mTICI score ≥2b.
e-ASPECTS acute ischemic volume Hemorrhage volume (if any)
(AIV)
Participants
Thrombus length on NCCT (if Midline shift
Eligibility criteria (for the active arm and historical control
identified) group) are listed in Table 2.
CTA
Treatment
CTA collateral score (CTA-CS) NCCT at 30 day
CTA collateral vessel density Final infarct volume
Cerebrolysin Treatment (Cerebrolysin Group)
The first Cerebrolysin infusion (30 ml mixed with 250 ml of
Location of large vessel occlusion
(proximal vs. distal) saline) is intended to be initiated as soon as possible after
CTP successful recanalization is achieved and within 8 h of AIS
Ischemic core volume (estimate,
stroke onset. Cerebrolysin treatment will be continued (30 ml/d)
relative CBF <30%) once daily until day 21 (first cycle). The patients will receive
Hypoperfusion volume (estimate, a second cycle of treatment (30 ml/d for 21 days given in the
Tmax >6 s) Outpatient Department or Neurorehabilitation Clinic) from day
Mismatch ratio 69–90 (± 3 days).
Mismatch volume
Alternative estimate of ischaemic core All Patients (Cerebrolysin Group and Historical Controls)
volume (defined using rCBF threshold All patients will receive care in the neurointensive care unit and
of <38%) stroke unit and they will receive a standardized stroke treatment
Hypoperfusion intensity ratio and diagnosis according to the national and international
guidelines. The patients will receive iv rt-PA in a 4.5-h window
e-ASPECTS, Alberta Stroke Program Early CT Score; NCCT, non contrast CT; CTA, CT
angiography; CBF, cerebral blood flow; CTP, perfusion CT. if they meet the accepted criteria. All patients will be assessed
for their rehabilitation needs and they will receive rehabilitation
(physiotherapy, occupational, and speech therapy) at the Stroke
Unit following day 1 until discharge and in Neurorehabilitation
Thrombectomy Protocol Clinic with a minimum of 45 min of physiotherapy 5 days a
Patients will be qualified for MT according to the American
week and according to local standards (the average rehabilitation
Heart Association/American Stroke Association (AHA/ASA)
duration is 3 months post stroke, with the maximum 4 months).
and European Stroke Organization—European Society of
Minimally Invasive Neurological Therapy (ESO-ESMINT) Neurological and Neuropsychological Assessment
guidelines (61, 62). Thrombectomy will be performed with Neurological assessments will be based on a routine evaluation
any FDA-approved thrombectomy device (stent retriever or scheme performed in both Cerebrolysin and control patients by
aspiration thrombectomy or its combination to achieve safe a senior neurologist before and following MT, at 24 h post MT,
recanalization) at the discretion of the neurointerventionalist at hospital discharge (by mRS and NIHSS), and at 30, 90 days,
(63, 64). The mechanical thrombectomy procedures were and 12 months (by mRS, BI, and EQ-5D-5L). The 12-month
done from groin access by operators familiar with assessed assessments will be performed through telephone questionnaires
stent-retrievers and who had performed at least 50 endovascular which have been shown to have good validity and reliability to
stroke treatment procedures. MT was performed under local on-site assessment. Assessments of language function (by the 15-
or general anesthesia at the discretion of the operator. Eligible item Boston Naming Test), hemispatial neglect (by line bisection
patients will be qualified for bridging r-tPA (0.9 mg/kg of rtPA) test), global cognitive function (by The Montreal Cognitive
according to current guidelines (65). Angiographic studies from Assessment), and depression (by Hamilton Depression Rating
the endovascular procedure will be assessed for recanalization Scale) will be performed at 30 and 90 days by experienced
by two independent raters, who will be unaware of any other neuropsychologist in only Cerebrolysin group as these tests are
imaging and clinical data, and a consensus will be reached not routinely performed in control patients. The assessors will
in cases of disagreement. The modified treatment in cerebral be blinded for the results of the MT. Age, sex, side of lesion,
infarction (mTICI score) will be used to measure the reperfusion stroke risk factors, time from onset of symptoms to hospital, to
grade post thrombectomy (0- no reperfusion; 1-antegrade CT, to needle, to groin (femoral artery puncture), and to end of
reperfusion past the initial occlusion, but limited distal branch the procedure, and adverse events will be collected throughout
filling with little or slow distal reperfusion; 2a- antegrade the study and analyzed with regards to outcome measures.
reperfusion of less than half of the occluded target artery
previously ischemic territory (e.g., in one major division of the Outcome Measures
middle cerebral artery (MCA) and its territory); 2b- antegrade The primary outcome measure will be the overall proportion of
reperfusion of more than half of the previously occluded target subjects receiving Cerebrolysin compared to the control group

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TABLE 2 | Study eligibility criteria.

Clinical inclusion criteria Clinical exclusion criteria Neuroimaging inclusion criteria Neuroimaging exclusion criteria

Age 18–80 years Other than AIS serious, advanced, or CT ASPECTS ≥6 prior to MT Acute symptomatic arterial occlusions in
terminal illness or life expectancy ≤ 6 more than one vascular territory***
months
Signs and symptoms consistent Pre-existing medical, neurological or ICA or MCA-M1 or –M2 occlusion (carotid Evidence of intracranial tumor (except
with the diagnosis of an anterior psychiatric disease that would confound occlusions can be cervical or intracranial; small meningioma), acute intracranial
circulation AIS the neurological or functional evaluations ** without tandem MCA lesions) by CTA hemorrhage, neoplasm, or arteriovenous
malformation
Stroke onset to groin <6 h* Pregnancy or lactation Target mismatch profile on CTP (ischemic Significant mass effect with midline shift
core volume <70 ml, mismatch ratio >1.8
and mismatch volume > 15 ml)
mRS ≤1 prior to qualifying stroke Known allergy to iodine that precludes an Moderate-to-good collateral status on Treatment with another investigational
(functionally independent for all endovascular procedure multiphase CTA (>50% MCA territory) drug within the last 30 days that may
ADLs) interfere with this study’s medications
moderate to severe stroke: Acute or chronic renal failure with Effective reperfusion mTICI ≥2b following Patients with nondiagnostic NCCT or CTP
NIHSS score of ≥5 with calculated creatinine clearance <30 MT maps
presence of any cortical signs ml/min/1.73 m2 or unable to undergo a
(gaze, visual fields, language, or contrast brain perfusion scan with CT
neglect)
Initiation of treatment with Inability to tolerate or comply with study
Cerebrolysin <8 h following procedures
stroke onset (Cerebrolysin
group)
Patient has signed the Informed Any condition that would represent a
Consent form contraindication for Cerebrolysin
administration (e.g., allergy)

* Stroke onset is defined as the time the patient was last known to be at their neurologic baseline (wake-up strokes are eligible if they meet the above time limits).
** E.g., Alzheimer’s disease, vascular dementia, Parkinson’s disease, demyelinating disease, encephalopathy of any cause,a history of significant alcohol or drug abuse.
*** E.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion.

experiencing a favorable functional outcome (mRS 0–2) at 90 according to their clinical relevance to stroke outcome. In the
days following stroke onset. case of multiple matches, controls will be selected randomly.
The secondary objectives are to determine the efficacy of The expected proportions of functional independence are 40
Cerebrolysin as compared to the control group in reducing the and 75% in the historical controls and Cerebrolysin groups,
risk of symptomatic and asymptomatic secondary hemorrhagic respectively. Such assumptions are based on the results of MT
transformation, brain edema with midline shift, improving trials that used CTP for patient selection (ESCAPE, SWIFT
neurological outcome (NIHSS 0-2 and mRS at day 7, day 30, and PRIME, and substudy of MR CLEAN) (66–68).
90); reducing mortality rates (over the 90-day and 12 months Based on the estimated effect size of 35%, a total of 100 patients
study period); and improving: activities of daily living (by BI), will be required to test the null hypothesis with an α value of
health-related quality of life (as measured by the EQ-5D-5L) 0.05 and a power of 0.8. The Shapiro–Wilk test will be used
assessed at day 30, 90, and 12 months. Imaging endpoints to assess the normality of the variables. Continuous variables
will include (at 24 h): final infarct volume; infarct growth will be reported as mean±SD if normally distributed or median
(FIV – AIV); infarct growth-CTP (FIV – rCBF<30% volume); (interquartile range) if nonparametric. Categorical variables will
and penumbral salvage (1- [Infarct growth-CTP / mismatch be reported as proportions. Between groups, comparisons for
volume]). The other measures of efficacy in the Cerebrolysin continuous/ordinal variables will be made with Student t-test,
group will include: changes over time between day 30 and day Mann–Whitney U-test, ANOVA, paired t-test, or Wilcoxon rank
90 assessments in language function (by the 15-item Boston sum test, as appropriate. Categorical variables will be compared
Naming Test), hemispatial neglect (by line bisection test), global by χ2 test, Fisher exact test, or McNemar test for discordant pairs,
cognitive function (by The Montreal Cognitive Assessment) and as appropriate. The overall distribution of mRS will be compared
depression (by Hamilton Depression Rating Scale). between groups (shift in disability levels) using the van Elteren
test or Wilcoxon signed-rank test to account for the matching.
Statistical Analysis Binary logistic regression analysis will be performed to identify
A matched case-control design will be implemented to address the predictive factors for functional outcomes. Changes over
the objective of this study. Matching will be blinded to the time in neuropsychological variables in the Cerebrolysin group
outcome and will be performed with the use of SPSS 22 algorithm will be assessed by paired t-test. Variables with P < 0.1 from
based on prespecified baseline measures, which were selected the univariate analysis will be included for multivariate logistic

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Staszewski et al. Cerebrolysin Add-On Treatment to Thrombectomy

TABLE 3 | Study flow and eligibility criteria.

Baseline 1–21 day 7 day 30 day 69–89 day 90 day 12 months

Cerebrolysin group
Eligibility criteria x
Informed consent x
Cerebrolysin infusion x x
mRS x x x x x
NIHSS x x x x
BI x x x
EQ-5D-5L x x x
Neuropsychological assessment* x x
Control CT, CTP 24 h post MT** x
Neurorehabilitation x x x x
Historical control group
mRS x x x x x
NIHSS x x x x
BI x x x
EQ-5D-5L x x x
Control CT 24 h post MT**
Neurorehabilitation x x x x

* The 15-item Boston Naming Test, line bisection test, the Montreal Cognitive Assessment, Hamilton Depression Rating Scale.
** NCCT.

regression models. A two-sided P < 0.05 will be considered to be Limitations of the Study
statistically significant. Lack of randomization is the main limitation of the present
research. We acknowledge that the studied group is small, and
Study Flow and Timelines a historical control group potentially may introduce multiple
The study flow is summarized in Table 3. All patient biases compared to a concurrent control. However, as it is
identification data will be scrambled to ensure confidentiality. a proof-of-concept study, we believe these biases may be
Ethics approval has been received from the Institution Review minimized and become acceptable by careful choice of controls
Board of the Wojskowy Instytut Medyczny w Warszawie, and fulfilling the same selection criteria, having similar prognostic
all patients will have to give informed written consent for the factors, and subjected to the same procedures from stroke
participation in the study. This study will be conducted in onset to 12 months of follow-up (70). Adjustments for well-
accordance with the Declaration of Helsinki. The targeted end known prognostic factors and simple endpoints used in this
date for recruitment is December 2022. study will also help to reduce the complexity and subjectivity of
the assessment (71). We decided to use the historical controls
because we have a recent, large (containing more than 300
DISCUSSION records), broad-based local dataset which we are obliged to
The study will investigate whether combining cytoprotection conduct and provide to the National Health Found, which
with reperfusion therapy may modulate stroke recovery with contains high quantity and quality clinical, neuropsychological,
a view to describing the optimal treatment window (acute and radiological data of patients treated with MT and followed-
and postacute phase of stroke). We will evaluate clinical and up for 12 months (72). There are also some advantages of using
imaging markers for potential use in future clinical trials on carefully chosen historical data, such as costs and enrolment time
cytoprotection. The results of this pilot study will not only shed can be cut dramatically and more resources can be allocated
light on the potential efficacy of Cerebrolysin as an adjunct to the experimental group (73). We also believe the results of
treatment for AIS but will be essential in shaping a further the current study will supplement the current knowledge about
double-blind RCT on Cerebrolysin or will supplement ongoing neuroprotection use in AIS and will enable us to conduct a
larger-scale projects on other neuroprotection agents in both further trial with the use of a PROBE design to avoid part of
acute and postacute stroke patients. Although Cerebrolysin is these biases.
used clinically in over 50 European and Asian countries, it has The therapeutic time delay over 6 h may weaken the efficacy
not been approved for use in the USA or Australia. Therefore, of Cerebrolysin on the neurologic functional recovery; however
more robust clinical trials with a greater number of participants based on the current practice in our center, we expect that at least
are needed to clarify the clinical application of Cerebrolysin as a 50% of subjects are to receive Cerebrolysin in <6 h post-stroke
monotherapy and in combination with other therapeutics (69). onset. Penumbra imaging could select patients with better rates

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Staszewski et al. Cerebrolysin Add-On Treatment to Thrombectomy

of spontaneous recovery because of collateral circulation, thereby of 12 months, which will enable us to evaluate both short-
reducing the power to detect a benefit of neuroprotection, but and long-term outcomes. The study methodology minimizes
on the other hand, the lack of reperfusion reduces substantially heterogeneity through imaging-based selection and ensures
the power of a stand-alone neuroprotection trial to detect that the neuroprotective effect is amplified through reperfusion.
treatment effects. Also, the addition of advanced imaging to We believe that previously tested cytoprotective drugs warrant
identify a “responder” population leads to a reduced sample re-evaluation since they were tested in studies where LVO
size (74). Another limitation is that the study population is recanalization was rarely achieved. Further investigation of
limited to patients recruited from one center, which restrains the clinical effects of Cerebrolysin as an add-on therapy to
the generalizability of the results to other populations. There is reperfusion therapy is therefore reasonable because there is
also a lack of robust imaging endpoints to study the presumed an unmet need for neuroprotective or neurotrophic drugs
biological effects of Cerebrolysin; however we will evaluate with good efficacy in neurological functional recovery in
hemorrhagic transformation and cerebral edema by midline shift, AIS patients.
both of which are associated with BBB permeability. For these
limitations, further studies are therefore warranted. ETHICS STATEMENT
Strengths and Relevance The studies involving human participants were reviewed and
The presented study has several advantages. First, there approved by Institution Review Board of the Wojskowy
is a lack of clinical trials on cytoprotective agents in Instytut Medyczny w Warszawie (No. 53/WIM/2020). The
combination with reperfusion therapy in AIS. Preliminary patients/participants provided their written informed consent to
results from different studies indicate a high potential for participate in this study.
some neuroprotective treatments in addition to reperfusion;
however more data is needed (75). Second, Cerebrolysin has AUTHOR CONTRIBUTIONS
been regarded as an ideal agent for functional recovery after
AIS because of its multiple attributes including cytoprotective JS, PP, AS, and AM are on the Scientific Committee for the
properties and neurotrophic activity. Although MT and current project. All authors were involved in the design of the
Cerebrolysin treatment can be beneficial in patients with protocol, revised the draft, and approved the final manuscript.
large ischemic core, for the purpose of the current study
and to minimize subject heterogeneity, we have decided FUNDING
to include patients based on clinical and neuroradiological
criteria and with criteria that are validated by other trials on The study was granted by the internal scientific grant by the
MT. Importantly, we have planned a long-term follow-up Wojskowy Instytut Medyczny w Warszawie (No. 00589).

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Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the Conflict of Interest: ZC, DB, BK, RN, and GH were employed by Brainomix Ltd.
American Heart Association/American Stroke Association. Stroke. (2019)
50:e344–418. doi: 10.1161/STR.0000000000000211 The remaining authors declare that the research was conducted in the absence of
62. Turc G, Bhogal P, Fischer U, Khatri P, Lobotesis K, Mazighi M, et al. any commercial or financial relationships that could be construed as a potential
European Stroke Organisation (ESO) - European Society for Minimally conflict of interest.
Invasive Neurological Therapy (ESMINT) Guidelines on Mechanical
Thrombectomy in Acute Ischemic Stroke. J Neurointerv Surg. (2019) 11:535– Publisher’s Note: All claims expressed in this article are solely those of the authors
538. doi: 10.1136/neurintsurg-2018-014569 and do not necessarily represent those of their affiliated organizations, or those of
63. Mokin M, Ansari SA, McTaggart RA, Bulsara KR, Goyal M, Chen M, et the publisher, the editors and the reviewers. Any product that may be evaluated in
al. Society of NeuroInterventional Surgery. Indications for thrombectomy in this article, or claim that may be made by its manufacturer, is not guaranteed or
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Frontiers in Neurology | www.frontiersin.org 10 July 2022 | Volume 13 | Article 910697