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 of Follow-Up

Abstract

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 with acute ischemic stroke (AIS). We have planned a single center, prospective, open-label, single-arm study with a 12-month follow-up of 50 patients with moderate to severe AIS, with a small established infarct core and with good collateral circulation who achieve significant reperfusion following MT and who receive additional Cerebrolysin within 8 h of stroke onset compared to 50 historical controls treated with MT alone, matched for age, clinical severity, occlusion location, baseline perfusion lesion volume, onset to reperfusion time, and use of iv thrombolytic therapy. The primary outcome measure will be the overall proportion of subjects receiving Cerebrolysin compared to the control group experiencing a favorable functional outcome (by modified Rankin Scale 0–2) at 90 days, following stroke onset. The secondary objectives are to determine the efficacy of Cerebrolysin as compared to the control group in reducing the risk of symptomatic secondary hemorrhagic transformation, improving neurological outcomes (NIHSS 0–2 at day 7, day 30, and 90), reducing mortality rates (over the 90-day and 12 months study period), and improving: activities of daily living (by Barthel Index), health-related quality of life (EQ-5D-5L) assessed at day 30, 90, and at 12 months. The other measures of efficacy in the Cerebrolysin group will include: assessment of final stroke volume and penumbral salvage (measured by CT/CTP at 30 days) and its change compared to baseline volume, changes over time in language function (by the 15-item Boston Naming Test), hemispatial neglect (by line bisection test), global cognitive 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.

Cerebrolysin as an Early Add-on to Reperfusion Therapy: Risk of Hemorrhagic Transformation after Ischemic Stroke (CEREHETIS), a prospective, randomized, multicenter pilot study

“…Although their Cerebrolysin course was initiated after rtPA, our findings have not contradicted their results. Another ongoing clinical trial, the efficacy of Cerebrolysin treatment as an add-on therapy to mechanical thrombectomy in patients with AIS due to large vessel occlusion, has set the rate of symptomatic HT as a secondary endpoint [ 24 ].…”

Unequal Efficacy of Different Infarct Location in Predicting Futile Recanalization of Patients With Acute Ischemic Stroke

“…For an ASPECTS region of early ischemic change, 1 point was subtracted, which was defined as the presence of hypoattenuation and/or loss of gray matter-white matter differentiation, with or without cortical swelling. The pre-existing infarct regions were defined as very obvious areas of hypoattenuation, which was based on the concept that very definite hypoattenuation does not occur within 3 h of stroke onset, and did not score (20). The abnormal signal volume in the ASPECTS subregions should be >1 ml before scoring, and no score was given for punctate infarction.…”

The Possible Role of Cerebrolysin in Prevention of Hemorrhagic Transformation after Acute Ischemic Stroke

“…The concepts of cytoprotection and neurorecovery have been investigated in multiple preclinical and clinical studies in acute or chronic stroke in the past decades. Despite promising results with different agents, suggesting that they can ameliorate the evolution of the penumbra to core infarction, reduce reperfusion injury, improve tissue reperfusion, brain plasticity, or neurogenesis, none of these strategies have been recommended in humans so far [7,8]. A number of reasons could explain this outcome e.g., lack of persistent recanalization or reperfusion, too late intervention, suboptimal dosage, single mechanism of action targeting only one pathophysiological aspect of the ischemic cascade, or one type of cells in neurovascular unit (NVU), mismatch between animals and humans, and/or unrobust methodological approaches that resulted in inconsistent evidence [7,9,10].…”

“…Despite promising results with different agents, suggesting that they can ameliorate the evolution of the penumbra to core infarction, reduce reperfusion injury, improve tissue reperfusion, brain plasticity, or neurogenesis, none of these strategies have been recommended in humans so far [7,8]. A number of reasons could explain this outcome e.g., lack of persistent recanalization or reperfusion, too late intervention, suboptimal dosage, single mechanism of action targeting only one pathophysiological aspect of the ischemic cascade, or one type of cells in neurovascular unit (NVU), mismatch between animals and humans, and/or unrobust methodological approaches that resulted in inconsistent evidence [7,9,10]. Therefore, the focus of modern stroke treatment should be shifted from neuroprotection to a neurovascular protection approach because elements of NVU show differential vulnerability evolving over differing time scales and their roles are crucial in blood-brain-barrier (BBB) regulation, cell preservation, inflammatory immune response during or after AIS [7,11,12].…”

“…It displays multifactorial cytoprotective properties, improves cellular survival, inhibits glutamate excitotoxicity, free radical formation, and proinflammatory mediators (e.g., TNF-a, IL-1b, IL-6, and NF-kB). Furthermore, it mimics the action of endogenous neurotrophic factors in brain protection and recovery [7,[14][15][16].…”