Randomized, Double-blind, Placebo-controlled Trial to Investigate Safety and Efficacy of Cerebrolysin™ in Patients With Aneurysmal Subarachnoid Hemorrhage (CESAR)
This is a randomized, placebo-controlled, single-center clinical trial investigating the effectiveness of administrating intravenous Cerebrolysin™ (EVER NEURO Pharma, Austria), a preparation of low-molecular weight neurotrophic peptides and free amino acids, in improving the functional outcome of patients suffering from aneurysmal subarachnoid haemorrhage ( SAH).
Cerebrolysin™ is a porcine-derived intravenous formulation composed of multiple lipid-soluble active agents that can cross the blood-brain barrier. It is a registered medication in several countries indicated for stroke and Alzheimer's disease. It contains several low molecular weight neuropeptides and free amino acids that possess neuroprotective and neurotrophic properties. It has been proven to arrest or mitigate several crucial steps along the ischemic cascade in preclinical studies. Cerebrolysin™ has been extensively investigated in patients suffering from Alzheimer's disease, brain trauma and ischemic stroke with promising clinical results. It's use in SAH patients has never been investigated and it is believed that it may play a role in improving clinical outcomes.
Consecutive patients aged 18 to 70 years-old diagnosed to have spontaneous subarachnoid hemorrhage secondary to a ruptured intracranial aneurysm will be randomly allocated into one of two study arms: (1) to receive intravenous Cerebrolysin™ in additional to standard of care (intervention group) or (2) to receive usual standard of care alone (control group). Permuted-block randomization will be carried out once the eligibility criteria have been fulfilled using a computer system with an allocation list of random order. Instructions on study arm allocation will be contained in sealed envelopes labeled with sequential study numbers. Patients presenting beyond 96 hours after onset of symptoms or if recruitment and randomization cannot be performed within this time period will be excluded. The reason being that post-SAH arterial vasospasm and delayed cerebral ischemia usually occurs four days after aneurysm rupture and lasts for two weeks i.e. 14 days. Should this complication arise before Cerebrolysin™ is administered there would be significant confounding of trial outcome measures . The timing of intervention is in keeping with several landmark clinical studies that have dealt with neuroprotective agents in subarachnoid hemorrhage.
Patients in the intervention group will receive in a daily total dose of 30ml of intravenous Cerebrolysin™. The study medication will be administered in three separate 10ml doses (every eight hours) diluted in 0.9% NaCl saline to a total volume of 100 ml as an intravenous infusion over a time period of 15 minutes. An identical amount of 0.9% sodium chloride (NaCl) saline (100 ml) will be used as placebo for patients allocated to the control study group. The total duration of study medication or placebo administration will be 14 days.
Cerebrolysin™ is a clear yellow solution. Since it is susceptible to photo-degeneration the preparation after dilution with 0.9% NaCl saline requires masking with a opaque plastic wrap as well as special photo-protective infusion sets. The dilution of the Cerebrolysin™ solution will be performed by ward nursing staff . Subjects in both trial groups will receive identically wrapped preparations so that both the functional outcomes assessor and patient are blind to the study arm allocation.
In addition to general demographic data, clinical data including the admission Glasgow Coma Score, severity grading of SAH, hospital stay as well as the extended Glasgow Outcome Score and modified Rankin Score upon discharge, at three months and six months will be prospectively collected. The functional outcomes assessor will be an occupational therapist unaware of the subject's trial group allocation.
Hypothesis: compared to patients receiving standard care for the management of aneurysmal subarachnoid hemorrhage alone (control), the additional administration of intravenous Cerebrolysin™ (intervention) within the acute phase of stroke is safe and improves functional outcome at six months after stroke.
Delayed Cerebral Ischemia
Delayed Ischemic Neurological Deficit
Drug: Intravenous Cerebrolysin
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Randomized, Double-blind, Placebo-controlled Pilot Trial to Investigate Safety and Efficacy of Cerebrolysin™ in Patients With Aneurysmal Subarachnoid Hemorrhage|
- Global functional performance [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
Global functional performance upon discharge, at three and six months after stroke in terms of the extended Glasgow Outcome Scale (E-GOS) and modified Rankin Scale (mRS). Binary outcomes are defined as 'good/ moderate' or 'poor' in terms of these scales.
For the E-GOS, 'good/ moderate' outcome is defined by a score of 7-8 (i.e. good recovery) and poor outcome is defined as 0-6 (i.e. moderate recovery to death). For the mRS, 'good/ moderate' outcome is defined by a score of 0-2 (i.e. asymptomatic to slight disability) and poor outcome is defined as 3-6 (moderate disability to death).
- Delayed ischemic neurological deficit (DIND) or delayed cerebral ischemia [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
- Modified Barthel Index [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
- Health Survey Short-form-12™ (SF-12™) [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
- Mini-mental state examination (MMSE) [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
- Neurobehavioural cognitive state examination (NCSE) [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
- Length of hospital stay [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: Yes ]
- Cerebrolysin™-related adverse reactions [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
- Mortality [ Time Frame: At six months after stroke ] [ Designated as safety issue: Yes ]
|Study Start Date:||June 2013|
|Estimated Study Completion Date:||February 2016|
|Estimated Primary Completion Date:||November 2015 (Final data collection date for primary outcome measure)|
Placebo Comparator: Control: standard management
Standard management for patient suffering from aneurysmal subarachnoid haemorrhage
Active Comparator: Intervention: standard management AND Cerebrolysin
Standard management for aneurysmal subarachnoid hemorrhage and a 14-day administration of intravenous Cerebrolysin
Drug: Intravenous Cerebrolysin
14-day course of intravenous Cerebrolysin started within 4 days of ictus
Please refer to this study by its ClinicalTrials.gov identifier: NCT01787123
|Contact: Peter YM Woo, FRCS (SN)||852+ 3517 2275 ext firstname.lastname@example.org|
|China, Hong Kong|
|Kwong Wah Hospital||Not yet recruiting|
|Hong Kong, Hong Kong, China, N.A.|
|Contact: Peter YM Woo, FRCS (SN) 852+ 3517 2275 ext 2275 email@example.com|
|Principal Investigator: Peter YM Woo, FRCS (SN)|