Randomized, Double-blind, Placebo-controlled Trial to Investigate Safety and Efficacy of Cerebrolysin™ in Patients With Aneurysmal Subarachnoid Hemorrhage (CESAR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01787123
Recruitment Status : Unknown
Verified February 2013 by Peter Woo Yat Ming, Kwong Wah Hospital.
Recruitment status was:  Not yet recruiting
First Posted : February 8, 2013
Last Update Posted : February 8, 2013
Information provided by (Responsible Party):
Peter Woo Yat Ming, Kwong Wah Hospital

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Subarachnoid Hemorrhage Intracranial Aneurysm Delayed Cerebral Ischemia Delayed Ischemic Neurological Deficit Drug: Intravenous Cerebrolysin Phase 2 Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, 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
Study Start Date : June 2013
Estimated Primary Completion Date : November 2015
Estimated Study Completion Date : February 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bleeding

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Global functional performance [ Time Frame: At six months after stroke ]

    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).

Secondary Outcome Measures :
  1. Delayed ischemic neurological deficit (DIND) or delayed cerebral ischemia [ Time Frame: At six months after stroke ]
  2. Modified Barthel Index [ Time Frame: At six months after stroke ]
  3. Health Survey Short-form-12™ (SF-12™) [ Time Frame: At six months after stroke ]
  4. Mini-mental state examination (MMSE) [ Time Frame: At six months after stroke ]
  5. Neurobehavioural cognitive state examination (NCSE) [ Time Frame: At six months after stroke ]
  6. Length of hospital stay [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 4 weeks ]
  7. Cerebrolysin™-related adverse reactions [ Time Frame: At six months after stroke ]
  8. Mortality [ Time Frame: At six months after stroke ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Subarachnoid hemorrhage secondary to a ruptured intracranial aneurysm confirmed by computed tomography, magnetic resonance imaging or digital subtraction angiography.
  2. Any clinical grade of subarachnoid hemorrhage provided there is a reasonable prospect of survival.
  3. Initiation of trial medication within 96 hours from the time of presenting symptoms.
  4. Ethnic Chinese
  5. Age 18-70 years-old
  6. Reasonable expectation of completion of outcome measures at follow-up
  7. Written informed consent

Exclusion Criteria:

  1. Unsalvageable patients: fixed and dilated pupils after resuscitation or signs of brainstem herniation that precludes definitive therapy.
  2. No previous history of Cerebrolysin™ exposure.
  3. No known allergy to Cerebrolysin™ or porcine tissue-derived products.
  4. Pregnancy or breast feeding.
  5. Evidence of pre-existing major health problems
  6. Suspected or known additional disease process that threatens life expectancy, for example malignancy.
  7. Known or strong suspicion of drug dependency including alcohol
  8. Known epilepsy
  9. Any neurological or non-neurological condition independent from SAH that might influence the functional outcome or other efficacy outcome measures

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01787123

Contact: Peter YM Woo, FRCS (SN) 852+ 3517 2275 ext 2275

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   
Principal Investigator: Peter YM Woo, FRCS (SN)         
Sponsors and Collaborators
Kwong Wah Hospital

Responsible Party: Peter Woo Yat Ming, Associate Consultant, Kwong Wah Hospital Identifier: NCT01787123     History of Changes
Other Study ID Numbers: CESAR Study
First Posted: February 8, 2013    Key Record Dates
Last Update Posted: February 8, 2013
Last Verified: February 2013

Additional relevant MeSH terms:
Subarachnoid Hemorrhage
Intracranial Aneurysm
Brain Ischemia
Cerebral Infarction
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Intracranial Arterial Diseases
Brain Infarction
Neuroprotective Agents
Protective Agents
Physiological Effects of Drugs
Nootropic Agents