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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified February 2013 by Kwong Wah Hospital
Sponsor:
Information provided by (Responsible Party):
Peter Woo Yat Ming, Kwong Wah Hospital
ClinicalTrials.gov Identifier:
NCT01787123
First received: February 5, 2013
Last updated: February 6, 2013
Last verified: February 2013
  Purpose

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 Intervention Phase
Subarachnoid Hemorrhage
Intracranial Aneurysm
Delayed Cerebral Ischemia
Delayed Ischemic Neurological Deficit
Drug: Intravenous Cerebrolysin
Phase 2
Phase 3

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Kwong Wah Hospital:

Primary Outcome Measures:
  • 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).



Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 50
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)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01787123

Contacts
Contact: Peter YM Woo, FRCS (SN) 852+ 3517 2275 ext 2275 peterymwoo@gmail.com

Locations
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    peterymwoo@gmail.com   
Principal Investigator: Peter YM Woo, FRCS (SN)         
Sponsors and Collaborators
Kwong Wah Hospital
  More Information

No publications provided

Responsible Party: Peter Woo Yat Ming, Associate Consultant, Kwong Wah Hospital
ClinicalTrials.gov Identifier: NCT01787123     History of Changes
Other Study ID Numbers: CESAR Study
Study First Received: February 5, 2013
Last Updated: February 6, 2013
Health Authority: Hong Kong: Ethics Committee

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

ClinicalTrials.gov processed this record on July 20, 2014