Randomized, Double-blind, Placebo-controlled Trial to Investigate Safety and Efficacy of Cerebrolysin™ in Patients With Aneurysmal Subarachnoid Hemorrhage
Condition: Subarachnoid Hemorrhage; Intracranial Aneurysm; Delayed Cerebral Ischemia; Delayed Ischemic Neurological Deficit
MeSH terms: Subarachnoid Hemorrhage; Intracranial Aneurysm; Brain Ischemia; Cerebral Infarction; Aneurysm; Hemorrhage; Ischemia
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    


Intervention name(s): Intravenous Cerebrolysin; Normal Saline
Intervention type(s): Drug; Drug
Intervention description(s): 14-day course of intravenous Cerebrolysin started within 4 days of ictus; 14-day course of intravenous normal saline started within 4 days of ictus
Other intervention name(s): Placebo
Intervention MeSH terms: Cerebrolysin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment