The proposed study was set up to evaluate the tolerability and safety of 25% human albumin
(HA) therapy in patients with subarachnoid hemorrhage (SAH). It is estimated that 37,500
people in the USA have SAH every year. SAH is associated with a 51% mortality rate and one
third of survivors are left functionally dependent. Cerebral vasospasm (CV) has been
identified as the most important reason for neurological deterioration. CV may be due to
multiple molecular mechanisms. The use of a neuroprotective agent with various actions,
likes HA, would be important for prevention of CV and improved clinical outcome in patients
with SAH. The proposed open-label, dose-escalation study will have important public health
implications by providing necessary information for a definitive phase III clinical trial
regarding the efficacy of treatment with HA in patients with SAH. The study was to enroll a
maximum of 80 patients with SAH who meet the eligibility criteria. Four dosages of HA
(0. 625, 1. 25, 1. 875, and 2. 5 g/kg) administered daily for seven days will be evaluated. The
lowest dosage was to be evaluated in the first group of 20 subjects. A specific safety
threshold was defined based on data from previous studies. The Data and Safety Monitoring
Board approved or disapproved advancing to the next higher HA dosage based on the evaluation
of the rate of congestive heart failure (CHF). The study assessed three outcomes: safety and
tolerability of the HA dosages and the functional outcome. The primary tolerability outcome
was defined as the subject's ability to receive the full allocated dose of HA without
incurring frank CHF that requires termination of treatment. Secondary safety outcomes were
serious adverse events (including neurological and medical complications, and anaphylactic
reactions). Neurological complications comprise incidence of CV, rebleeding, hydrocephalus,
and seizures after treatment. The three-month functional outcome determined, by Glasgow
Outcome Scale, Barthel Index, modified Rankin Scale, NIH Stroke Scale and Stroke Impact
Scale was measured to obtain a preliminary estimate of the treatment effect of HA. The
timeline of the study is three years.
Minimum age: 18 Years.
Maximum age: 80 Years.
Gender(s): Both.
Inclusion Criteria:
- Patients (male or female) must be at least 18 but younger than 80 years of age.
- Onset of new neurological signs of subarachnoid hemorrhage within 72 hours at
the time of evaluation and initiation of treatment with 25% human albumin.
- Clinical signs consistent with the diagnosis of subarachnoid hemorrhage
including severe thunderclap headache, cranial nerve abnormalities, decreased
level of consciousness, meningismus and focal neurological deficits.
- Head computed tomography demonstrates subarachnoid hemorrhage (rating scale
2-4).
- Cerebral angiography reveals the presence of saccular aneurysm(s) in a location
that explains the subarachnoid hemorrhage.
- Treatment of cerebral aneurysm must be carried out prior to treatment initiation
but within 72 hours of symptom onset. Accepted treatments of aneurysms include
surgical clipping or endovascular embolization.
- Signed and dated informed written consent by the subject or his/her legally
authorized representative.
Exclusion Criteria:
- Time of symptom onset cannot be reliably assessed.
- No demonstrable aneurysm by cerebral angiography.
- Evidence of traumatic, mycotic, or fusiform aneurysm by cerebral angiography.
- World Federation of Neurological Surgeons scale of IV and V
- Head computed tomography rating scale of 0 - 1
- History within the past 6 months, and/or physical findings on admission of
decompensated heart failure (NYHA Class III and IV or heart failure requiring
hospitalization).
- Patient has received albumin prior to treatment assignment during the present
admission.
- Hospitalization for or diagnosis of acute myocardial infarction within the preceding
3 months.
- Symptoms or electrocardiographic signs indicative of acute myocardial infarction on
admission.
- Electrocardiographic evidence and/or physical findings compatible with second- or
third-degree heart block, or of cardiac arrhythmia associated with hemodynamic
instability.
- Echocardiogram performed before treatment revealing a left ventricular ejection
fraction > or = 40% (if available).
- Serum creatinine > 2. 0 mg/dl or creatinine clearance < 50 ml/min.
- Pregnancy, lactation or parturition within previous 30 days.
- Known allergy to albumin.
- Severe prior physical disability (Rankin Scale > 2) that precludes evaluation of
clinical outcome measures.
- History of severe chronic obstructive lung disease (FEV1 < 50% predicted, increased
shortness of breath, and repeated exacerbations which have an impact on patients'
quality of life).
- History of confirmed or suspected liver failure (increased prothrombin time, elevated
liver enzymes, hypoalbuminemia, and hyperbilirrubinemia with or without peripheral
edema and encephalopathy)
- Current participation in another drug treatment protocol.
- Severe terminal disease with life expectancy less than 6 months.