Clinical trial NCT00283400: Treatment of Subarachnoid Hemorrhage With Human Albumin
Official title: Treatment of Subarachnoid Hemorrhage With Human Albumin
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Subarachnoid Hemorrhage
Keywords: subarachnoid hemorrhage
SAH
human albumin
HA
cerebral vasospasm
aneurysm
neuroprotective
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2006-01-27
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the tolerability and safety of 25 percent human albumin therapy in patients with subarachnoid hemorrhage.

Detailed description: An estimated 37,500 people in the United States have subarachnoid hemorrhage (SAH) every year. SAH is usually secondary to a brain aneurysm that has burst. In SAH the bleeding accumulates around the lining of the brain. SAH is associated with a 51percent mortality rate, and one third of survivors are left functionally dependent. Cerebral vasospasm, which is a delayed narrowing of the cerebral arteries following SAH, has been identified as the most important reason for neurological deterioration and bad outcome in cases of SAH. Cerebral vasospasm may be caused by multiple mechanisms.

Treatment with a neuroprotective agent, such as human albumin (HA), may be beneficial for prevention of cerebral vasospasm and improved clinical outcome in patients with SAH. HA is a major protein found in blood and is responsible for maintaining fluid balance in the vascular system (blood vessels). The purpose of this study was to determine the safety and tolerability of 25 percent HA therapy in patients with SAH. This open-label, dose-escalation study will provide necessary information for a future definitive phase III clinical trial on the efficacy of treatment with HA in patients with SAH.

The study was designed to enroll 80 patients at 5 centers in the US. Patients with eligible SAH first underwent surgical or endovascular repair, which was considered standard care. Endovascular repair was a repair of the aneurysm from the inside of the blood vessel.

Following neurosurgical or endovascular treatment, participants were given a daily infusion of HA for 7 days. The HA dose was allocated as follows: the first tier (20 patients) would receive 0.625 grams (g) of HA per kilogram (kg) of body weight; patients in the second tier would receive 1.25g of HA per kg; patients in the third tier would receive 1.875g of HA per kg; and patients in the fourth tier would receive 2.5g of HA per kg. Safety and tolerability was evaluated by the Data and Safety Monitoring Board (DSMB) after each tier was completed and before the study advanced to the next dose tier. A specific safety threshold for congestive heart failure and other adverse events was defined based on data from previous studies.

In the follow-up phase, patients participated in study-related evaluations of their health at 15 days and three months. Duration of the study for participants was 90 days.

Eligibility criteria: Inclusion Criteria:

* Patients (male or female) were 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.
* Computed tomography demonstrated subarachnoid hemorrhage.
* Cerebral angiography revealed the presence of saccular aneurysm(s) in a location that explains the subarachnoid hemorrhage.
* Treatment of cerebral aneurysm was carried out prior to initiation of HA infusion but within 72 hours of symptom onset. Accepted treatments of aneurysms include surgical clipping or endovascular embolization.

Exclusion Criteria:

* Time of symptom onset could 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
* Computed tomography scale of 0-1
* History within the past 6 months, and/or physical findings on admission of decompensated congestive heart failure (NYHA Class IV or congestive heart failure requiring hospitalization).
* Patient 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 ≤ 40% (if available).
* Serum creatinine \> 2.0 mg/dl or creatinine clearance \< 50 ml/min.
* Pregnancy, lactation or parturition within previous 30 days.
* Allergy to albumin.
* Severe prior physical disability that precludes evaluation of clinical outcome measures.
* History of chronic lung disease
* Current participation in another drug treatment protocol.
* Severe terminal disease with life expectancy less than 6 months.

Primary outcomes:
measure: Safety and Tolerability of the 25% Human Albumin Dosages and the Functional Outcome.
timeFrame: 9 days after enrollment
Secondary outcomes:
measure: Serious Adverse Events
timeFrame: within 3 months after enrollment
measure: Good Clinical Outcome Was Defined as a Glasgow Outcome Scale Score of 0-1
timeFrame: 3 months after enrollment
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Hershey
country: United States
facility: Penn State University
state: Pennsylvania
city: Charleston
country: United States
facility: Data Coordination Unit, Department of Biostatistics, Bioinformatics and Epidemiology, at the Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
Study officials:
affiliation: Baylor College of Medicine
name: Jose I. Suarez, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Suarez JI, Shannon L, Zaidat OO, Suri MF, Singh G, Lynch G, Selman WR. Effect of human albumin administration on clinical outcome and hospital cost in patients with subarachnoid hemorrhage. J Neurosurg. 2004 Apr;100(4):585-90. doi: 10.3171/jns.2004.100.4.0585.
citation: Suarez JI, Qureshi AI, Yahia AB, Parekh PD, Tamargo RJ, Williams MA, Ulatowski JA, Hanley DF, Razumovsky AY. Symptomatic vasospasm diagnosis after subarachnoid hemorrhage: evaluation of transcranial Doppler ultrasound and cerebral angiography as related to compromised vascular distribution. Crit Care Med. 2002 Jun;30(6):1348-55. doi: 10.1097/00003246-200206000-00035.
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citation: Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. 2001 Aug 7;135(3):149-64. doi: 10.7326/0003-4819-135-3-200108070-00007.
citation: Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247-56. doi: 10.1056/NEJMoa040232.
citation: Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke. 2001 Feb;32(2):553-60. doi: 10.1161/01.str.32.2.553.
citation: Osterloh K, Ewert U, Pries AR. Interaction of albumin with the endothelial cell surface. Am J Physiol Heart Circ Physiol. 2002 Jul;283(1):H398-405. doi: 10.1152/ajpheart.00558.2001.
citation: Zhang WJ, Frei B. Albumin selectively inhibits TNF alpha-induced expression of vascular cell adhesion molecule-1 in human aortic endothelial cells. Cardiovasc Res. 2002 Sep;55(4):820-9. doi: 10.1016/s0008-6363(02)00492-3.
citation: Suarez JI, Martin RH, Calvillo E, Dillon C, Bershad EM, Macdonald RL, Wong J, Harbaugh R; ALISAH Investigators. The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes. Stroke. 2012 Mar;43(3):683-90. doi: 10.1161/STROKEAHA.111.633958. Epub 2012 Jan 19.
citation: Suarez JI, Martin RH, Calvillo E, Bershad EM, Venkatasubba Rao CP. Effect of human albumin on TCD vasospasm, DCI, and cerebral infarction in subarachnoid hemorrhage: the ALISAH study. Acta Neurochir Suppl. 2015;120:287-90. doi: 10.1007/978-3-319-04981-6_48.