Journal Club

Presenter: Eugene Terkoski

Citation: Ginsberg MD, Palesch YY, Hill MD, Martin RH, Moy CS, Barsan WG, Waldman BD, Tamariz D,
Ryckborst KJ. High-dose albumin treatment for acute ischaemic stroke (ALIAS) Part 2: a randomized,
double-blind, phase 3, placebo-controlled trial. Lancet Neurol. 2013 Nov;12(11):1049-58. doi:
10.1016/S1474-4422(13)70223-0. PMID: 24076337

The Authors:
Dr. Ginsberg is an experienced physician and researcher. He is certified by the American Board of
Psychiatry & Neuro-Neurology. He studied at Harvard and did his residency at Massachusetts General.
Currently, he holds the Peritz Scheinberg Endowed Chair in Neurology and serves as Professor of
Neurology at the University of Miami Miller School of Medicine, and Attending Neurologist at Jackson
Memorial Hospital. He served for six years as the Editor-in-Chief of the Journal of Cerebral Blood Flow
and Metabolism, and has authored approximately 300 manuscripts and 45 chapters.
1


The second author is the biostatistician, Yuko Y. Palesch, PhD. She is a Professor of Biostatistics and
Director of the Division of Biostatistics and Epidemiology at the Medical University of South Carolina. She
is one of the leading biostatisticians in the world for clinical trials pertaining to cerebrovascular diseases
and interventional neurology. Previously she worked at the National Institute on Aging and the National
Institute of Neurological Disorders and Stroke in Bethesda, MD. Her statistical research interests are in
efficient clinical trials design (futility design, randomization methods), and in statistical analysis topics.
2


The Sponsors:
U.S. National Institutes of Health (National Institute of Neurological Disorders and Stroke)
- Funding Sponsor

National Institute of Neurological Disorders and Stroke
- Regulatory Sponsor: Oversaw the safety and performance of the trial, provided independent
medical monitors for adjudication of safety events and a Data Safety and Monitoring Board for
independent oversight

Baxter Healthcare Corporation
- Manufactured and provided the study agent, Human albumin 25% solution
- Provided funds to extend the trial to Finland
- No study oversight or input in the design, undertaking, or interpretation

U.S. Department of Health and Human Services, Supply Service Center
- Study-drug kits were assembled and distributed to the sites
- No study oversight or input in the design, undertaking, or interpretation

The primary investigator obtained an investigational new drug application with the US Food and Drug
Administration and a Clinical Trial Application at Health Canada.

The Journal:
The Lancet Neurology is a reputable, peer-reviewed journal which will consider for publication original
research that advances or highlights neurological clinical practice. The Lancet Neurology is currently
ranked first among clinical neurology journals.
3
The Lancet Neurologys parent publication, The Lancet,
has an impact factor of 39.060 second only to The New England Journal of Medicine. The Lancet
Oncology and The Lancet Infectious Diseases are other related publications.
4

Background Stroke
Stroke is the fourth leading cause of death in North America.
Stroke is the second leading cause of death in the world.
About 80% of strokes are ischemic in nature and are caused when a blood vessel
becomes blocked.
Currently the only treatment shown to improve outcomes in patients with acute ischemic
stroke is intravenous (IV) alteplase (tissue plasminogen activator, tPA)
The therapeutic benefit of IV alteplase declines sharply in the first few hours after an
ischemic stroke onset.
Preclinical studies have implicated the contribution of various injurious biochemical,
molecular, and vascular events in ischemic brain injury.
It is believed that the brain could be protected from damage by strategies designed to
counteract the suspected injury mechanisms of ischemia.
To date, the translation of these approaches into treatment methods for patients with
ischemic stroke have been disappointing.
5


Albumin (Preclinical)
A few preclinical studies showed high doses of 25% human albumin (ALB) can function
as a neuroprotectant. The results showed trends in reducing the volume of brain
infarction, diminishing cerebral edema, and improving behavioral function.
6


Albumin (Pilot)
A dose-escalation, pilot safety trial study conducted to assess the safety of ALB therapy
in ischemic stroke.
The analyzed data provided a dose for further studies and suggested a trend of
treatment efficacy.
7


Albumin (Part 1)
The Albumin in Acute Stroke (ALIAS) Part 1 Trial tested whether 2 g/kg IV of 25%
human albumin (ALB) within 5 hours of ischemic stroke onset would improve clinical
outcome.
After 434 subjects had been enrolled, the study was halted by an external Data Safety
and Monitoring Board for safety reasons during an interim analysis.
An unmasked safety analysis of that trial showed that more patients died in the first 30
days in the albumin group than in the placebo group, with patients older than 83 years
mostly affected.
Deaths were also increased in patients in the albumin group who had received
excessive IV fluids.
Analysis of the study outcomes suggested a trend toward a favorable primary outcome
in subjects treated with ALB and supported the validity of the studys statistical
assumptions.
8

The exclusion criteria were modified and the study (ALIAS part 2) was started with
frequent supervision from the DSMB.

Objectives The primary objective of the trial was to determine if a weight adjusted IV infusion of 25%
albumin within 5 hours of having a stroke would increase the proportion of patients with
favorable outcomes at 90 days compared with those given isotonic saline.
9


Methods
Study Design The ALIAS Trial was an efficacy study that consisted of a multicenter, randomized, double-
blind, parallel, two-arm Phase III trial to assess whether IV ALB therapy is neuroprotective in
acute ischemic stroke and if it is better than the current standard of care among patients with
acute ischemic stroke. Eligible subjects were randomized 1:1 to either ALB or saline and the
primary outcome was assessed at the 3-month clinic visit.

Subjects were followed for 12 months from randomization to determine the durability of the
effect of ALB therapy. Subjects were allowed to receive thrombolytic therapy and were
expected to receive such therapy in a timely fashion according to the standard of care.
9

Study Patients The study population consisted of acute ischemic stroke patients from sites in the United
States, Canada, Finland, and Israel. It was expected that greater than 95% of the recruitment
would occur in the Emergency Department (ED).

All potential stroke subjects were to be identified by a triage physician or nurse in the ED. If an
acute stroke was suspected, the personnel responsible for acute stroke care were available at
the bedside within approximately 10 minutes. All participating sites were expected to be
capable of mounting an acute stroke response, which included the potential for thrombolytic
therapy. Subjects were randomization stratified according to whether or not they received
thrombolytic therapy.

Inclusion Criteria:
- Acute ischemic stroke
- Age 18 years through 83 years (have not had their 84
th
birthday).
- National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater as assessed
immediately prior to thrombolysis treatment if the patient is eligible for thrombolysis, or
before randomization for patients not eligible for thrombolysis.
- Start of ALB/placebo within 5 hours of stroke onset, and within 90 minutes of the start
of thrombolysis with intravenous (IV) tPA if that therapy is used.
- Signed and dated informed consent has been obtained.

Exclusion Criteria:
- An episode or exacerbation of congestive heart failure (CHF) from any cause in the
past 6 months. An episode of congestive heart failure was any heart failure that
required a change in medication, change in diet or hospitalization.
- Known valvular heart disease with CHF in the last 6 months.
- Known (or in the Investigators clinical judgment) existence of severe aortic stenosis
or mitral stenosis.
- Cardiac surgery involving thoracotomy (e.g., coronary artery bypass graft (CABG),
valve replacement surgery) in the last 6 months.
- Acute myocardial infarction in the last 6 months.
- Signs or symptoms of acute myocardial infarction, including EKG findings, on
admission.
- Elevated serum troponin level on admission (> 0.1 mcg/L)
- Suspicion of aortic dissection on admission.
- Acute arrhythmia (including any tachycardia or bradycardia) with hemodynamic
instability on admission (systolic blood pressure < 100 mmHg).
- Findings on physical examination of any of the following:
jugular venous distention (jugular venous pressure > 4 cm above the sternal
angle); 3rd heart sound; resting tachycardia (heart rate 100/min) attributable
to CHF; lower extremity pitting edema attributable to CHF; bilateral rales;
and/or definite evidence of pulmonary edema, bilateral pleural effusion, or
pulmonary vascular redistribution on chest x-ray, if done.
- Current acute or chronic lung disease requiring supplemental chronic or intermittent
oxygen therapy.
- Historical modified Rankin Scale (mRS) >2. Patients who live in a nursing home or
who are not fully independent for activities of daily living (toileting, dressing, eating,
cooking and preparing meals, etc.), immediately prior to the stroke are not eligible for
the trial.
- In-patient stroke.
- Profound dehydration.
- Fever, defined as core body temperature > 38.0oC (100.4oF).
- Serum creatinine > 2.0 mg/dL or 180 mol/L.
- Severe chronic anemia (hemoglobin < 7.5 g/dL or 75g/L).
- Evidence of intracranial hemorrhage (intracerebral hematoma, intraventricular
hemorrhage, subarachnoid hemorrhage (SAH), epidural hemorrhage, acute or
chronic subdural hematoma (SDH)) on the baseline CT or MRI scan.
- History of or known allergy to albumin.
- History of or known allergy to natural rubber latex.
- Pregnancy, breastfeeding or positive pregnancy test. (Women of childbearing age
must have a negative pregnancy test prior to study drug administration.)
- Concurrent participation in any other therapeutic clinical trial.
- Evidence of any other major life-threatening or serious medical condition that would
prevent completion of the study protocol, impair the assessment of outcome, or in
which ALB therapy would be contraindicated or might cause harm to the subject.
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Intervention Due to the fact that a stroke is an emergency randomization and treatment assignments
needed to be done quickly and still ensure an even distribution in the treatment groups. In this
ALIAS Trial, this was accomplished with a centralized randomization process, via the study
website and used a stratified (by clinical site) biased coin approach. Subjects were randomly
assigned in a 1:1 ratio. This accounted for the status of treatment group balance within and
across sites.

Upon randomization, each subject received infusion of either ALB or isotonic saline solution
over the course of 2 hours. The total dose of ALB (2.0 g/kg) was based on the subjects
estimated weight at the time of randomization. The study drug infusion must have started
within 90 minutes of the start of thrombolysis with intravenous (IV) tPA if that therapy was
given and within 90 minutes of randomization in all other subjects. It must have been
administered through a dedicated IV line.

As this was a double blinded trial, all study personnel and the subjects were masked to the
identity of the study drug. The article discussed the level of effort made to standardize
between the two treatment groups, including using opaque sheathing to conceal the IV tubing.
From a clinical standpoint, it is almost impossible to mask different color fluid from the
clinicians responsible for the administration.

Vital signs and serum chemistry were monitored during hospitalization. A CT or MRI was done
at 24 hours. The patients neurological and cardiac status, including NIHSS score were
assessed at 24 and 48 hours post intervention. These tests were then repeated at 7 days or
discharge, whichever occurred first.
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Outcomes
Measures
A favorable outcome was defined as a NIH Stroke Scale (NIHSS) score of 0 or 1, a modified
Rankin Score (mRS) of 0 or 1, or both. These primary efficacy outcomes were assessed at 3
months from randomization at a clinic visit. Additionally, each patient was contacted for clinical
and quality-of-life assessments at 1, 6, 9 and 12 months from randomization.

The trials target sample size was set at 1100 patients in order for the trial to have a power of
85%. They calculated that this would give them an 0.025 probability of type I error and a 0.10
probability of type II error.
9

Data Analysis The primary hypothesis of the trial was tested using the generalized linear model with log link
function. These values were adjusted for thrombolysis use and baseline NIHSS score. Other
analyses were conducted in order to analyze pertinent factors, such as clinical site, age, and
NIHSS score at baseline.

Results
Number of
Patients
When the study stopped, there were 848 subjects enrolled of the expected 1100. There
were 422 subjects in the group that received Albumin and 419 subjects in the group that
received placebo.
9


Baseline
Characteristics
There was an even balance between the active and placebo groups especially for factors
that were not stratified for or were not specifically part of the study, such as sex, age, and
medical history.

The main differences in the baseline characteristics were found in the areas that were left
up to the local investigators discretion such as the distribution and type of thrombolytic
procedures.
5

Outcome Results This trial was stopped early for futility. At the time of interim analysis it was discovered that
the primary outcome did not differ between patients in the albumin group and those in the
saline group (186 [44%] vs 185 [44%]; risk ratio 0.96, 95% CI 0.841.10), even adjusted for
baseline NIHSS scores and thrombolysis stratum. Compared to the Phase I trial, the rate of
favorable outcome in patients given albumin remained consistent at 4445% over the
course of the trial; however, the cumulative rate of favorable outcome in patients given
saline rose steadily from 31% to 44%.

The study showed no clinical benefit in using 25% ALB in subjects with ischemic stroke, but
that there was a higher risk for mild-to-moderate pulmonary edema in subjects who received
albumin than in those given saline (54 [13%] of 412 vs 5 [1%] of 412 patients). It was also
discovered that symptomatic intracranial hemorrhage within 24 hours was more common in
patients in the albumin group than in the placebo group (17 [4%] of 415 vs 7 [2%] of 414
patients). In addition to these adverse effects atrial fibrillation and shortness of breath was
found to be more common in the ALB group.
5

Authors
Discussion and
Conclusions
The author believed that this study did not find the results that were hoped for because
preclinical studies supporting albumin as a neuroprotective agent were done in rodents but
not in primates. He suspects that the mechanism of inducing the focal cerebral ischemia in
rodents was different than what was seen in real patients (mechanical occlusion vs.
thrombus or embolus). He also suspects that reperfusion was induced by the withdrawal of
the mechanical occlusion rather than by reduction of thrombolysis. Additionally, the animals
studied were young and free of medical comorbidities. Whereas, humans with ischaemic
strokes are typically middle-aged and elderly patients who often have other medical
disorders.
5


Reviewers
Summary
This study doesnt change the standard of care, since ALB immediate post stroke is not
commonly used. The idea of using an agent that would be neuroprotectant in an ischemic
brain to counteract further injury is something that needs to be further explored. Albumin is
one possibility frequently mentioned, so the study may help to stop off-label use in stroke
patients.

The weakness of the preclinical and pilot data had me questioning the reason behind
advancing this hypothesis. The background presented in the protocol and in a search of the
literature on the use of ALB as a neuroprotectant did not seem to justify the phase III trial
that was started. The literature suggests that they did a small Pilot study and then
immediately launched a large scale Phase III trial.

There were also some other details of the study that led me to question the quality of the
study.
- There was great detail in both the article and the protocol on the blinding
procedures, but I noticed that only participants in the placebo group had data
collected outside of the protocol window. This leaves you to wonder if the study
personnel were really blinded. For example, there were ten subjects in the placebo
group that had their 90 day assessments outside of the plus or minus 30 day
window or were not followed up with. Conversely, there were zero that had their 90
day assessments outside of the plus or minus 30 day window.
- It was confusing that the investigators referred to the first study as Part 1,
especially since it was closed by a DSMB for patient safety. The investigators even
published on this first study. However, it seems that the investigators used this
unusual terminology because they used the subjects from their first study as part of
their cohort in the second study.

While this initially appears to be unsuccessful, any study that definitively answers the
scientific question is a successful study. Additionally, it could be perceived that closing the
study is another indication that the study was poorly designed or poorly executed. In
actuality, it is a credit to the investigators who designed the study and analyzed the data
that they realized that their study results would not statistically change even if it continued to
the target enrollment. It was a good ethical decision to not place additional subjects at risk
for a study thats results could not be changed. An even better ethical decision might have
been to do more extensive Phase II studies before placing over 800 people in the trial.


Works Cited:

1. Find a Doctor. University of Miami Health System. http://uhealthsystem.com/doctors/profile/1047
2. Yuko Y. Palesch, PhD. International Congress of Interventional Neurology.
http://icineuro.org/presenters/yuko-y-palesch-phd/

3. Writing for The Lancet Neurology. The Lancet. http://www.thelancet.com/writing-for-the-lancet-
neurology

4. The Lancet. Elsevier. http://www.journals.elsevier.com/the-lancet/

5. Ginsberg MD, Palesch YY, Hill MD, Martin RH, Moy CS, Barsan WG et al. High-dose albumin
treatment for acute ischaemic stroke (ALIAS) Part 2: a randomized, double-blind, phase 3,
placebo-controlled trial. Lancet Neurol. 2013 Nov;12(11):1049-58.

6. Belayev L, Zhao W, Pattany PM, Weaver RG, Huh PW, Lin B, Busto R, Ginsberg MD. Diffusion-
weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin
therapy in focal cerebral ischemia. Stroke 1998; 29: 258799. PMID: 9836772

7. Palesch YY, Hill MD, Ryckborst KJ, Tamariz D, Ginsberg MD. The ALIAS Pilot Trial: a dose-
escalation and safety study of albumin therapy for acute ischemic stroke--II: neurologic outcome
and efficacy analysis. Stroke. 2006 Aug;37(8):2107-14. Epub 2006 Jun 29. PMID: 16809570

8. Hill MD, Martin RH, Palesch YY, Tamariz D, Waldman BD, Ryckborst KJ, Moy CS, Barsan WG,
Ginsberg MD. The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis. Stroke.
2011 Jun;42(6):1621-5. doi: 10.1161/STROKEAHA.110.610980. Epub 2011 May 5. PMID:
21546491

9. (Protocol). Albumin in Acute Stroke Trial: A Phase III Randomized Multicenter Clinical Trial of
High-Dose Human Albumin Therapy for Neuroprotection in Acute Ischemic Stroke. Major
projects. Medical University of South Carolina (MUSC).
https://dcu.musc.edu/Images/PDF/ALIAS2Protocol.pdf