The Albumin in Acute Stroke Part 1 Trial: An Exploratory Efficacy Analysis

Michael D. Hill, Renee H. Martin, Yuko Y. Palesch, Diego Tamariz, Bonnie D.

Waldman, Karla J. Ryckborst, Claudia S. Moy, William G. Barsan, Myron D.
Ginsberg and on behalf of the ALIAS Investigators and the Neurological Emergencies
Treatment Trials (NETT) Network
Stroke 2011;42;1621-1625; originally published online May 5, 2011;
DOI: 10.1161/STROKEAHA.110.610980
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The Albumin in Acute Stroke Part 1 Trial

An Exploratory Efficacy Analysis
Michael D. Hill, MD, MSc, FRCPC; Renee H. Martin, PhD; Yuko Y. Palesch, PhD;
Diego Tamariz, MD; Bonnie D. Waldman, JD; Karla J. Ryckborst, RN; Claudia S. Moy, PhD;
William G. Barsan, MD; Myron D. Ginsberg, MD; on behalf of the ALIAS Investigators and the
Neurological Emergencies Treatment Trials (NETT) Network
Background and PurposeThe Albumin in Acute Stroke (ALIAS) Part 2 Trial is directly testing whether 2 g/kg of 25%
human albumin (ALB) administered intravenously within 5 hours of ischemic stroke onset results in improved clinical
outcome. Recruitment into Part 1 of the ALIAS Trial was halted for safety reasons. ALIAS Part 2 is a new, reformulated
trial with more-stringent exclusion criteria. Our aim was to explore the efficacy of ALB in the ALIAS Part 1 data and
to assess the statistical assumptions underlying the ALIAS Part 2 Trial.
MethodsALIAS is a multicenter, blinded, randomized controlled trial. Data on 434 subjects, comprising the ALIAS Part
1 subjects, were analyzed. We examined both the thrombolysis and nonthrombolysis cohorts combined and separately
in a target population by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter
comprised patients 83 years of age, those with elevated baseline troponin values, and those with in-hospital stroke.
We examined the differences in the primary composite outcome, defined as a modified Rankin Scale score of 0 to 1
and/or a National Institutes of Health Stroke Scale score of 0 to 1 at 90 days after randomization.
ResultsIn the combined thrombolysis plus nonthrombolysis cohorts of the target population, 44.7% of subjects in the
ALB group had a favorable outcome compared with 36.0% in the saline group (absolute effect size8.7%; 95% CI,
2.2% to 19.5%). Among thrombolyzed subjects of the target population, 46.7% had a favorable outcome in the ALB
group compared with 36.6% in the saline group (absolute effect size10.1%; 95% CI, 2.0% to 20.0%).
ConclusionsPreliminary results from the ALIAS Part 1 suggest a trend toward a favorable primary outcome in subjects
treated with ALB and support the validity of the statistical assumptions that underlie the ALIAS Part 2 Trial. The ALIAS
Part 2 Trial will confirm or refute these results.
Clinical Trial RegistrationURL: http://www.clinicaltrials.gov/ALIAS. Unique identifier: NCT00235495.
(Stroke. 2011;42:1621-1625.)
Key Words: ischemic stroke albumin neuroprotection adjuvant stroke therapy acute treatment

he Albumin in Acute Stroke (ALIAS) Part 1 Trial

randomized patients with acute ischemic stroke within 5
hours from symptom onset to treatment with 25% human
albumin (ALB): 2 g/kg infused intravenously over 2 hours or
to equivolemic normal saline similarly infused. The trial was
initiated with a 2-parallel-cohort design, with 1 cohort receiving standard care thrombolysis and 1 receiving conservative
care; randomization to ALB or saline control took place
independently in each cohort. Enrollment into the study was
suspended prematurely for safety reasons at the recommendation of the National Institutes of Healthappointed Data

and Safety Monitoring Board after 434 subjects had been

enrolled. Our unblinded analysis of safety data only revealed
an excess of early deaths in the ALB treatment group, which
was predominantly observed among subjects who were elderly, had clinically severe stroke, received excessive fluid
during the first 48 hours of treatment, or had concurrent
evidence of myocardial damage (elevated troponin levels at
admission).1 After a halt in enrollment of a year and extensive
discussion and protocol revisions, the study was restarted
anew as the ALIAS Part 2 Trial with a single-cohort design,
but with exclusion of patients who (1) were 83 years of age;

Received December 9, 2010; accepted January 11, 2011.

From the Departments of Clinical Neurosciences, Medicine, Radiology and Community Health Sciences (M.D.H.), Faculty of Medicine, University
of Calgary, Calgary, Alberta, Canada; Division of Biostatistics and Epidemiology (R.H.M., Y.Y.P., B.D.W.), Department of Medicine, Medical
University of South Carolina, Charleston, SC; Department of Neurology (D.T.), University of Miami Miller School of Medicine, Miami, FL; Department
of Clinical Neuroscience (K.J.R.), Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; National Institutes of Neurological Disorders
and Stroke (C.S.M.), Bethesda, MD; Department of Emergency Medicine (W.G.B.), University of Michigan Medical School, Ann Arbor, MI; and
Department of Neurology (M.D.G.), University of Miami Miller School of Medicine, Miami, FL.
The online-only Data Supplement is available at http://stroke.ahajournals.org/content/full/stroke.110.610980/DC1.
Correspondence to Michael D. Hill, Calgary Stroke Program, Department of Clinical Neurosciences, University of Calgary, Foothills Hospital, Room
1242A, 1403 29th St NW, Calgary, Alberta, T2N 2T9, Canada. E-mail michael.hill@ucalgary.ca
2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.110.610980

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1621by Evelyn Nuryani on June 27, 2011

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Stroke

June 2011

(2) had troponin T or I levels 0.1 g/L (ng/mL); or (3) had

an in-hospital or periprocedural stroke. Additional major
procedural changes in the Part 2 Trial include the mandatory
use of a loop diuretic at 18 to 24 hours after treatment,
restriction of additional intravenous fluid administration during the first 48 hours after treatment, and comprehensive site
retraining to ensure that these changes were implemented.
These changes in enrollment criteria and study procedures
were made exclusively with knowledge of safety data only;
the Steering Committee remained blinded to the efficacy data
until ALIAS Part 2 had begun enrollment.
The statistical and methodologic decision to restart the
study as an independent study with subsequent planned
meta-analysis at the end of Part 2 has provided us an
opportunity to examine the Part 1 data for preliminary
evidence of treatment efficacy. This also allows us to assess
the assumptions made about certain parameters, such as the
proportion of good outcomes in the reference (saline) group
and the interaction effect between tissue-type plasminogen
activator and the study drug. We have recently reported the
safety data and considerations for design of the ongoing
ALIAS Part 2 Trial.1 We believed that this was our primary
ethical obligation after the trial enrollment was halted. In this
report, we examine the ALIAS Part 1 data for preliminary
signals of efficacy.

Methods
The ALIAS Part 1 Trial was originally designed as 2 separate but
concurrently-implemented double-blind, phase III multicenter trials
with 1:1 randomization to 25% ALB (2 g/kg IV administered over
120 minutes) or equivolemic 0.9% saline control. One cohort
consisted of subjects who received standard-of-care thrombolytic
therapy (intravenous tissue-type plasminogen activator, intra-arterial
tissue-type plasminogen activator, endovascular mechanical
thrombolysis with approved devices and catheters, or a combination
of intravenous and endovascular treatment). The other cohort consisted of subjects who were not thrombolyzed. The administration of
thrombolytic therapy was based on local clinical judgment informed
by then-current guidelines.2 The eligibility criteria for the study are
shown in the Table in the online-only Data Supplement.
We undertook intense internal debate about whether to plan a
single cohort with examination for a thrombolysisstudy drug
interaction effect or 2 separate parallel cohorts. On the basis of data
from the ALIAS Pilot Trial, wherein a potential thrombolysisALB
interaction was suspected, we elected to proceed with 2 parallel
cohorts.3,4 The ALIAS Part 1 Trial sought to detect a 10% absolute
difference in the primary outcome. This was judged to be the
minimal clinically important effect size based on recently completed
and ongoing trials in acute stroke.57 We were particularly interested
in the effect of ALB plus thrombolysis, based on the outcome of the
ALIAS Pilot Trial.3
A centralized step-forward, Web-based, 1:1 randomization process was used.8 All study personnel and subjects were blinded,
except for 1 statistician who generated the closed reports for the Data
and Safety Monitoring Board and interacted with the Data and Safety
Monitoring Board in a partially unblinded manner. A biased-coin
minimization algorithm adjusted for clinical site within each cohort.
Study drug kits consisted of a 500-mL and a 250-mL bottle of either
25% ALB or saline encased in blinding boxes and delivered via
tinted intravenous tubing. ALB was manufactured for the trial by
Baxter Healthcare Corp, Westlake Village, CA. A bedside nurse or
other personnel not involved with the trial administered the study
drug (8 mL/kg) by constant intravenous infusion over 2 hours, 15
minutes). Subjects weighing 94 kg (207 lbs) or more received a
maximum volume of 750 mL.

The primary outcome was assessed at 3 months by a study

investigator who was blinded to the subjects treatment. Raters were
asked if they knew the treatment assignment at the time of the
3-month assessment, and they were no better than chance at
identifying the treatment allocated.
A favorable primary outcome was defined as a National Institutes
of Health Stroke Scale score of 0 to 1 and/or a modified Rankin Scale
score of 0 to 1 at 90 days after randomization. With a 2-sided type
I error probability of 0.05, power of 80% to detect a 10% absolute
effect size in the primary outcome, and an assumption of the control
groups favorable-outcome proportion to be 40%, the required
sample size was 900 in each cohort, or a total of 1800 subjects.
Because the primary analysis was based on the intent-to-treat
principle, this sample size was inflated to account for crossovers and
missing data as well as for 3 interim analyses for overwhelming
efficacy or futility.
Owing to premature suspension of the trial after 434 subjects had
been enrolled, neither the thrombolytic nor the nonthrombolytic
cohort had sufficient power to test the primary hypothesis. The target
population for the analysis presented in this article is defined as an
intent-to-treat population that would have fulfilled the entry criteria
for ALIAS Part 2. Thus, subjects with age 83 years, elevated
troponin (0.1 ng/L [g/mL]) or elevated creatine kinase-MB
values at baseline, and/or an in-hospital stroke were excluded.
Subjects with missing baseline troponin or baseline creatine
kinase-MB values (n30) were considered to have a normal value
when the 24-hour value was normal. (We did not exclude subjects on
the basis of their 48-hour total intravenous fluid volume, as this was
not a baseline variable. This variable was a predictor of death in our
prior safety analysis of the Part 1 subjects; as a result, the Part 2
protocol has been modified to prevent excess fluid administration.)

Statistical Methods
We used a primary unadjusted analysis and then adjusted for baseline
National Institutes of Health Stroke Scale score, as was specified
a priori in the statistical analysis plan. Second, we explored the data
by using a multivariable approach and assessed primary outcome and
death at 90 days. We considered both the 2 cohorts combined as well
as the individual thrombolysis and nonthrombolysis cohorts. We
performed a sensitivity analysis to assess the effect of 10 missing
subject outcomes by imputing a worst-possible-outcome score, as
specified in the protocol. We performed a secondary assessment of
those subjects who were treated with at least 20% of the expected
treatment dose, excluding those who did not receive the study drug;
in practice, this excluded all patients who received only 100 mL or
less of the study drug. Thus, we examined 5 groupings of subjects:
(1) cohort combining thrombolysis and nonthrombolysis groups; (2)
thrombolysis cohort only; (3) nonthrombolysis cohort only; (4)
thrombolysis cohort treated with at least 100 mL of the study drug;
and (5) sensitivity cohort with imputed worst possible outcomes.
Data are presented as standard descriptive statistics. Adjusted
estimates of risk ratios (RRs) were derived from a generalized linear
model by using a binomial distribution and log link. Multivariable
analysis was clustered by site to account for randomization, which
was stratified by site.

Results
Among 434 subjects randomized in ALIAS Part 1, 118 (27%)
would have been excluded by the new criteria for ALIAS Part
2. These 118 subjects were, by definition, older and had
characteristics associated with older age, including a greater
proportion of atrial fibrillation and higher baseline serum
creatinine values; they were equally randomized into the
study drug (52%, n61) and control (48%, n57) groups.
The target population for this analysis (n316) was distributed such that 82% were thrombolyzed and 18% were not.
The nonthrombolysis cohort was slightly less severely affected neurologically (median National Institutes of Health

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Hill et al
Table 1.

Baseline Characteristics (N434 Subjects)

Exploratory Efficacy Analysis of ALIAS 1

Table 2. Target Population, Thrombolysis Cohort,
Intent-to-Treat Analysis

Target Population (n316)

Nontarget
Thrombolysis Nonthrombolysis Population
(n258)
(n58)
(n118)

Thrombolysis CohortTarget
Population
ALB (n127)

Demographics
Age, y
Sex (male)

68 (20)
59% (152)

1623

Saline (n131)

Demographics

68 (16)

84 (16)

48% (28)

42% (49)

Age, y

68 (19)

68 (22)

57% (75)

61% (77)

Ethnicity (Caucasian)

83% (106)

77% (103)

81% (209)

81% (47)

91% (107)

Sex (male)

Hypertension

71% (182)

78% (45)

81% (95)

Medical history

Atrial fibrillation

20% (51)

21% (12)

33% (39)

Hypertension

72% (92)

69% (90)

Atrial fibrillation

18% (23)

21% (28)

Ethnicity (Caucasian)
Medical history

Past CHF

3% (9)

2% (1)

1% (1)

Past MI

13% (34)

10% (17)

17% (20)

Past CHF

3% (4)

4% (5)

Diabetes mellitus

22% (56)

26% (15)

19% (22)

Past MI

16% (20)

11% (14)

Hyperlipidemia

34% (87)

47% (27)

33% (39)

Diabetes mellitus

24% (30)

20% (26)

4% (5)

Hyperlipidemia

34% (43)

34% (44)

Peripheral vascular disease

9% (12)

7% (9)

Chronic renal failure

6% (7)

8% (11)

13% (17)

17% (22)

11 (9)

12 (9)

Peripheral vascular disease

Chronic renal failure
Past stroke

8% (21)

7% (4)

7% (18)

3% (2)

7% (8)

15% (39)

38% (22)

13% (15)

Past stroke

Clinical
Baseline NIHSS
Baseline ASPECTS
Baseline ASPECTS 7
OCSP

12 (5)

10 (7)

9 (3)

9 (2)

65% (162)

75% (43)

12 (11)
9 (2)
80% (90)

Clinical
Baseline NIHSS
Baseline ASPECTS
Baseline ASPECTS 7

9 (3)

9 (3)

60% (73)

68% (89)

n256

n57

n117

TACS

28% (72)

19% (11)

33% (39)

PACS

53% (136)

58% (33)

49% (57)

TACS

28% (36)

28% (36)

LACS

13% (32)

18% (10)

10% (12)

PACS

53% (67)

53% (69)

8% (9)

LACS

13% (16)

12% (16)

159 (40)

POCS

6% (7)

7% (9)
150 (34)

POCS
SBP, mm Hg

6% (16)
152 (32)

5% (3)
161 (47)

OCSP

Glucose, mmol/L

6.5 (2.4)

6.8 (3.1)

6.3 (2.4)

SBP, mm Hg

155 (32)

Hemoglobin, g/L

142 (22)

135 (27)

137 (21)

Glucose, mmol/L

6.4 (3.1)

6.4 (3.0)

93 (26)

Hemoglobin, g/L

142 (33)

142 (33)

88 (37)

88 (34)

Creatinine, mol/L

88 (45)

88 (35)

Creatinine, mol/L

All values are presented as median (interquartile range) or percent (No.). The
target population consists of those patients who would have been eligible for
the Albumin in Acute Stroke Part 2 Trial.
CHF indicates congestive heart failure; MI, myocardial infarction; NIHSS,
National Institutes of Health Stroke Scale; ASPECTS, Alberta Stroke Program
Early CT Score; OCSP, Oxfordshire Community Stroke Project; TACS, total
anterior circulation syndrome; PACS, partial anterior circulation syndrome;
LACS, lacunar syndrome; POCS, posterior circulation syndrome; and SBP,
systolic blood pressure.

All values are presented as the median (interquartile range) or percent (No.).
ALB indicates albumin; CHF, congestive heart failure; MI, myocardial
infarction; NIHSS, National Institutes of Health Stroke Scale; ASPECTS, Alberta
Stroke Program Early CT Score; OCSP, Oxfordshire Community Stroke Project;
TACS, total anterior circulation syndrome; PACS, partial anterior circulation
syndrome; LACS, lacunar syndrome; POCS, posterior circulation syndrome; and
SBP, systolic blood pressure.

Stroke Scale score, 10 versus 12; Tables 1 and 2). There were
no study drug crossovers.
There were 10 subjects (2.3%) with missing 3-month
outcomes. The overall absolute effect size in the combined
thrombolysis and nonthrombolysis cohorts of the target population was 8.7% (95% CI, 2.2% to 19.5%). Among
subjects who were thrombolyzed, the 90-day risk of a good
outcome was 10.1% (95% CI, 2.0% to 20.0%) greater in the
ALB group compared with the saline control group (RR1.3
in unadjusted analysis; Table 3). Four subjects in the
thrombolysis cohort did not receive the study drug or received 100 mL. The effect size according to the imputed
worst-possible outcomes was 9.9%. As expected, owing to
the premature halt in recruitment of the trial, none of the

observed effects was statistically significant. Using multivariable analysis, we first considered adjustment for the baseline
National Institutes of Health Stroke Scale score because this
was prespecified in the statistical analysis plan. More complex models adjusting for age, sex, baseline Alberta Stroke
Program Early CT Score, and baseline glucose did not make
any substantial difference in the observed estimate of effect
size and are not presented. A formal test for an
ALBthrombolysis interaction did not show any evidence of
heterogeneity between the thrombolysis and nonthrombolysis
cohorts (P0.513).
No substantial treatment effect was observed in the
nonthrombolysis target population. In the nontarget population (patients who would have been excluded according to the
ALIAS Part 2 criteria), the 90-day risk of a good outcome in

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1624

Stroke
Table 3.

June 2011
Proportion With Good (Primary) Outcome at 90 Days and Relative Risk (RR), by Population
ALB

Saline

Absolute Risk
Difference (95% CI)

RR (95% CI)

Adjusted
RR (95% CI)*

Target population (thrombolysis),

n255 (3 missing outcomes)

46.7%

36.6%

10.1% (2.0 to 20.0)

1.3 (0.9 to 1.7)

1.2 (0.9 to 1.5)

Target population (nonthrombolysis),

n56 (2 missing outcomes)

34.6%

33.3%

1.3% (23.6 to 26.1)

1.0 (0.5 to 2.2)

0.8 (0.4 to 1.4)

Target population, n311 (both;

5 missing outcomes)

44.7%

36.0%

8.7% (2.2 to 19.5)

1.2 (0.9 to 1.6)

1.1 (0.8 to 1.4)

Nontarget population, n113

(5 missing outcomes)

19.3%

44.6%

25.3 (41.9 to 8.8)

0.43 (0.23 to 0.79)

0.5 (0.2 to 0.8)

ALB was 25% human serum albumin. A good outcome (primary outcome of the trial) was defined as having achieved a modified
Rankin Scale score of 0 to 1 or an NIHSS score of 0 to 1 at 90 days after randomization.
ALB indicates albumin; NIHSS, National Institutes of Health Stroke Scale.
*Adjusted for baseline NIHSS score.

the ALB group was statistically inferior compared with that

of saline control (RR0.5; 95% CI, 0.2 to 0.8). Thus, post
hoc, there was a qualitative difference in the direction of the
ALB effect between the nontarget population and the target
population.
In the thrombolysis cohort of the target population, the
90-day risk of death in the ALB group was the same as that
in the saline control group (RR1.2; 85% CI, 0.6 to 2.3). In
the nonthrombolysis cohort of the target population, there
was nonsignificant increase in the 90-day risk of death
(RR1.7; 95% CI, 0.5 to 5.5). In the combined thrombolysis
and nonthrombolysis cohorts of the nontarget population, the
rate of 90-day death was 31.6% in the ALB group, which was
15.5% higher than in the saline group (RR1.96; 95% CI,
0.96 to 4.00). Outcomes according to the 90-day modified
Rankin Scale score are shown in the Figure.

Discussion
The clinical need for neuroprotective therapies for acute
ischemic stroke has never been greater. These exploratory
analyses suggest that ALB therapy potentially offers a 10%
absolute benefit and a 25% relative benefit for acute stroke
subjects who are concurrently thrombolyzed. No similar

Figure. Modified Rankin Scale (mRS) outcomes at 90 days

in the Albumin in Acute Stroke Part 1 target population,
thrombolysis cohort (that is, age 83 years, normal baseline
troponin values, and out-of-hospital stroke) who were treated
with at least 100 mL of the study drug.

benefit was seen in the small nonthrombolysis cohort. It is

essential to understand that these are the results of a post hoc
and underpowered analysis and will need to be confirmed.
Furthermore, the ALIAS Part 2 inclusion and exclusion
criteria were derived after review of the safety data only. This
is important, because if the inclusion and exclusion criteria
used to define the target population for this analysis had been
changed on the basis of efficacy, then the result presented
here would be a sophism. The excluded patients were equally
randomized between saline and ALB arms and not differentially to the study drug arm. Importantly for the current
ALIAS Part 2 Trial, this analysis suggests that the current
assumptions about effect size and control outcome rates are
essentially on target. The control outcome rates are actually
slightly lower than the assumed 40%, but this lower number
will result in slightly greater power at the current sample size
of 1100. Therefore, we can conclude that the Part 2 Trial
should be powered adequately to detect a 10% treatment
effect and a thrombolysisALB treatment interaction.
The putative mechanisms by which ALB might be a
promising adjuvant or neuroprotective therapy for stroke are
many.9 13 The fact that there appears to be more promise in
the thrombolytic group may be due to subject selection or
perhaps to the role of ALB as a reperfusion-enhancing or
reperfusion-sustaining agent.14 ALB has important antioxidant properties and has been shown to promote perfusion in
the microcirculation in preclinical animal models in vivo.15,16
These properties suggest that ALB may function in the
cerebral microcirculation as a perfusion-enhancing agent
rather than merely as a classic neuroprotectant.
The safety message bears repeating. Older subjects or
subjects with acute myocardial injury (even if apparently
minor, defined as a minimal elevation of troponin levels
without ECG changes or clinical cardiac symptoms) or
subjects with stroke arising as a complication of hospitalization appear to be at greater risk of death from high-volume
ALB. Although we carefully reviewed all deaths in the
ALIAS Part 1 Trial,1 the majority were due to large stroke
with or without common complications of stroke, such as
pneumonia. However, an excess of cardiopulmonary adverse
events was observed. We concluded that the effect of highdose ALB on elderly subjects in ALIAS Part 1 must have
been cardiopulmonary, and this interacted with stroke to

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Hill et al
produce the poor outcomes.1 Recent data suggest that patients
without known congestive hart failure who have elevated
baseline serum troponin T levels will have a greater mortality
compared with those without elevated troponin levels. Some
of our patients may therefore have been susceptible to
adverse outcomes.17 We can speculate that lower doses or
longer infusion times might have been tolerated better in this
group, but this hypothesis needs to be tested. The safety of
ALIAS Part 2 is being very closely monitored with frequent
safety review by the Executive Committee, the medical safety
monitors (blinded to treatment assignment), and the Data and
Safety Monitoring Board (unblinded to treatment assignment).
Overall, in the ALIAS Part 1 Trial, the absolute effect size
in the thrombolyzed target population was 10%. The
ALIAS Part 2 Trial (NCT00235495) is ongoing and will
directly verify whether this result can be replicated in an
adequately powered, randomized, clinical trial.

Exploratory Efficacy Analysis of ALIAS 1

6.

7.

8.
9.

10.

11.

Sources of Funding
The ALIAS Trial is funded by National Institutes of Health cooperative agreements U01 NS040406 and U01 NS054630.

12.

Disclosures
None.

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