Albumin In SubArachnoid Hemorrhage: The ALISAH Study

Jose I Suarez, M.D.Professor of Neurology

Neurointensivist and Vascular NeurologistHead Section of Neurocritical Care and Vascular Neurology

Department of NeurologyBaylor College of Medicine, Houston, TX

Baylor St Luke’s Medical Center

SAH: epidemiology

Leading cause of non-traumatic SAH is aneurysmal rupture:≈37,000/y in US

Mean age of presentation is 55 and women are more likely than men to experience it (1.6:1.0)

The average case fatality for SAH is 51%, with approximately one third of survivors remaining dependent

Leading cause of non-traumatic SAH is aneurysmal rupture:≈37,000/y in US

Mean age of presentation is 55 and women are more likely than men to experience it (1.6:1.0)

The average case fatality for SAH is 51%, with approximately one third of survivors remaining dependent

SAH: complications

Virtually everybody experiences a medical complication

SAH patients are critically ill In about 40% of cases complications are life-

threatening Anticipating and preventing complications is

very important

SAH: complications

Delayed Cerebral Ischemia (46% of patients) Vasospasm Emboli Microthrombi formation

Hydrocephalus (20%) Rebleeding (7%) Seizures (24%) Hyponatremia (30%)

Springborg, J. B. et al. Br. J. Anaesth. 2005 94:259-270 with permission

Schematic review of the complex interplay of secondary insults leading to secondary brain damage after SAH

Human Albumin

He & Carter, Nature 1992;358:209-215

25% Human Albumin

Wilkes & Navickis: small-trial bias favoring control group: no evidence that albumin affected mortality: RR for death 1.1 (CI 0.95 – 1.28) (Ann Int Med 2001;135:149-64)

Cochrane Library report: neither improved outcome nor increased survival (Cochrane Database Syst Rev 2002;2:CD000567)

SAFE: randomized double-blind controlled trial of fluid resuscitation in the intensive care: similar outcomes at 28 days; treated group (4% human albumin) achieved better intravascular treatment (N Engl J Med 2004;350:2247-56)

SAH and ALB (Suarez et al., J Neurosurg 2004;100:585-90)

Features Group 1 with HA(n=37)

Group 2 without HA(n=47)

p-value

Age in years 53.0±15 54.9±14 0.5Hospital days 15.8±11 14.5±6 0.2In-hospital death (%)

16 27 0.07

Hypomagnesemia after admission (%)

5.4 49 <0.001

CHF (%) 16 19 0.7Hydrocephalus (%)

27 47 0.03

Sympt VSP (%) 19 28 0.2Hospital cost (thousands US$)

62±39 81±49 0.02

GOS ≤ 2 (%) 68 39 <0.05Logistic regression (adjusting for age, sex, race, GCS, head CT on admission) the use of HA wasIndependently associated with good outcome (OR 3.2, 95%CI 1.1-11)

Albumin in Subarachnoid Hemorrhage (ALISAH) Study

Supported by the NINDS 1RO1NS049135-01Study intervention provided by: GRIFOLS InternationalIND sponsored by FDA: BB-IND # 13022ClinicalTrials.gov Identifier: NCT00283400

ALISAH ALISAH was a three-year multicenter open-label non-

randomized dose-finding clinical trial funded by NINDS

ALISAH was to include a maximum of 80 patients with SAH

Six centers recruited patients: BCM (St Luke’s and Ben TaubHosp), Johns Hopkins (JHH and Bayview Hosp), U of Toronto, Penn State, U of Calgary, Case Western Reserve University

Data Coordinating Center: Medical University of South Carolina

ALISAH Aims

Determine the maximum tolerated dose of ALB therapy based on the rate of treatment related serious adverse events during treatment: severe-to-life-threatening heart failure and anaphylactic reaction.

Obtain preliminary estimates of the ALB treatment effect using (1) the incidence of symptomatic vasospasm within 15 days after symptom onset, (2) Glasgow Outcome Scale, (3) Barthel Index, (4) modified Rankin Scale, (5) NIH Stroke Scale, and (6) Stroke Impact Scale at 3 months.

ALISAH: ALB Dosage Regimen: 70 kg person

Dosage level number

Dosage (g/kg body weight/dayx 7days)

Volume to infuse (ml) per day

Infusion rate (ml/hour)

Dosage delivery time (hours)

1 0.625 175 58 3

2 1.25 350 117 3

3 1.875 525 175 3

4 2.5 700 233 3

Results (Suarez JI et al., Acta Neurochirurgica – 2015)

Outcome Tier 1 (0.625

g/kg)

Tier 2 (1.25

g/kg)

Tier 3 (1.875

g/kg)

All groups

TCD vasospasm 15/20 (75%) 11/20 (55%) 2/7 (28.6%) 28/47 (59.6%)

DCI 4/20 (20%) 3/20 (15%) 1/7 (14.3%) 8/47 (17%)

Cerebral infarction:

- New

- Old

- Vascular

territory

5/11 (45%)

3/11 (27%)

2/11 (18%)

All MCA

3/18 (16%)

3/18 (16%)

0

1 MCA, 2 ACA

1/4 (25%)

0

1/4 (25%)

MCA

9/33 (27%)

6/33 (18%)

3/33 (9%)

7 MCA, 2 ACA

ALISAH II

We wanted to undertake a Phase II study: Futility analysis design

Discussions with NINDS: Concerns about wasting time and money Concerns about trial fatigue Decision to move to a Phase III clinical trial

ALISAH III

A multicenter blinded, randomized, controlled Phase III design

Study period: 4-5 years Study population:18-80 year old patients

presenting within 72 hours of SAH Study sites: 85 sites from North America, South

America, Australia and New Zealand, Hong Kong, and Europe

ALISAH II

Phase III randomized, placebo-controlled clinical trial

NSDK review: Why Phase III at this stage? Resubmit as Phase II Wait for ALIAS to be completed It has not worked for other conditions Is human albumin still used for SAH? More animal data

Human Albumin Usage Survey

Albumin usage questionnaire We constructed a 27-question survey to gauge

intensivists’ views on their current use of human albumin in SAH patients.

We obtained IRB approval at the Baylor College of Medicine

Survey was e-mailed to members of the Neurocritical Care Society (NCS), and selected practitioners caring for SAH patients from Canada (members of CCCTG), Australia and New Zealand (ANZICS-CTG) and Hong Kong (Chinese University of Hong Kong)

Time line: 11/15/12 – 12/15/12

Results

We received 361 responses Response rate:

NCS: 50% Canada: 100% Australia: 100% Hong Kong: 100%

Most responders were physicians (80%) who work in academic institutions (73%)

Does your hospital have a set protocol for SAH management?

Does your protocol include human albumin administration?

Do you administer human albumin outside your management protocol?

Human albumin concentration commonly used

Indications for human albumin administration

Albumin Use in US Academic Centers: UHC database

Suarez JI et al, Crit Care Med 2016 In Press

METHODS

We used the University HealthSystemConsortium (UHC) database to identify all hospitalized adult patients (≥ 18 years of age) who received albumin between 2009 and 2013 including SAH patients

UHC is an alliance of more than 90% of academic medical centers in the US (120 academic medical centers and their 299 affiliated hospitals

UHC database: 12,366,264 records

6.2% 6.5% 6.8% 7.1% 7.5%

11.7%12.4%

13.4%14.1%

15.1%

2.5% 2.7% 2.7% 2.9% 3.0%

0%

2%

4%

6%

8%

10%

12%

14%

16%

2009 2010 2011 2012 2013

Pat

ien

ts R

ecei

vin

g A

lbu

min

as

% o

f A

ll D

isch

arge

s

Year of Discharge of Patients

Trends in Patients' Receiving Albumin as a Percent of All Inpatients Discharged Between 2009 and 2013 by Year and Type

of Hospitalization

All cases Surgical Medical

UHC database: 12,366,264 records

1.80% 1.78% 1.79% 1.77% 1.79%

10.6%10.1%

9.6% 9.4%9.1%

2.34% 2.31% 2.32% 2.31% 2.35%

0%

2%

4%

6%

8%

10%

12%

2009 2010 2011 2012 2013

Mor

talit

y, %

Year of Discharge from Hospital

Trend in Mortality by Albumin Administration Status

No albumin Received albumin All discharges

Albumin use is SAH: UHC database

We studied 38,066 adult SAH patients: 8,413 (22%) received HA and 29,653 (78%) did not.

Most patients were White (61%) and female (67%). HA use has remained low and unchanged in medical

patients but has decreased in surgical cases, especially in higher-volume centers.

Patients with low SOI had a higher mortality rate (4.0% in albumin group and 0.9% in non-albumin group, p < 0.001), whereas those with high SOI had a significantly lower mortality rate (28.8% in albumin group and 45.5% in no albumin group, p < 0.001).

Surgical cases that received albumin had lower mortality compared to medical cases (30.0% vs 4.0%).

Mortality rates were lower in surgical cases that received albumin compared to those who did not (25.5% vs 34.6%).

UHC database: SAH (n=30,461)

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

2009 2010 2011 2012 2013

Trend in Albumin Use Among Surgical SAH Patients by Center Average Annual SAH

Volume

< 20

20-40

41-60

> 60

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

2009 2010 2011 2012 2013

Trend in Albumin Use Among Medical SAH Patients by Center Average Annual SAH

Volume

< 20

20-40

41-60

> 60

Recent Animal Data

Critical Care Medicine, 2015

What’s next?

ALISAH II

ALISAH II

The proposed ALISAH II study will be a five-year multicenter, adaptive randomized, placebo-controlled, double-masked Phase II clinical trial investigating the futility of the administration of 25% HA compared to placebo in SAH patients

Primary Aim

AIM 1 is to determine the potential of 25% HA for further development and application in patients with SAH.

The primary null hypothesis is that the intervention (25% HA) reduces the proportion of patients with poor outcome compared to the hypothesized poor outcome rate: duration

Primary efficacy outcome measure is the GOS, dichotomized to define poor functional outcome as GOS ≥ 3 at 90 days.

AIM 2 To assess further safety of 25%HA:

Incidence of neurological deterioration within 15 days after symptom onset;

Incidence of rebleeding, hydrocephalus, seizures, and delayed cerebral ischemia within 15 days;

Incidence of delayed cerebral ischemia (with and without vasospasm) within 15 days;

Plasma osmolality and serum albumin within 15 days;

Serum magnesium, blood pressure, and heart rate within 15 days;

BI, mRS, NIHSS, MOCA and Stroke Impact Scale at 3 and 6 months.

AIM 3

To determine feasibility of effectively blinding therapeutic interventions.

We will mask both saline placebo and 25% HA. A questionnaire will be prepared for distribution to each site after every patient is enrolled.

AIM 4

To evaluate feasibility of application of study protocol in a larger number of sites ALISAH II will have between 30-40 clinical sites in the US and Canada (NIH StrokeNet and Neurocritical Care Research Network – NCRN).

Proposed design

Eligible subjects will be randomized to either HA (4 arms) or normal saline placebo (1 arm) and the primary outcome will be assessed at the 90-day clinic visit.

The 4 HA treatment arms will be as follows: 1.25 g/Kg/d x 7 days; 1.25 g/Kg/d x 5 days; 1.25 g/Kg/d x 3 days; and 1.25 g/Kg/d x 1 day.

Proposed design ALISAH II will follow a novel adaptive design

and will proceed in six stages. As the trial progresses no interim hypothesis

tests will be conducted. Rather, the interim goal will be to allocate a majority of the albumin treated patients to the arm with the maximum effect through a response adaptive allocation (RAR) algorithm.

Upon completion of the trial, a hypothesis test comparing the maximum effect arm and the control will be conducted.

AlbumininSubarachnoidHemorrhageTrial(ALISAHII)

N = 35

N = 13

N = 13

N = 13

N = 13

N = 13

Control(N=100)

N = 80

1:1:1:1

N = 29

RAR

N = 29

RAR

N = 29

RAR

N = 29

RAR

N = 29

RAR

Albumin(N=225)

StageI StageII StageIII StageIV StageV StageVI

Purpose of adaptive design

This adaptive design seeks to answer two questions: (1) Which duration yields the maximum

treatment effect, and (2) Is the selected duration non-futile when

compared to a saline control.

Inclusion Criteria Patients (male or female) must be at least 18 but younger than 80. Onset of new neurological signs of SAH within 72 hours of initiation of

treatment with 25% HA. Clinical signs consistent with the diagnosis of SAH including severe

thunderclap headache, cranial nerve abnormalities, decreased level of consciousness, meningismus and focal neurological deficits.

Head CT demonstrates SAH (modified Fisher rating scale 2-4). DSA or CTA reveals the presence of saccular aneurysm(s) in a location that

explains the SAH. Treatment of cerebral aneurysm carried out prior to treatment initiation and

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 (LAR).

25%HA infusion must be initiated within 72 hours of SAH symptom onset

Exclusion Criteria Time of symptom onset cannot be reliably assessed. No demonstrable aneurysm by DSA or CTA. Evidence of traumatic, mycotic, or fusiform aneurysm by DSA. World Federation of Neurological Surgeons (WFNS) scale of V Head CT 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 HA prior to treatment assignment during the present admission.

Hospitalization for or diagnosis of acute coronary syndrome (AMI) within the preceding 3 months

Symptoms or electrocardiographic signs indicative of AMI on admission

Exclusion Criteria

ECG evidence and/or physical findings compatible with second- or third-degree heart block, or ofcardiacarrhythmia associated with hemodynamic instability

Echocardiogram performed before treatment revealing a left ventricular ejection fraction < 40%

Serum creatinine > 2.0 mg/dl or creatinine clearance < 50 ml/min

Pregnancy, lactation or parturition within previous 30 days

Known allergy to albumin

Exclusion Criteria Severe prior physical disability that precludes evaluation of

clinical outcome measures (mRs > 2) History of severe chronic obstructive lung disease (FEV1 < 50%

predicted, increased shortness of breath, repeated exacerbations which have an impact on patients’ quality of life, and a fixed ratio postbronchodilator FEV1/FVC <0.7)

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 Inability to follow the protocol or return for the 90-day visit

Thank you!

Baylor St Luke’s Medical Center