Albumin In SubArachnoid Hemorrhage: The ALISAH Study

Transcription

1 Albumin In SubArachnoid Hemorrhage: The ALISAH Study Jose I Suarez, M.D. Professor of Neurology Neurointensivist and Vascular Neurologist Head Section of Neurocritical Care and Vascular Neurology Department of Neurology Baylor College of Medicine, Houston, TX Baylor St Luke s Medical Center

2 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

3 SAH: complications Virtually everybody experiences a medical complication SAH patients are critically ill In about 40% of cases complications are lifethreatening Anticipating and preventing complications is very important

4 SAH: complications Delayed Cerebral Ischemia (46% of patients) Vasospasm Emboli Microthrombi formation Hydrocephalus (20%) Rebleeding (7%) Seizures (24%) Hyponatremia (30%)

5 Schematic review of the complex interplay of secondary insults leading to secondary brain damage after SAH Springborg, J. B. et al. Br. J. Anaesth : with permission

6 Human Albumin He & Carter, Nature 1992;358:

7 25% Human Albumin Wilkes & Navickis: small-trial bias favoring control group: no evidence that albumin affected mortality: RR for death 1.1 (CI ) (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: )

8 Features SAH and ALB (Suarez et al., J Neurosurg 2004;100:585-90) Group 1 with HA (n=37) Group 2 without HA (n=47) Age in years 53.0± ± Hospital days 15.8± ±6 0.2 In-hospital death (%) Hypomagnesemi a after admission (%) p-value <0.001 CHF (%) Hydrocephalus (%) Sympt VSP (%) Hospital cost 62±39 81± (thousands US$) GOS 2 (%) <0.05 Logistic regression (adjusting for age, sex, race, GCS, head CT on admission) the use of HA was Independently associated with good outcome (OR 3.2, 95%CI )

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10 Albumin in Subarachnoid Hemorrhage (ALISAH) Study Supported by the NINDS 1RO1NS Study intervention provided by: GRIFOLS International IND sponsored by FDA: BB-IND # ClinicalTrials.gov Identifier: NCT

11 ALISAH ALISAH was a three-year multicenter open-label nonrandomized 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 Taub Hosp), 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

12 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.

13 ALISAH: ALB Dosage Regimen: 70 kg person Dosage level number Dosage (g/kg body weight/da yx 7days) Volume to infuse (ml) per day Infusion rate (ml/hour) Dosage delivery time (hours)

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16 Results (Suarez JI et al., Acta Neurochirurgica 2015) Outcome Tier 1 (0.625 Tier 2 (1.25 Tier 3 (1.875 All groups g/kg) g/kg) g/kg) 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: 5/11 (45%) 3/18 (16%) 1/4 (25%) 9/33 (27%) - New 3/11 (27%) 3/18 (16%) 0 6/33 (18%) - Old 2/11 (18%) 0 1/4 (25%) 3/33 (9%) - Vascular All MCA 1 MCA, 2 ACA MCA 7 MCA, 2 ACA territory

17 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

18 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

19 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

20 Human Albumin Usage Survey

21 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 ed 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

22 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%)

23 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?

24 Human albumin concentration commonly used Indications for human albumin administration

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28 Albumin Use in US Academic Centers: UHC database Suarez JI et al, Crit Care Med 2016 In Press

29 METHODS We used the University HealthSystem Consortium (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

30 UHC database: 12,366,264 records Trends in Patients' Receiving Albumin as a Percent of All Inpatients Discharged Between 2009 and 2013 by Year and Type of Hospitalization Patients Receiving Albumin as % of All Discharges 16% 14% 12% 10% 8% 6% 4% 2% 0% 15.1% 14.1% 13.4% 11.7% 12.4% 7.5% 6.2% 6.5% 6.8% 7.1% 2.5% 2.7% 2.7% 2.9% 3.0% Year of Discharge of Patients All cases Surgical Medical

31 UHC database: 12,366,264 records 12% Trend in Mortality by Albumin Administration Status 10% 10.6% 10.1% 9.6% 9.4% 9.1% 8% Mortality, % 6% 4% 2% 2.34% 2.31% 2.32% 2.31% 2.35% 1.80% 1.78% 1.79% 1.77% 1.79% 0% Year of Discharge from Hospital No albumin Received albumin All discharges

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33 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%).

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36 UHC database: SAH (n=30,461) Trend in Albumin Use Among Surgical SAH Patients by Center Average Annual SAH Volume Trend in Albumin Use Among Medical SAH Patients by Center Average Annual SAH Volume 50% 50% 45% 45% 40% 40% 35% 35% 30% 25% 20% 15% < > 60 30% 25% 20% 15% < > 60 10% 10% 5% 5% 0% %

37 Recent Animal Data

38 Critical Care Medicine, 2015

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42 What s next?

43 ALISAH II

44 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

45 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.

46 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.

47 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.

48 AIM 4 To evaluate feasibility of application of study protocol in a larger number of sites ALISAH II will have between clinical sites in the US and Canada (NIH StrokeNet and Neurocritical Care Research Network NCRN).

49 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.

50 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.

51 Albumin in Subarachnoid Hemorrhage Trial (ALISAH II) Stage I Stage II Stage III Stage IV Stage V Stage VI Control (N = 100) N = 35 N = 13 N = 13 N = 13 N = 13 N = 13 Albumin (N = 225) N = 80 1:1:1:1 N = 29 RAR N = 29 RAR N = 29 RAR N = 29 RAR N = 29 RAR

52 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.

53 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 legallyauthorized representative (LAR). 25%HA infusion must be initiated within 72 hours of SAH symptom onset

54 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

55 Exclusion Criteria ECG evidence and/or physical findings compatible with second- or third-degree heart block, or ofcardiac arrhythmia 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

56 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

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58 Thank you! Baylor St Luke s Medical Center