Phase 2/3 study of intravenous thrombolysis and hypothermia for acute treatment of ischemic stroke (ICTuS 2/3)

Patrick D. Lyden, MD, FAAN, FAHA

Chairman, NeurologyLouis and Carmen Warschaw Chair in Neurological Research

Wu&GrottaLancet Neurol 2013; 12:275-84

3

Mild hypothermia is protective

• Hypothermia is an effective neuroprotectant

• (Yenari—Stanford Stroke Center)

38C

33C

101 studies3353 animals

We conclude that in animal models offocal cerebral ischaemia, hypothermia improves outcome by about one-third under conditions that may be achievable for large numbers of patients with ischaemic stroke.

Neurons Hypothermia 33oC vs 35oC-24 hours- OGD 2 Hours

Intravascular Cooling in the Treatment of acute Stroke – Longer t-PA window

ClinicalTrials.gov identifier: NCT00283088

ICTuS-LSPOTRIAS No. P50N5044148

7

ICTuS-L: Conclusions

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Endovascular cooling can performed in awake patients after moderate to severe stroke

Endovascular cooling can be combined with thrombolytic therapy

Increased SAE Ratio with Hypothermia

Increase risk of pneumonia with Hypothermia

Pneumonia did not effect outcome at 90 days

Hemmen et at Stroke 2010.

AccutrolTM Catheter and RTx Console

Thermoregulatory Control

10

Threshold(°C)

95% Confidence Interval

Sweating

Vasoconstriction

Shivering

[Meperidine] (µg/mL)

38

36

34

320.1 0.3 0.5

Anesthesiology 1997; 86:1046-54

1. MeperidineBolus 1 mg/Kg before cooling (max 100mg)Slowly given over 10-15 minInfusion 25mg/hr (adjusted to sedation and shivering)If shivering, then:

a. 10-25 mg IV bolus, PRNb. increase infusion by 5 mg/hr

2. Buspirone30 mg p.o. after randomization15 mg p.o. at hour 8 and 16 and 24

3. Skin warmingHeating blanket – Medium setting

Anti-shivering protocol

Treatment Times to Target in 26 Cooled Patients (PP)

Lyden, Neurocrit Care, 16:413-420, 2012

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Multivariate Model

Variable Estimate PTime to Reach 34°C

(Intercept) 1258.14 NS

Age -25.8 0.051Weight 16.8 <0.05Gender 67.9 NSMeperidine

-0.5 <0.05

Shivering 33.3 NS

Lyden, Neurocrit Care, 16:413-420, 2012

Multivariable Analysis

Variable Estimate P

AUC under 34°C (Intercept) 3774.7150 <0.01R2=0.51, p<0.01 Age -5.3761 NS

BSA -1718.9852 <0.001

Meperidine 0.4721 <0.05Shivering -18.2924 <0.05

AUC under 35°C (Intercept) 6980.7695 <0.01R2=0.54, p<0.01 Age 1.232 NS

BSA -3407.079 <0.001

Meperidine 1.0799 <0.05Shivering -37.249 <0.05

Conclusions From ICTuS L Exploratory Analyses

Time to reach target is a function of age, weight, and shivering control

Maintaining hypothermia depends on weight, and to a lesser extent on shivering control

Pneumonia has been reduced in ICTuS 2

Vigilant surveillancePreventive measuresEarly empiric antibiotics“Permissive Hypothermia”

Implications from ICTuS L and ICTuS 2

Permissive hypothermia

In Ictus 3, patients will be cooled as quickly as possible. The target reached early will be the target for the 24 hour cooling period.

Methods and Protocol

International Journal of Stroke 9.1 (2014): 117-125.

Effect size 7%Power 80%Alpha 0.05

Purpose To determine whether the combination of thrombolysis and hypothermia is superior to thrombolysis alone for the treatment of acute ischemic stroke.

Design Prospective, randomized, single-blind, multi-center Phase 2/3 study

Outcome Favorable outcome defined as a 90 day Modified Rankin score of 0 or 1

•Age 22 to 82•IV rt-PA <3 hours•NIHSS 7 – 20/24•Pre-stroke mRS 0-1•No posterior circulation strokes•No I/A at this time

Inclusion/Exclusion

Enrollment/Recruitment Update

112 Subjects enrolled to date!

16 sites actively recruiting (1 in Europe) 13 sites in start up phase

Transition Plan if we enter StrokeNET

•End ICTuS 2 when SPOTRIAS funding ends. Begin ICTuS 3 upon entering StrokeNET

•We will have about 200 patients by May 2015

•First Interim (futility/efficacy) planned for 400 patients

•Second Interim at 800

•DSMB could ask for a Third Interim at 1200

Eliminate saline bolus and simplify protocol

Add sites – Canada, Australia, Europe

Propose to StrokeNET

Status Report

Questions

Back Up Slides