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, Neurology
Louis and Carmen Warschaw Chair in
Neurological Research
Wu&Grotta
Lancet Neurol 2013; 12:275-84
Mild hypothermia is protective
38C
• Hypothermia is an
effective neuroprotectant
• (Yenari—Stanford Stroke Center)
33C
3
101 studies
3353 animals
We conclude that in animal models of
focal 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-L
SPOTRIAS No. P50N5044148
7
ICTuS-L: Conclusions
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.
8
AccutrolTM Catheter and RTx Console
Thermoregulatory Control
Anesthesiology 1997; 86:1046-54
10
Anti-shivering protocol
1. Meperidine
Bolus 1 mg/Kg before cooling (max 100mg)
Slowly given over 10-15 min
Infusion 25mg/hr (adjusted to sedation and shivering)
If shivering, then:
a. 10-25 mg IV bolus, PRN
b. increase infusion by 5 mg/hr
2. Buspirone
30 mg p.o. after randomization
15 mg p.o. at hour 8 and 16 and 24
3. Skin warming
Heating blanket – Medium setting
Treatment Times to Target in 26 Cooled Patients (PP)
Lyden, Neurocrit Care, 16:413-420, 2012
13
Multivariate Model
Variable
Time to Reach 34°C (Intercept)
Estimate
P
1258.14
NS
Age
-25.8
0.051
Weight
16.8
<0.05
Gender
67.9
NS
Meperidine -0.5
<0.05
Shivering
NS
33.3
Lyden, Neurocrit Care, 16:413-420, 2012
Multivariable Analysis
Variable
Estimate
P
3774.7150
<0.01
Age
-5.3761
NS
BSA
-1718.9852
<0.001
0.4721
-18.2924
<0.05
<0.05
6980.7695
<0.01
Age
1.232
NS
BSA
-3407.079
<0.001
1.0799
-37.249
<0.05
<0.05
AUC under 34°C (Intercept)
R2=0.51, p<0.01
Meperidine
Shivering*
AUC under 35°C (Intercept)
R2=0.54, p<0.01
Meperidine
Shivering*
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 surveillance
Preventive measures
Early 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
Design
Outcome
To determine whether the combination of
thrombolysis and hypothermia is superior to
thrombolysis alone for the treatment of acute
ischemic stroke.
Prospective, randomized, single-blind, multicenter Phase 2/3 study
Favorable outcome defined as a 90 day Modified
Rankin score of 0 or 1
Inclusion/Exclusion
•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
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
Status Report
Eliminate saline bolus and simplify
protocol
Add sites – Canada, Australia, Europe
Propose to StrokeNET
Questions
Back Up Slides