Post on 25-Jun-2020
Evolution of Stroke Thrombolytics
Roop Pawar, MD
▪ Neurologists were seen as astute diagnosticians
▪ Great at “chin-scratching”
▪ Not much good at making real difference to people’s lives
▪ Once diagnosis made, often no treatments to offer, and often no
great need or point to continue to see patients on regular and
frequent follow-up
Diagnose - Adios
Sleeping beauty
Time is Brain!
Saver JL, Stroke 2006
STROKE
Time lost is Brain
lost
Time Neurons
Lost
Synapses
Lost
Myelinated
fibers Lost
Premature
Aging
1 second 32,000 230 million 200 m 8.7 hours
1 minute 1.9 million 14 billion 12 km 3.1 weeks
1 hour 120 million 830 billion 714 km 3.6 years
Complete 1.2 billion 8.3 trillion 7140 km 36 years
Penumbra & Oligemia
Ischemic Cell Damage (DWI)
Penumbra & Oligemia
Critically Hypoperfused tissue
(PWI)
▪ Interventions:
• IV tPA (0-3 hours) Approved 1996
• IV tPA (3-4.5 hours) Updated 2010
▪ Devices Cleared for clot removal 2004, 2008, 2012
• Thrombectomy
2015
Acute Stroke Treatments
IV Thrombolysis
NINDS rt-PA Stroke Study Group NEJM (1995)
randomized, placebo-controlled trial of intravenous recombinant tissue plasminogen activator within 3 hours
of acute ischemic stroke
• Seizure at onset
• Hypo/hyperglycemia
• Rapidly improving symptoms
IV tPA Contraindications
• GI/GU bleeding within 21 days
• Major surgery within 14 days
• Non-compressible arterial puncture within 7 days
• Recent MI
• Thrombocytopenia (plt < 100K)
• Coagulopathy (INR>1.7)
• Heparin therapy within 48 hours with PTT > upper limit of normal
NINDS rt-PA Stroke Study Group NEJM (1995)
• Clinical suspicion for SAH
• BP >185/110 or aggressive antihypertensive therapy
• Time of onset >3 hours*
• Extensive area of infarction >1/3 MCA territory visible on head CT
• Intracranial hemorrhage history
• Stroke within 3 months
• Head trauma within 3 months
IV tPA Evaluation
12
0
10
20
30
40
50
60
NIHSS (0-1) Barthel Index(95-100)
ModifiedRankin Scale(0-
1)
GlasgowOutcome Scale
(1)
38
54
47 47
21
39
27 31 % of
patients
NINDS t-PA Stroke Trial Excellent Outcome at 3 Months
t-PA placebo
(NINDS t-PA Stroke Study Group, NEJM 333:1581-1587; 1995)
NINDS t-PA Stroke Trial:
NINDS t-PA Stroke Trial: Results
3-Month Outcome by Stroke Subtype*
*18 patients with other stroke subtypes were excluded from this analysis
75
50
63
40
63
43 47
33
0
20
40
60
80
% P
atients
with
Favora
ble
Outc
om
e
Bartel Mod. Rankin Glasgow NIHSS
Small-Vessel Occlusive
t-PA
(n = 51)
Placebo (n
= 30)
Large-Vessel Occlusive
46
37 38
28
39
31 29
20
0
10
20
30
40
50
Bartel Mod. Rankin Glasgow NIHSS
Cardioembolic
t-PA
(n = 117)
Placebo (n
= 135)
t-PA
(n = 135)
Placebo (n
= 137)
49
36 40
22
45
28 33
18
0
10
20
30
40
50
Bartel Mod. Rankin Glasgow NIHSS
% P
atients
with
Favora
ble
Outc
om
e
% P
atients
with
Favora
ble
Outc
om
e
NINDS tPA trial
NINDS rt-PA Stroke Study Group NEJM (1995)
risk of hemorrhage
6.4% with tPA
0.6% with placebo
Time to treatment influences
Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and
NINDS rt-PA stroke trials. Lancet 2004;363:768–74
NNT= 2-3 NNT= 4 NNT= 9
NNT is number of
patients needed
to treat for one to
have a
significantly
improved
outcome.
▪Same as NINDS trial but:
▪Treatable between 3 and 4.5 hours of
onset
▪Age<80
▪No prior stroke AND diabetes
▪Not on warfarin
▪CT without ICH or major early infarct
signs
ECASS 3: IV t-PA Eligibility
(The Short Version)
ECASS 3
Hacke et al. NEJM (2008)
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
IV tPA placebo
Excellent Recovery After 3 Months
ARR = 7.2%
RCT of IV tPA within 3 to 4.5 hours of acute ischemic stroke
(Stroke. 2009;40:2945-2948.)
Future
NEW DRUG NEW TIME WINDOW
▪Genetically remodeled tPA
▪ Higher fibrin specificity
▪Longer half-life
▪Single injection vs 1 hour Infusion
▪Ease of transportation
▪Cheaper
Why Tenecteplase?
Tenecteplase in Acute Ischemic Stroke
© 2018 Genentech, Inc. All rights reserved.
Disclaimer
© 2018 Genentech, Inc. All rights reserved.
Please note: The information provided herein may include references to
alteplase or tenecteplase, or a use of alteplase or tenecteplase that the
FDA has not approved; because the FDA has not approved such product
or use, no conclusions regarding safety or efficacy can be made. Providing
this information should not be construed as recommendation for use of
alteplase or tenecteplase for unapproved uses. For FDA-approved
products, please consult the product's full prescribing information for a
complete discussion of risks and benefits of the product for its approved
indication(s).
Prescribing Information, Indication(s), and Important Safety Information:
ACTIVASE® (alteplase)- https://www.gene.com/medical-
professionals/medicines/activase
TNKASE® (tenecteplase)- https://www.gene.com/medical-
professionals/medicines/tnkase
This deck may contain animations, please review this slide deck in “slide
show” mode to ensure fair-balance display of content.
Tenecteplase in Acute Ischemic Stroke:
Historical and Ongoing Studies
© 2018 Genentech, Inc. All rights reserved.
EVT=endovascular therapy; h=hours; IV=intravenous.
2009 2012 2017 2016 2014 2011 2015 2013 2010 2005 2008
IV administration within 3 h of stroke
█ Pilot Dose Escalation. Haley et al. Stroke 2005
█ Phase 2b/3. Haley et al. Stroke 2010
IV administration within 4.5 h of stroke
█ ATTEST. Huang et al. Lancet Neurology 2015
█ ATTEST Markers. Huang et al. Stroke 2015
Imaging-guided patient selection with IV administration
█ Pilot imaging. Parsons et al. Neurology 2009
█ Phase 2b imaging. Parsons et al. NEJM 2012
Meta-analysis of tenecteplase vs alteplase
█ Meta-analysis. Huang et al. Stroke 2016
IV administration in minor stroke
█ TEMPO-1. Coutts et al. Stroke 2015
Combination IV therapy
█ Alteplase+Tenecteplase. Smadja et al. Stroke 2011
Intra-arterial administration
█ 3 hospitals. Georgiadis et al. J Neuroimaging 2012
2017 and beyond
█ NOR-TEST. Logallo et al. Lancet Neurology 2017
█ EXTEND-IA TNK Tenecteplase, tenecteplase vs
alteplase before EVT. Campbell et al. NEJM 2018
█ TIAS, tenecteplase, 4.5–24 h, imaging
TASTE, tenecteplase vs alteplase, 0–4.5 h, imaging
ATTEST-2, tenecteplase vs alteplase, 0–4.5 h
TEMPO-2, tenecteplase vs standard care, mild stroke
TWIST, tenecteplase vs standard care, wake-up
stroke
EXTEND-IA TNK part 2, 0.25 mg/kg vs 0.40 mg/kg
tenecteplase
Norwegian Tenecteplase Stroke Trial (NOR-TEST):
A Phase 3, Randomized, Open-Label, Blinded
Endpoint Trial of Tenecteplase vs Alteplase for
Management of Acute Ischemic Stroke
© 2017 Genentech, Inc. All rights reserved.
NOR-TEST: Study Design
© 2017 Genentech, Inc. All rights reserved. 27
*From 13 stroke units in Norway; †R=randomization via block randomization (block of 4) stratified for site of inclusion but not baseline
characteristics; ‡IV tenecteplase was provided as a single bolus to a max of 40 mg while IV alteplase was administered at 10% of dose as the
initial bolus, followed by 90% in a 1-hour infusion to a max of 90 mg.
IV=intravenous.
Logallo N et al. Lancet Neurol. 2017 Aug 2 [Epub ahead of print].
R† 1:1
Patients* (eligible for thrombolytic therapy)
N=1107
MULTICENTER (NORWAY), PROSPECTIVE, RANDOMIZED, OPEN-LABEL,
CONTROLLED DESIGN WITH BLINDED OUTCOME EVALUATION (PROBE)
IV alteplase (0.9 mg/kg)‡
IV tenecteplase (0.4 mg/kg)‡
NOR-TEST: Patient Disposition
© 2017 Genentech, Inc. All rights reserved. 28
*7 patients were not included in the intention-to-treat (ITT) analysis because informed consent was withdrawn or eligibility for thrombolytic
treatment was reconsidered prior to randomization; †patients excluded from PP analysis had one or more protocol violations: disorders other than
stroke (stroke mimics), mRS score of >2 before admission, NIHSS score of 0 at admission, randomization in the NOR-SASS trial to transcranial
ultrasound and microbubble contrast (not sham), or missing data at 3 months.
ITT=intention-to-treat; PP=per protocol; mRS=modified Rankin Scale; NIHSS=National Institutes of Health Stroke Scale;
NOR-SASS=Norwegian Sonothrombolysis in Acute Stroke Study; u/s=ultrasound.
Logallo N et al. Lancet Neurol. 2017 Aug 2 [Epub ahead of print].
Excluded†
n=160 Stroke mimics (n=91)
Premorbid mRS>2 (n=35)
Admission NIHSS=0 (n=14)
NOR-SASS u/s (n=31)
Missing data (n=19)
Enrolled
N=1107 Excluded (not treated)*
n=7
Withdrawn consent or
reconsidered eligibility
Tenecteplase
n=549
(ITT)
Alteplase
n=551
(ITT)
Tenecteplase
n=382
(PP)
Alteplase
n=391
(PP)
Excluded†
n=167 Stroke mimics (n=99)
Premorbid mRS >2 (n=27)
Admission NIHSS=0 (n=20)
NOR-SASS u/s (n=31)
Missing data (n=17)
NOR-TEST: Patient Demographics (cont)
© 2017 Genentech, Inc. All rights reserved. 29
NIHSS=National Institutes of Health Stroke Scale; SD=standard deviation; IQR=interquartile range; TOAST=Trial of Org 10172 in Acute Stroke
Treatment.
Logallo N et al. Lancet Neurol. 2017 Aug 2 [Epub ahead of print].
Tenecteplase
(n=549)
Alteplase
(n=551)
NIHSS score
Mean (SD) 5.6 (5.4) 5.8 (5.2)
Median (IQR) 4 (2–7) 4 (2–8)
Mild (0–7), n (%) 426 (78) 401 (73)
Moderate (8–14), n (%) 75 (14) 98 (18)
Severe (≥15), n (%) 48 (9) 52 (9)
TOAST classification, n (%)
Patients with available data, n 470 481
Large vessel disease (atherosclerosis) 92 (20) 94 (20)
Cardioembolism 100 (21) 129 (27)
Small vessel disease (lacunar infarct) 72 (15) 60 (12)
Other causes 23 (5) 27 (6)
Unknown or several causes 183 (39) 171 (36)
Time, min (range)
Patients with available data, n 521 514
Onset to admission 79.0 (46–131) 74.5 (47–123)
Admission to thrombolysis 32.0 (22–47) 34.0 (25–50)
Onset to thrombolysis 118.0 (79–180) 111 (80–174)
NOR-TEST:
Patients with mRS of 0‒1 at 3 months (%), Primary Endpoint
© 2018 Genentech, Inc. All rights reserved.
CI=confidence interval; ITT=intention-to-treat; mRS=modified Rankin Scale; OR=odds ratio; PP=per protocol.
Logallo N et al. Lancet Neurol. 2017;16:781-788.
0
10
20
30
40
50
60
70
80
90
100
Pati
en
ts w
ith
mR
S 0
‒1
at
3 M
on
ths (
%)
OR (95% CI): 1.08 (0.84–1.38)
P=0.52
64%
Tenecteplase
(n=549)
63%
Alteplase
(n=551)
OR (95% CI): 0.99 (0.74−1.33)
P=0.98
64%
Tenecteplase
(n=382)
64%
Alteplase
(n=391)
ITT PP
NOR-TEST: Distribution of mRS Scores at 3 Months
© 2018 Genentech, Inc. All rights reserved.
ITT=intention-to-treat; mRS=modified Rankin Scale; PP=per-protocol.
Logallo N et al. Lancet Neurol. 2017;16:781-788.
mRS score 0 6 3 1 4 5 2
Tenecteplase
(n=549)
Alteplase
(n=551)
37%
(n=202)
28%
(n=152)
12%
(n=67)
9%
(n=48)
9%
(n=47)
31%
(n=173)
31%
(n=172)
16%
(n=87)
9%
(n=47)
7%
(n=36)
<1%
(n=4) 5%
(n=29)
2%
(n=10)
5%
(n=26)
Proportion of Patients (%)
Tenecteplase
(n=382)
Alteplase
(n=391)
35%
(n=132)
29%
(n=112)
14%
(n=54)
8%
(n=30)
8%
(n=32)
30%
(n=117)
34%
(n=133)
17%
(n=68)
7%
(n=27)
6%
(n=22)
<1%
(n=2) 5%
(n=20)
0 20 40 60 80 100
2%
(n=8)
4%
(n=16)
ITT
PP
NOR-TEST: Secondary Outcomes (ITT)
© 2017 Genentech, Inc. All rights reserved. 32
*Any hemorrhagic transformations or parenchymal hematoma according to ECASS I criteria; †Fisher’s exact test; ‡defined according to ECASS III
criteria; §NIHSS score of 0 or improvement of at least 4 points compared with baseline.
ITT=intention-to-treat; CI=confidence interval; ICH=intracranial hemorrhage; sICH=symptomatic intracranial hemorrhage; mRS=modified Rankin
Scale; NA=not applicable; ECASS=European Cooperative Acute Stroke Study; NIHSS=National Institutes of Health Stroke Scale.
Logallo N et al. Lancet Neurol. 2017 Aug 2 [Epub ahead of print].
Tenecteplase Alteplase
Odds Ratio
(95% CI) P Value
Any ICH* at 24–48 h, n/N (%) 47/549 (9) 50/551 (9) 0.94 (0.60–1.45) 0.82†
sICH‡ at 24–48 h, n/N (%) 15/549 (3) 13/551 (2) 1.16 (0.51–2.68) 0.70†
Major clinical improvement at 24 h§,
n/N (%) 229/549 (42) 214/551 (39) 1.12 (0.89–1.43) 0.97
Ordinal shift analysis of mRS at
3 months NA/549 NA/551 1.12 (0.91–1.39) 0.28
Death within 3 months, n/N (%) 29/549 (5) 26/551 (5) 1.12 (0.63–2.02) 0.68†
EXTEND-IA TNK
33
Tenecteplase vs Alteplase Before Thrombectomy for Ischemic Stroke
(EXTEND-IA TNK): Background, Study Design, and Hypothesis1,2
© 2018 Genentech, Inc. All rights reserved.
*From 13 centers in Australia and New Zealand.
LVO= cerebral vascular occlusion on CT angiography of internal carotid artery, first segment of middle cerebral artery, second segment of middle
cerebral artery, or basilar artery
AIS=acute ischemic stroke; IV=intravenous; LVO=large vessel occlusion; R=randomization.
1. Campbell BC et al. N Engl J Med. 2018;378:1573-1582;
2. https://clinicaltrials.gov/ct2/show/NCT02388061. Accessed May 2, 2018.
• Designed to compare reperfusion in patients planned to undergo thrombectomy
of tenecteplase vs alteplase administered within 4.5 hours of AIS onset
• Hypothesis: Tenecteplase is noninferior to alteplase in achieving reperfusion at initial
angiogram
R 1:1
Patients with LVO*
eligible for thrombolysis
N=202
PHASE 2, MULTICENTER, PROSPECTIVE, RANDOMIZED, OPEN-LABEL,
CONTROLLED DESIGN WITH BLINDED OUTCOME EVALUATION (PROBE)
IV tenecteplase (0.25 mg/kg)
Max dose = 25 mg
IV alteplase (0.9 mg/kg)
Max dose= 90 mg
EXTEND-IA TNK: Primary and Secondary
Endpoints
© 2018 Genentech, Inc. All rights reserved.
*Defined as restoration of blood flow to >50% of the affected arterial territory; †including subarachnoid hemorrhage that was associated with
clinical symptoms and symptomatic intracerebral hemorrhage that was adjudicated centrally by a panel as parenchymal hematoma type 2 within
36 hours after treatment, combined with an increase in NIHSS score of ≥4.
CT=computed tomography; mRS=modified Rankin scale; mTICI=modified Treatment in Cerebral Ischemia; NIHSS=National Institutes of Health
Stroke Scale; sICH=symptomatic intracranial hemorrhage.
1. Campbell BC et al. N Engl J Med. 2018;378:1573-1582;
2. https://clinicaltrials.gov/ct2/show/NCT02388061. Accessed May 2, 2018.
Primary Endpoint1,2
▪ Angiographic reperfusion (mTICI) score
of 2b/3* or absence of retrievable
thrombus at initial angiogram
Secondary and Safety Endpoints1,2
▪ NIHSS improvement (≥8) or 0–1 at
3 days (early neurological recovery)
▪ Ordinal analysis of mRS at 90 days
▪ mRS 0–1 and 0–2 at 90 days
▪ Death due to any cause at 90 days
▪ sICH† within 36 hours
EXTEND-IA TNK: Patient Disposition
© 2018 Genentech, Inc. All rights reserved.
*All evaluated for primary outcome, early neurological improvement at 3 days, and mRS at 90 days.
ITT=intention-to-treat; mRS=modified Rankin Scale; PP=per protocol.
Campbell BC et al. N Engl J Med. 2018;378:1573-1582.
Enrolled
N=204 Excluded (not treated)
n=2
Withdrawn consent, n=1
Investigator randomization error, n=1
Tenecteplase
n=101
(ITT)
Alteplase
n=101
(ITT)
Tenecteplase
n=101*
(PP)
Alteplase
n=101*
(PP)
ITT population was identical to PP population
Lost to 90 day
follow-up
n=0
Lost to 90-day
follow-up
n=0
EXTEND-IA TNK: Baseline Characteristics and
Demographics*
© 2018 Genentech, Inc. All rights reserved.
*There were no significant differences between groups. Percentages may not total 100 because of rounding; †scores on the NIHSS range from 0
(normal function) to 42 (death), with lower scores indicating less severe stroke.
IQR=interquartile range; IV=intravenous; NIHSS=National Institutes of Health Stroke Scale; SD=standard deviation.
Campbell BC et al. N Engl J Med. 2018;378:1573-1582.
Tenecteplase
n=101
Alteplase
n=101
Age (years)
Mean (SD) 70.4 (15.1) 71.9 (13.7)
Sex, n (%)
Male 58 (57) 52 (51)
NIHSS score†
Median (IQR) 17 (12‒22) 17 (12‒22)
Cause of stroke, n (%)
Cardioembolic occlusion 46 (46) 54 (53)
Large-artery occlusion 21 (21) 18 (18)
Undetermined/other 34 (34) 29 (29)
Time (min), median (IQR)
Stroke onset to hospital arrival 60 (44–89) 72 (53–104)
Stroke onset to IV thrombolysis 125 (102‒156) 134 (104‒176)
IV thrombolysis to arterial puncture 43 (25‒57) 42 (30‒63)
IV thrombolysis to initial angiographic assessment 54 (34–67) 56 (40–77)
EXTEND-IA TNK: Baseline Characteristics and
Demographics* (cont)
© 2018 Genentech, Inc. All rights reserved.
*There were no significant differences between groups. Percentages may not total 100 because of rounding; †ischemic core volumes were
calculated with the use of a threshold of relative cerebral blood volume <30% of that in normal brain. The perfusion lesion was defined as the
volume of brain with a time to maximum perfusion >6 seconds. CT perfusion imaging was performed, but the requirement for mismatch and an
ischemic core volume <70 mL was removed in a protocol amendment when approximately 80 patients were enrolled.
CT=computed tomography; IQR=interquartile range.
Campbell BC et al. N Engl J Med. 2018;378:1573-1582.
Tenecteplase
n=101
Alteplase
n=101
Interhospital transfer for thrombectomy, n (%) 27 (27) 23 (23)
Site of vessel occlusion, n (%)
Internal carotid artery 24 (24) 24 (24)
Basilar artery 3 (3) 3 (3)
Middle cerebral artery
First segment 59 (58) 60 (59)
Second segment 15 (15) 14 (14)
Volume (mL) at initial imaging, median (IQR)†
Ischemic core 14 (0–33) 11 (0–24)
Perfusion lesion 145 (105–175) 134 (103–170)
EXTEND-IA TNK: Primary Endpoint
© 2018 Genentech, Inc. All rights reserved.
*Substantial reperfusion was defined as the restoration of blood flow >50% of the involved territory or no retrievable thrombus at the time of the
initial angiographic assessment. The analysis was adjusted for the site of vessel occlusion strata; †when tested for noninferiority. Upon reaching
statistical significance for noninferiority, a test for superiority showed that P=0.02.
CI=confidence interval; IR=incidence ratio; OR=odds ratio.
Campbell BC et al. N Engl J Med. 2018;378:1573-1582.
0
10
20
30
40
50
60
70
80
90
100
22
10
P=0.002†
Tenecteplase
(n=101)
Alteplase
(n=101)
Pa
tie
nts
wit
h s
ub
sta
nti
al
rep
erf
us
ion
or
ab
se
nc
e o
f re
trie
va
ble
thro
mb
us
at
init
ial a
ng
iog
ram
(%
) Incidence difference (95% CI): 12 (2−21)
Adjusted IR (95% CI): 2.2 (1.1–4.4)
Adjusted OR (95% CI): 2.6 (1.1−5.9)
Patients with substantial reperfusion* or absence of
retrievable thrombus at initial angiogram
EXTEND-IA TNK: Distribution of mRS* Scores at
Day 90
© 2018 Genentech, Inc. All rights reserved.
*Scores range from 0 (no neurologic deficit) to 6 (death). A functionally independent outcome was defined as an mRS score of 0 to 2 or no change
from baseline. An excellent outcome was defined as an mRS score of 0 or 1 or no change from baseline; †adjusted for NIHSS score and age at
baseline; ‡effect size was assessed with a common odds ratio from ordinal logistic regression;§effect size was assessed as an incidence or risk
ratio from Poisson regression and as an odds ratio from logistic regression.
mRS=modified Rankin scale; N/A=not available; IQR=interquartile range; IR=incidence ratio; OR=odds ratio.
Campbell BC et al. N Engl J Med. 2018;378:1573-1582.
Tenecteplase
(n=101)
Alteplase
(n=101)
mRS score
18%
28%
23%
21%
9%
14%
12%
14%
14%
8%
7%
6%
18%
10%
0 1 2 3 4 5 6
Tenecteplase
(n=101)
Alteplase
(n=101)
IR (95% CI),
P Value
OR (95% CI),
P Value
mRS at 90 days (ordinal analysis), median (IQR)†‡ 2 (0–3) 3 (1–4) N/A 1.7 (1.0–2.8),
0.04
Functionally independent outcome (mRS 0-2), n (%)†§ 65 (64) 52 (51) 1.2 (1.0–1.5),
0.06
1.8 (1.0–3.4),
0.06
Excellent outcome (mRS 0-1), n (%)†§ 52 (51) 43 (43) 1.2 (0.9–1.6),
0.20
1.4 (0.8–2.6),
0.23
EXTEND-IA TNK: Safety
© 2018 Genentech, Inc. All rights reserved.
*Adjusted for NIHSS score and age at baseline. Effect size was assessed as an incidence or risk ratio from Poisson regression and as an odds
ratio from logistic regression; ‡defined as a large parenchymal hematoma (blot clot occupying >30% of infarct volume with mass effect) and ≥4
point increase in NIHSS; §defined as intraparenchymal blood clot with mass effect.
CI=confidence interval; NIHSS=National Institutes of Health Stroke Scale; OR=odds ratio; RR=risk ratio; sICH=symptomatic intracranial
hemorrhage.
Campbell BC et al. N Engl J Med. 2018;378:1573-1582.
Tenecteplase
(n=101)
Alteplase
(n=101)
RR (95% CI),
P Value
OR (95% CI),
P Value
Safety outcomes, n (%)*
Death <90 days 10 (10) 18 (18) 0.5 (0.3–1.0),
0.049
0.4 (0.2‒1.1),
0.08
sICH‡ 1 (1) 1 (1) 1.0 (0.1–15.9),
0.99
1.0 (0.1‒16.2),
0.99
Parenchymal hematoma§ 6 (6) 5 (5) 1.2 (0.4–3.8),
0.76
1.2 (0.4‒4.1),
0.76
2014 2017 2019 2016 2020 2018 2015 2009
Ph3: Tenecteplase vs SOC
in Wake-up Stroke
(TWIST)4
500
patients
Ph3: Tenecteplase vs Alteplase in AIS
(TASTE)1† 1024
patients
Ph3: Tenecteplase vs Alteplase
in AIS
(ATTEST-2)3
1870
patients
Ph3: Tenecteplase vs SOC for Minor IS
(TEMPO-2)2 1274
patients
Ongoing Trials of Tenecteplase in Acute Ischemic Stroke:
Estimated Timelines and Trial Sizes
© 2018 Genentech, Inc. All rights reserved.
*Some start dates are actual (see notes); †estimated date of last participant enrollment July 2018. AIS=acute ischemic stroke; Ph=Phase; SOC=standard of care. 1. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12613000243718; 2. https://clinicaltrials.gov/ct2/show/NCT02398656; 3. https://clinicaltrials.gov/ct2/show/NCT02814409; 4. https://clinicaltrials.gov/ct2/show/NCT03181360; 5. https://clinicaltrials.gov/ct2/show/record/NCT03340493. All sites accessed March 1, 2018. .
Arrow start/ends are
start/completion estimates*
Patient numbers are
enrollment estimates
Arrow width reflects
estimated trial size
#
Ph2: Determining the Optimal Dose of Tenecteplase Before EVT for IS (EXTEND-IA TNK part 2)5
188
patients
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Primary & Secondary Efficacy Outcomes
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EXTEND TRIAL
▪ Ischema View Rapid Imaging
▪ Patient selection 4.5-9hr of onset
▪ IV alteplase
▪ mRS 0-1
• 44% more than placebo
Evolution Continues
60