Evolution of Stroke Thrombolytics · IV administration within 3 h of stroke Pilot Dose Escalation....

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

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjfrIWM1obUAhXFSyYKHQxhBO8QjRwIBw&url=https://www.amazon.co.uk/Draper-32894-Plunger-Handle-135mm/dp/B0001K9SLQ&psig=AFQjCNEmEx1St7aGxQDVmJSopcTR_wdHrw&ust=1495651414121744

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


• 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


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


% P

atients

with

Favora

ble

Outc

om

e

% P

atients

with

Favora

ble

Outc

om

e

NINDS tPA trial


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


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.

https://www.gene.com/medical-professionals/medicines/activase



https://www.gene.com/medical-professionals/medicines/tnkase



Tenecteplase in Acute Ischemic Stroke:

Historical and Ongoing Studies


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


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


*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.


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)


NIHSS=National Institutes of Health Stroke Scale; SD=standard deviation; IQR=interquartile range; TOAST=Trial of Org 10172 in Acute Stroke

Treatment.


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


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


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)


*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.


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


*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


*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


*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*


*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.


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)


*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.


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


*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.


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


*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.


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


*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.


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


*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

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

WAKE UP

Primary & Secondary Efficacy Outcomes

WAKE UP

WAKE UP

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

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