THERAPY Trial - PowerPoint Presentation

Slide1

THERAPY Trial

ESO ConferenceGlasgow, ScotlandApril 17, 2015

J Mocco

1

, Osama Zaidat

2

,

Rüdiger

von Kummer

3

, Albert Yoo

4

, Rishi Gupta

5

, Demetrius Lopes

6

, Don

Frei

7

,

Pooja

Khatri

8

for

the Penumbra THERAPY Trial Investigators

1

Mount

Sinai Health System, New York,

2

Medical College of Wisconsin, Milwaukee, WI,

3

Universitätsklinikum Dresden,

Dresden, Germany,

4

Massachusetts General Hospital/Harvard, Boston, MA,

5

WellStar

Health

System, Marietta, GA,

6

Rush University, Chicago, IL,

7

Swedish Medical Center, Denver, CO,

8

University

of Cincinnati, Cincinnati, OH. Slide2

Personal Disclosures

NIH:

NIH 1U01NS086492-01 (CO-PI)

NIH 1R01NS078828-01A1 (CO-

Inv

)

National/International PI/Co-PI:

COAST (Co-PI)

THERAPY

(PI)

FEAT (PI)

LARGE (Co-PI)

POSITIVE (Co-PI)

Steering Committee: MAPS

Consultant: Lazarus Effect, Medina, Pulsar, Edge Therapeutics

Investor: Blockade Medical, Medina

Medical, Lazarus Effect

Advisory Board: Codman NeurovascularSlide3

Trial Disclosures

THERAPY funded by Penumbra, Inc.Slide4

THERAPY BackgroundTHERAPY sought to evaluate the Penumbra System

® in a population of LVO patients thought to be particularly at risk for poor outcome from IV tPAClot length > 8mm from thin-sliced NCCTSlide5

Study DesignProspective, RCT, randomized 1:1

Control: Monotherapy IV rtPAIntervention: Combined IV rtPA + IA Penumbra System692 patients to be enrolled at up to 75 centersPowered by an expected 10.6% absolute difference in 90 day mRS 0-2

1, 2,

3

Bhatia R, Hill MD,

Shobha

N, et al. Low Rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke:

Real

-world experience and a call for action. Stroke. 2010;41:2254-2258.

Tarr

R, Hsu D,

Kulcsar

Z, et al. The POST Trial: Initial post-market experience of the Penumbra System. Revascularization of large vessel occlusion

in

acute ischemic stroke in the United States and Europe. J

Neurointerv

Surg. 2010;2:341-344.

Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal Stroke Trial: Safety and effectiveness of a new generation of mechanical devices

for

clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40:2761-2768

.Slide6

Study DesignEnrollment halted on October 29, 2014

108 patients enrolledTrial halted by steering committee secondary to external evidence from MR CLEAN, EXTEND IA, and ESCAPE that indicated a lack of equipoise. Not due to DSMB review of data for evaluation of stopping rules. Slide7

Patient presents with acute ischemic stroke

from LVO within 4.5hrs from onset, treated with IV rtPA

Informed

Consent, Screened for eligibility,

>

8mm clot length from thin-sliced NCCT,

IA initiated within 5

hours, Randomized

1:1

Monotherapy

IV

rtPA

24 Hour and 7 Day/Discharge

30 Day Follow Up

90 Day Follow Up

Combined IV

rtPA

+ IA Penumbra

24 Hour and 7 Day/Discharge

30 Day Follow Up

90 Day Follow Up

Study DesignSlide8

Pre Specified EndpointsEfficacy (ITT and PP)

PrimaryGood functional outcome at 90 days follow-up as defined by a mRS of 0-2 SecondaryOrdinal improvement in 90-day mRSGood clinical outcome at 30 days post-procedure*24-hour infarct volume

Safety

Primary

Incidence

of serious adverse events up to 90 days from

enrollment

Secondary

Mortality

Incidence

of symptomatic and asymptomatic

hemorrhage

Note: All

primary and secondary efficacy endpoints

pre

-specified

for

both the intent-to-treat (ITT) population and per-protocol (PP) population.

*Good clinical outcome at 30 days post-procedure as defined by a 10 points or more improvement in the NIHSS at Discharge, NIHSS score or 0-1 at Discharge; or a 30-day mRS score of 0-2.Slide9

Blinded Core Lab AssessmentsImaging:

mTICI reperfusion scoresASPECTS MCA territory infarct sizeIntracerebral hemorrhage (ICH)Clot Length Clinical Outcomes:Video adjudication of Modified Rankin Score (mRS) Slide10

mRS

Video AssessmentsIn-person visit recorded using study camcorderStandard interview questionnaire for data reliabilityRankin Focused Assessment Tool (RFAT)1,2,3Independent blinded adjudication HIPAA compliant

Saver JL,

Filip

B, Hamilton S, et al. Improving the reliability of stroke disability grading in clinical trials and clinical practice: the Rankin Focused Assessment (RFA).

Stroke

. 2010;41:992-995

.

Quinn TJ, McArthur K, Dawson J, Walters MR, Lees KR. Reliability of structured modified

rankin

scale assessment. Stroke. 2010;41:e602

.

Quinn TJ, McArthur K, Dawson J, Walters MR, Lees KR. Reliability of structured modified

rankin

scale assessment. Stroke. 2010; 41:e603.Slide11

J

Mocco, MD, MSMount Sinai Health System, USAPooja Khatri, MD, MScUniversity of Cincinnati, USA

Osama

Zaidat

, MD, MSc

Medical College of Wisconsin, USA

Prof. Dr. med.

Rüdiger

von

Kummer

Universitätsklinikum

Carl Gustav

Carus

Technical University

of Dresden, Germany

Rishi Gupta,

MD,

MBA

Wellstar

Health System,

USA

Albert Yoo, MDImaging Core Lab

Massachusetts General Hospital, USA Randy Edgell, MDUS mRS AdjudicatorThe

Univ of Texas HS Center, USAProf. Dr. med. E. Bernd Ringelstein

EU mRS AdjudicatorUniversity Hospital Münster

, Germany

Academic Steering Committee

Core Labs

Thanh

Nguyen, MDBoston University, USA

Darren Orbach, MD, PhDBoston Children’s Hospital, USA

William Mack, MDUniversity of Southern California, USA

Scott Hamilton, PhDStanford University School of Medicine, USA

CEC and DSMB

Trial OrganizationSlide12

US Centers

EU Centers

Patients enrolled / planned sample size

108 / 692

Enrolling / Activated

36 / 48

Participating CentersSlide13

Inclusion Criteria18 - 85 years of age

IV tPA treatedCTA confirmed Large Vessel Occlusion (LVO)Clot length > 8mm Anterior circulation (ICA, M1, M2)NIHSS > 8

Signed informed

consentSlide14

Exclusion CriteriaHistory of stroke in the past 3 months Females who are pregnantPre-stroke

mRS score >2Known severe allergy to contrast mediaUncontrolled hypertension (systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg)CT evidence of the following conditions at randomization:Significant mass effect with midline shiftAcute ischemic changes in >1/3 of the affected middle cerebral artery territory Evidence of intracranial

hemorrhageSlide15

Exclusion CriteriaAngiographic evidence of tandem extracranial

occlusion or an arterial stenosis proximal to the occlusion that requires treatment prior to thrombus removalAngiographic evidence of preexisting arterial injuryRapidly improving neurological status prior to randomizationBilateral strokeIntracranial tumorsKnown history of cerebral aneurysm or arteriovenous malformationSlide16

ResultsSlide17

Randomized

(n=108)*If there is no response after 3 failed attempts to contact the patient, the site mails a certified letter to the patient’s last known address.

Randomization and Follow-upSlide18

Baseline Characteristics: Demographics

VariableIA + IV

IV

Alone

p-value

Age, mean

(

SD)

67.4

(

11.4)

70.1

(

10.3)

0.2257

Female

38.2

%

(21/55)

56.6

%

(30/53)

0.0823

Admission NIHSS,

median

[

IQR]

17

[13,22]

18

[

14,22]

0.4254

Glucose mg/

dL, median

[IQR

]

110.5

[

99.0,151.0]

116.0

[

103.0,133.0]

0.9305

Systolic

BP mmHg,

mean

(

SD)

148.2

(

22.3)

150.4

(

19.1)

0.4664Slide19

Baseline Characteristics: Medical History

CharacteristicsIA + IV

(N=55)

IV

Alone

(N=53)

p-value

Previous stroke

9.6

%

7.5

%

0.7415

Previous transient ischemic attack (TIA)

6.1%

3.8

%

0.6692

Myocardial infarction

8.0

%

1.9

%

0.1964

Angina/CAD

29.1

%

15.1

%

0.1058

Hypertension

77.8

%

78.8

%

1.0

CHF (congestive heart failure)

13.2%

7.7

%

0.5260

Dyslipidemia

43.4

%

49.0%

0.6942

Diabetes

32.1%

37.3

%

0.6810

Atrial fibrillation

30.9

%

49.1

%

0.0765

Peripheral artery disease

2.0

%

3.8

%

1.0

Extracranial cerebral artery disease

8.3

%

11.5

%

0.7429

Current or former smoker

59.6%

38.8%

0.0655Slide20

ASPECTS, median

(IQR)7.5 [6.0,9.0]8.0 [7.0,9.0]0.4867

0 to 4

11.1%

(6/54)

7.5%

(4/53)

0.7140

5 to 7

38.9%

(21/54)

35.8%

(19/53)

8 to 10

50.0%

(27/54)

56.6%

(30/53)

Clot length, median

(IQR)

12.9

[9.4,22.2]

14.1

[10.1,18.6]

0.8925

Characteristic

a

IA + IVIV

Alone

p-valueLocation of stroke: Left

hemisphere

60.0%(33/55)

58.5%

(31/53)

1.0

Site of primary occlusion

Intracranial

ICA

32.7%

(18/55)

22.6%

(12/53)

0.4365

MCA

M1

56.4%

(31/55)

67.9%

(36/53)

MCA

M2

10.9%

(6/55)

9.4%

(5/53)

a

As

adjudicated by the core

laboratory; imaging ASPECTS not available for 1 subject

Imaging CharacteristicsSlide21

64

[40,133] a57 [30,118] a

108

[86,138]

a

102

[80,154]

a

181

[129,221]

a

123

[80,166]

a

226

[184,263] a169

[132,224] aKey Time Metrics (minutes)

a Median [IQR] b Initial protocol allowed up to 8 hours, protocol revision for up to 5

hours (6.5% were > 5 hours)bSlide22

Devices UsedSeparator: 54%

Separator 3D: 25%Ace: 27%Ace64: 0%Other: 13%Slide23

mTICI Score

IA +

IV

mTICI

2/3

after Penumbra System

®

86%

mTICI 2b

/

3

after

Penumbra System

70%

Final mTICI 2b

/

3

after additional treatment

73%

Patients w

ith a

dditional

treatment

a

13%

a

Use

of Solitaire or Trevo in 7 patientsPatients (%)

Core Lab Assessed Reperfusion ResultsSlide24

Safety outcomeSlide25

Safety Outcomes: As Treated

OutcomeIA + IV

IV

Alone

p-value

Primary Endpoint:

Serious Adverse Event at 90 days

42

%

(18/43)

48

%

(30/62)

0.55

Pre-Specified

Secondary Endpoints:

Mortality

at 90

days (ITT)

12.0%

(6/50)

23.9%

(11/46)

0.1811

Symptomatic

ICH -

Core Lab with ≥ 4 point change in NIHSS

9.3%

(4/43)

9.7%

(6

/62)

1.0Slide26

Intent To Treat efficacy: Pre-specified Slide27

Efficacy Outcomes: Intent to Treat

OutcomeIA + IVIV

Alone

p-value

Primary Endpoint:

mRS

0-

2 at 90 days

38%

(19/50)

30%

(14/46)

0.44Slide28

Efficacy Outcomes: Intent to Treat

OutcomeIA + IVIV

Alone

p-value

Primary Endpoint:

mRS

0-

2 at 90 days

38.0%

(19/50)

30.4%

(14/46)

0.5206

Pre-Specified Secondary

Endpoint

:

Ordinal

mRS

Slide29

Efficacy Outcomes: Intent to Treat

OutcomeIA + IVIV

Alone

p-value

Primary Endpoint:

mRS

0-

2 at 90 days

38.0%

(19/50)

30.4%

(14/46)

0.5206

Pre-specified Secondary Endpoint:

Good

outcome

at

30

days

a

45.3

%

(24/53)

32.1%

(17/53)

0.2313

Additional Outcomes:

mRS

0-

1 at

90 days

26.0%

(13/50)

15.2%

(7/46)

0.2182

NIHSS

improvement at 24 hours,

median

[

IQR]

6.0

[-3.0,11.0]

1.0

[-1.0,9.0]

0.3036

NIHSS 0 to 2

at

90

days

40.9

%

(18/44)

29.5

%

(13/44)

0.3722

a. Good clinical outcome at 30 days post-procedure as defined by a 10 points or more improvement in the NIHSS

at Discharge, NIHSS score or 0-1 at Discharge; or a 30-day

mRS

score of 0-2.Slide30

per-Protocol

efficacy:Pre-specified Slide31

Per-Protocol Enrollment

Randomized(n=108)Slide32

Efficacy Outcomes: Per-Protocol

OutcomeIA + IV

IV

Alone

p-value

Primary

Endpoint:

mRS 0-2 at 90 days

41.5%

(17/41)

29.3%

(12/41)

0.3557Slide33

Efficacy Outcomes: Per-Protocol

Pre-Specified Secondary Endpoint: Ordinal mRS

Outcome

IA +

IV

IV

Alone

p-value

Primary

Endpoint:

mRS 0-2 at 90 days

41.5%

(17/41)

29.3%

(12/41)

0.3557Slide34

Efficacy Outcomes: Per-Protocol

OutcomeIA + IV

IV

Alone

p-value

Primary

Endpoint:

mRS 0-2 at 90 days

41.5%

(17/41)

29.3%

(12/41)

0.3557

Pre-Specified Secondary

Endpoint:

Good outcome at

30

days

a

51.2

%

(22/43)

34.0

%

(16/47)

0.1352

Additional Outcomes:

mRS

0-

1 at

90 days

29.3

%

(12/41)

14.6

%

(6/41)

0.1813

NIHSS

improvement at 24 hours,

median

[

IQR]

6.0

[

-2.0,10.5]

1.0

[

-2.0,9.0]

0.2359

NIHSS 0 to 2

at

90

days

47.2%

(17/36)

30.0%

(12/40)

0.1580

a. Good clinical outcome at 30 days post-procedure as defined by a 10 points or more improvement in the NIHSS

at Discharge, NIHSS score or 0-1 at Discharge; or a 30-day

mRS

score of 0-2.Slide35

DiscussionEarly termination secondary to MR CLEAN, ESCAPE, EXTEND-IA severely limits data interpretation

Natural imbalances occur in small cohortsSlide36

DiscussionEarly termination secondary to MR CLEAN, ESCAPE, EXTEND-IA severely limits data interpretation

Natural imbalances occur in small cohortsSlide37

DiscussionEarly termination secondary to MR CLEAN, ESCAPE, EXTEND-IA severely limits data interpretation

Natural imbalances occur in small cohortsPre-specified Secondary Outcome:Multivariable adjusted ordinal analysis ITT: OR 2.4, 95% CI 1.1,5.1; p-value=0.02

PP

:

OR 2.4, 95%CI: 1.1,5.8; p-value=0.03 Slide38

DiscussionTHERAPY used unique selection criteria

Impact is difficult to asses across this small populationSlide39

Discussion

StudySymptomatic ICH

IA

+

IV

Symptomatic

ICH

IV Alone

ESCAPE

(n=315)

3.6%

2.7%

SWIFT

-PRIME

(n=196)

1%

3.1%

EXTEND

IA

(n=70)

0%

6%

MR CLEAN

(n=500)

7.7%

6.4%

THERAPY

(n=108)

10.9%

11.3%

THERAPY used unique selection criteria Impact is difficult to asses across this small populationSlide40

Discussion

StudySymptomatic ICH

IA

+

IV

Symptomatic

ICH

IV Alone

ESCAPE

(n=315)

3.6%

2.7%

SWIFT

-PRIME

(n=196)

1%

3.1%

EXTEND

IA

(n=70)

0%

6%

MR CLEAN

(n=500)

7.7%

6.4%

THERAPY

(n=108)

10.9%

11.3%

THERAPY used unique selection criteria

Impact is difficult to asses across this small populationSlide41

Discussion

StudySymptomatic ICH

IA

+

IV

Symptomatic

ICH

IV Alone

ESCAPE

(n=315)

3.6%

2.7%

SWIFT

-PRIME

(n=196)

1%

3.1%

EXTEND

IA

(n=70)

0%

6%

MR CLEAN

(n=500)

7.7%

6.4%

THERAPY

(n=108)

10.9%

11.3%

THERAPY used unique selection criteria

Impact is difficult to asses across this small population

THERAPY using Swift Prime Definition 2.3% 4.8%Slide42

DiscussionHowever, despite being underpowered THERAPY demonstrates consistent suggestion of superiority for the endovascular arm Slide43

DiscussionPre-specified PP analysis of ordinal mRS

OR 2.25 95% CI (1.0, 5.0) p-value=0.047Pre-specified adjusted ITT analysis of ordinal mRS OR 2.4 95% CI (1.1, 5.1) p-value=0.02Pre-specified adjusted

PP

analysis of ordinal

mRS OR

2.4 95% CI (1.1, 5.8) p-value=

0.03

Data demonstrate

an effect size indicating benefit for the endovascular

arm across all measured parametersSlide44

Internal Validity: general trend in data

IA BetterIA WorsePrespecified

Primary and Secondary Endpoints Slide45

External ValidityTHERAPY’s relative effect size is consistent with MR CLEAN and other recent early-terminated trials

Slide46

Endovascular Trials: Mortality (ITT)

a ESCAPE adjusted analysis p<0.05aSlide47

Endovascular Trials: Mortality (ITT)

a ESCAPE adjusted analysis p<0.05aSlide48

Endovascular Trials: Ordinal mRS

IA BetterIA WorseSlide49

Endovascular Trials: Ordinal mRS

IA BetterIA WorseSlide50

Endovascular Trials: Ordinal mRS

IA BetterIA WorseSlide51

ConclusionWhile limited due to small sample size following early

termination, THERAPY demonstrates a consistent direction towards benefit across all outcome measures and an effect size comparable with current modern thrombectomy trialsSlide52

Enrolling Centers

Site InvestigatorRush University

Swedish Medical Center

Central

DuPage

Hospital

University

of Cincinnati

Kaiser Los Angeles

St. Joseph's Regional Medical Center

Riverside Methodist Hospital

Vanderbilt

Sunrise Hospital

and Medical Center

St. Joseph’s BNI

Erlanger Health System

Lutheran Medical Center

Medical College of Wisconsin

University of Chicago Medical Center

Miami Valley

Jackson

Memorial Hospital

Cedars-Sinai

The Valley Hospital

Methodist Hospital

Forsyth Medical Center

Sparrow Hospital

JFK Medical Center

Alexian

Brothers

Holy Cross

WellStar

Research Institute

Shands at University of Florida

Abbott Northwestern

UCSDKaleida Health

Grady Memorial Hospital

Lehigh Valley Hospital

Stony Brook Medical Center

Demetrius Lopes

Don

Frei

Harish

Shownkeen

Aaron Grossman

Zahra A. Ajani

Dorothea

Altschul

Ron

Budzik

J.Mocco

Lindsey Blake

Cameron McDougall

Blaise

Baxter

Jeffrey

Farkas

Brian

Fred Fitzsimmons

Seon

Kyu

Lee

John Terry

Dileep

Yavagal

Michael Alexander

Dorothea

Altschul

David Chiu

Don Heck

Syed

Hussain

Jawad

Kirmani

Tim MalischLaszlo MiskolcziRishi GuptaSpiros BlackburnJosser DelgadoAlexander KhalessiElad LevyRaul NogueiraChristian SchumacherHenry WooSite InvestigatorUniversitätsklinikum DresdenUniversitätsmedizin GöttingenUniversitätsklinikum AachenCharité BerlinRüdiger von KummerMichael Knauth

Martin WiesmannChristian Nolte

United States

EuropeSlide53

THANK YOUSlide54

ASPECTS AnalysisCore Lab Determined (ITT)

VariableIA + IV

Day 90 mRS 0-2

IV

Alone

Day 90 mRS 0-2

p-value*

ASPECTS 0 to 4

0%

(0/4)

33.3%

(1/3)

0.2514

ASPECTS 5 to 10

42.2%

(19/45)

30.2%

(13/43)

*p-value from logistic regression treatment interaction

**IA+IV group unable to read ASPECTS in 1 subjectSlide55

mTICI

aIA + IV

Day 90 mRS 0-2

p-value

mTICI

0 to 2a

after Penumbra

System

9%

0.0668

mTICI

2b to 3

after Penumbra

System

42%

a

As

adjudicated by the core laboratory

Exploratory Analysis:

mTICI

and Outcome (ITT)Slide56

Group

IA + IV

Day 90 mRS 0-2

N = 50

IV

Alone

Day 90 mRS 0-2

N = 46

p-

value

a

Age

< 65

41.2%

(

7/17)

45.5%

(

5/11)

0.3101

≥ 65

36.4%

(12/33)

25.7%

(

9/35)

NIHSS

< 20

32.3%

(10/31)

38.5%

(10/26)

0.1793

≥ 20

47.4%

(9/19)

20.0%

(4/20)

Occlusion Location

ICA

26.7%

(4/15)

10.0%

(1/10)

0.4946

M1

34.5%

(10/29)

33.3%

(11/33)

M2

83.3%

(5/6)

66.7%

(2/3)

Geographic Location

US

36.4%

(16/44)

27.9%

(12/43)

0.9958

Europe

50.0%

(3/6)

66.7%

(2/3)

a

p-value from logistic regression treatment interaction

Pre-specified Subgroups (ITT)Slide57

Intracranial ICA occlusion percentage

StudyIntracranial ICA

IA

+

IV

Intracranial ICA

IV Alone

ESCAPE

(n=315)

27.6%

(with

M1

)

26.5%

(with

M1

)

SWIFT

-PRIME

(n=196)

18.3%

16%

EXTEND

IA

(n=70)

31%

31%MR CLEAN (n=500)

25.7% (with/without M1)

29.3% (with/without

M1)

THERAPY (n=108)

32.7%

22.6%Slide58

mRS

0

mRS

1

mRS

2

mRS

3

mRS

4

mRS

5

mRS

6

a

OR 1.76 (95% CI: 0.86 to 3.59)

mRS

at 90 days

Pre-specified

Endpoint: Ordinal

mRS

(ITT)

aSlide59

a

2.28

OR 95% CI (

1.05, 4.96)

p value

= 0.0384

mRS

0

mRS

1

mRS

2

mRS

3

mRS

4

mRS

5

mRS

6

Pre-specified

Endpoint: Ordinal

mRS

(PP)

a

mRS

at 90 days