therapy trial eso conference glasgow, scotland april 17, 2015 j mocco 1, osama zaidat 2, rÜdiger...

THERAPY TRIALESO CONFERENCEGLASGOW, SCOTLANDAPRIL 17, 2015

J MOCCO1, OSAMA ZAIDAT2, RÜDIGER VON KUMMER3, ALBERT YOO4, RISHI GUPTA5,

DEMETRIUS LOPES6, DON FREI7, POOJA KHATRI8

FOR THE PENUMBRA THERAPY TRIAL

INVESTIGATORS 1MOUNT SINAI HEALTH SYSTEM, NEW YORK, 2MEDICAL COLLEGE OF WISCONSIN, MILWAUKEE, WI,

3UNIVERSITÄTSKLINIKUM DRESDEN, DRESDEN, GERMANY, 4MASSACHUSETTS GENERAL HOSPITAL/HARVARD,

BOSTON, MA, 5WELLSTAR HEALTH SYSTEM, MARIETTA, GA, 6RUSH UNIVERSITY, CHICAGO, IL, 7SWEDISH

MEDICAL CENTER, DENVER, CO, 8UNIVERSITY OF CINCINNATI, CINCINNATI, OH.

THERAPY Trial

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 Neurovascular

THERAPY Trial

Trial Disclosures

THERAPY funded by Penumbra, Inc.

THERAPY Trial

THERAPY Background

THERAPY sought to evaluate the Penumbra System® in a population of LVO patients thought to be particularly at risk for poor outcome from IV tPA

Clot length > 8mm from thin-sliced NCCT

THERAPY Trial

Study Design

Prospective, RCT, randomized 1:1Control: Monotherapy IV rtPA

Intervention: Combined IV rtPA + IA Penumbra System

692 patients to be enrolled at up to 75 centers

Powered by an expected 10.6% absolute difference in 90 day mRS 0-21, 2,

3

1.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.

2.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.

3.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.

THERAPY Trial

Study Design

Enrollment halted on October 29, 2014

108 patients enrolled

Trial 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.

THERAPY Trial

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 Design

THERAPY Trial

Pre Specified Endpoints

Efficacy (ITT and PP)

PrimaryGood functional outcome at 90 days follow-up as defined by a mRS of 0-2

SecondaryOrdinal improvement in 90-day mRS

Good clinical outcome at 30 days post-procedure*

24-hour infarct volume

Safety

PrimaryIncidence of serious adverse events up to 90 days from enrollment

SecondaryMortality

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.

THERAPY Trial

Blinded Core Lab Assessments

Imaging:• mTICI reperfusion scores• ASPECTS • MCA territory infarct size• Intracerebral hemorrhage (ICH)• Clot Length

Clinical Outcomes:• Video adjudication of Modified Rankin Score (mRS)

THERAPY Trial

mRS Video Assessments• In-person visit recorded using study camcorder

• Standard interview questionnaire for data reliability

• Rankin Focused Assessment Tool (RFAT)1,2,3

• Independent blinded adjudication

• HIPAA compliant

1.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.

2.Quinn TJ, McArthur K, Dawson J, Walters MR, Lees KR. Reliability of structured modified rankin scale assessment. Stroke. 2010;41:e602.

3.Quinn TJ, McArthur K, Dawson J, Walters MR, Lees KR. Reliability of structured modified rankin scale assessment. Stroke. 2010; 41:e603.

THERAPY Trial

J Mocco, MD, MSMount Sinai Health System, USA

Pooja Khatri, MD, MScUniversity of Cincinnati, USA

Osama Zaidat, MD, MScMedical College of Wisconsin, USA

Prof. Dr. med. Rüdiger von Kummer

Universitätsklinikum Carl Gustav Carus Technical University of Dresden, Germany

Rishi Gupta, MD, MBAWellstar Health System, USA

Albert Yoo, MDImaging Core Lab

Massachusetts General Hospital, USA

Randy Edgell, MDUS mRS Adjudicator

The Univ of Texas HS Center, USA

Prof. 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 Organization

THERAPY Trial

US Centers EU Centers

Patients enrolled / planned sample size 108 / 692

Enrolling / Activated 36 / 48

Participating Centers

THERAPY Trial

Inclusion Criteria

• 18 - 85 years of age

• IV tPA treated

• CTA confirmed Large Vessel Occlusion (LVO)

• Clot length > 8mm

• Anterior circulation (ICA, M1, M2)

• NIHSS > 8

• Signed informed consent

THERAPY Trial

Exclusion Criteria• History of stroke in the past 3 months • Females who are pregnant• Pre-stroke mRS score >2• Known severe allergy to contrast media• Uncontrolled 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 shift• Acute ischemic changes in >1/3 of the affected middle cerebral

artery territory • Evidence of intracranial hemorrhage

THERAPY Trial

Exclusion Criteria

• Angiographic evidence of tandem extracranial occlusion or an arterial stenosis proximal to the occlusion that requires treatment prior to thrombus removal

• Angiographic evidence of preexisting arterial injury• Rapidly improving neurological status prior to randomization

• Bilateral stroke• Intracranial tumors• Known history of cerebral aneurysm or arteriovenous malformation

THERAPY Trial

RESULTS

THERAPY Trial

Allocation:Penumbra System + IV tPA (n=55)

90 Day Follow-Up

Final Evaluation n=50:

Final Evaluation not available n=5:

- Lost to follow-up* n=3

- Withdrew consent n=2

Allocation:IV tPA alone (n=53)

90 Day Follow-Up

Final Evaluation n=46:

Final Evaluation not available n=7:

- Lost to follow-up* n=5

- Withdrew consent n=2

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-up

THERAPY Trial

Baseline Characteristics: Demographics

Variable IA + IV IV Alone p-value

Age, mean (SD)

67.4 (11.4)

70.1 (10.3)

0.2257

Female38.2%(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)

0.4664

THERAPY Trial

Baseline Characteristics: Medical History

CharacteristicsIA + IV(N=55)

IV Alone(N=53)

p-value

Previous stroke 9.6% 7.5% 0.7415Previous transient ischemic attack (TIA)

6.1% 3.8% 0.6692

Myocardial infarction 8.0% 1.9% 0.1964Angina/CAD 29.1% 15.1% 0.1058Hypertension 77.8% 78.8% 1.0CHF (congestive heart failure) 13.2% 7.7% 0.5260Dyslipidemia 43.4% 49.0% 0.6942Diabetes 32.1% 37.3% 0.6810Atrial fibrillation 30.9% 49.1% 0.0765Peripheral artery disease 2.0% 3.8% 1.0Extracranial cerebral artery disease

8.3% 11.5% 0.7429

Current or former smoker 59.6% 38.8% 0.0655

THERAPY Trial

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

Characteristica IA + IV IV Alone p-value

Location 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 Characteristics

THERAPY Trial

Onset to Groin Puncture

CT to Groin Puncture

Onset to Randomization

Onset to IV tPA

Onset to ED

0 50 100 150 200 250

IA+IV IV Alone

64 [40,133] a

57 [30,118] a

108 [86,138] a

102 [80,154] a

181 [129,221] a

123 [80,166] a

226 [184,263] a

169 [132,224] a

Key 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)

b

THERAPY Trial

Devices Used

Separator: 54%

Separator 3D: 25%

Ace: 27%

Ace64: 0%

Other: 13%

THERAPY Trial

0 1 2a 2b 30%

10%

20%

30%

40%

50%

60%

7% 7%

16%

51%

19%

mTICI after Penumbra System

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 with additional treatmenta

13%

a Use of Solitaire or Trevo in 7 patients

Pat

ien

ts (

%)

Core Lab Assessed Reperfusion Results

THERAPY Trial

SAFETY OUTCOME

THERAPY Trial

Safety Outcomes: As TreatedOutcome IA + 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)

1.0

THERAPY Trial

INTENT TO TREAT EFFICACY: PRE-SPECIFIED

THERAPY Trial

Efficacy Outcomes: Intent to TreatOutcome IA + IV IV Alone p-value

Primary Endpoint: mRS 0-2 at 90 days 38%

(19/50)30%(14/46)

0.44

THERAPY Trial

Efficacy Outcomes: Intent to TreatOutcome IA + IV IV 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

THERAPY Trial

Efficacy Outcomes: Intent to TreatOutcome IA + IV IV 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 daysa 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.

THERAPY Trial

PER-PROTOCOL EFFICACY:PRE-SPECIFIED

THERAPY Trial

Per-Protocol Enrollment

Allocation:Penumbra System + IV tPA (n=55)

Per-Protocol Enrollment n=43

Excluded from Per-Protocol analysis n=12

- Stenosis proximal to occlusion that requires treatment prior to thrombus removal (n=5)

- Infarct > 1/3 MCA territory (n=5)

- Pre-existing neurologic deficit (n=1)

- Clot length < 8mm (n=1)

90 Day Follow-Up

Final endpoint data available n=41

Final endpoint data not available n=2

- Lost to follow-up n=2

Allocation:IV tPA alone (n=53)

Per-Protocol Enrollment n=47

Excluded from Per-Protocol analysis n=6

- Stenosis proximal to occlusion that requires treatment prior to thrombus removal (n=1)

- Infarct > 1/3 MCA territory (n=4)

- Pre-existing neurologic deficit (n=1)

90 Day Follow-Up

Final endpoint data available n=41

Final endpoint data not available n=6

- Lost to follow-up n=4

- Withdrew consent n=2

Randomized(n=108)

THERAPY Trial

Efficacy Outcomes: Per-Protocol Outcome IA + IV IV Alone p-value

Primary Endpoint:

mRS 0-2 at 90 days 41.5%(17/41)

29.3%(12/41)

0.3557

THERAPY Trial

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)

0.3557

THERAPY Trial

Efficacy Outcomes: Per-Protocol Outcome IA + 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 daysa 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.

THERAPY Trial

Discussion

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

Natural imbalances occur in small cohorts

THERAPY Trial

Discussion

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

Natural imbalances occur in small cohorts

THERAPY Trial

Discussion

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

Natural imbalances occur in small cohorts

Pre-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

THERAPY Trial

Discussion

THERAPY used unique selection criteria

Impact is difficult to asses across this small population

THERAPY Trial

Discussion

StudySymptomatic ICH

IA + IVSymptomatic 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 Trial

Discussion

StudySymptomatic ICH

IA + IVSymptomatic 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 Trial

Discussion

StudySymptomatic ICH

IA + IVSymptomatic 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%

THERAPY Trial

Discussion

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

THERAPY Trial

Discussion

Pre-specified PP analysis of ordinal mRS OR 2.25 95% CI (1.0, 5.0) p-value=0.047

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

Pre-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 parameters

THERAPY Trial

Internal Validity: general trend in dataIA BetterIA Worse

Prespecified Primary and Secondary Endpoints

THERAPY Trial

External Validity

THERAPY’s relative effect size is consistent with MR CLEAN and other

recent early-terminated trials

THERAPY Trial

Endovascular Trials: Mortality (ITT)

ESCAPE

SWIF

T PRIM

E

EXTEND-IA

REVASCAT

MR C

LEAN

THERAPY0%

5%

10%

15%

20%

25%

30%

10% 9% 9%

18% 19%

12%

19%

12%

20%

16%18%

24%

IA+IV IV Alonea ESCAPE adjusted analysis p<0.05

a

THERAPY Trial

Endovascular Trials: Mortality (ITT)

ESCAPE

SWIF

T PRIM

E

EXTEND-IA

REVASCAT

MR C

LEAN

THERAPY0%

5%

10%

15%

20%

25%

30%

10% 9% 9%

18% 19%

12%

19%

12%

20%

16%18%

24%

IA+IV IV Alonea ESCAPE adjusted analysis p<0.05

a

THERAPY Trial

Endovascular Trials: Ordinal mRSIA BetterIA Worse

THERAPY Trial

Endovascular Trials: Ordinal mRSIA BetterIA Worse

THERAPY Trial

Endovascular Trials: Ordinal mRSIA BetterIA Worse

THERAPY Trial

Conclusion

While 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 trials

THERAPY Trial

Enrolling CentersSite Investigator

Rush UniversitySwedish Medical CenterCentral DuPage HospitalUniversity of CincinnatiKaiser Los AngelesSt. Joseph's Regional Medical CenterRiverside Methodist HospitalVanderbiltSunrise Hospital and Medical CenterSt. Joseph’s BNIErlanger Health System Lutheran Medical CenterMedical College of WisconsinUniversity of Chicago Medical CenterMiami ValleyJackson Memorial HospitalCedars-SinaiThe Valley HospitalMethodist HospitalForsyth Medical CenterSparrow HospitalJFK Medical CenterAlexian BrothersHoly CrossWellStar Research InstituteShands at University of FloridaAbbott NorthwesternUCSDKaleida HealthGrady Memorial HospitalLehigh Valley HospitalStony Brook Medical Center

Demetrius LopesDon FreiHarish ShownkeenAaron GrossmanZahra A. AjaniDorothea AltschulRon BudzikJ.MoccoLindsey BlakeCameron McDougallBlaise BaxterJeffrey FarkasBrian Fred FitzsimmonsSeon Kyu LeeJohn TerryDileep YavagalMichael AlexanderDorothea AltschulDavid ChiuDon HeckSyed HussainJawad KirmaniTim MalischLaszlo MiskolcziRishi GuptaSpiros BlackburnJosser DelgadoAlexander KhalessiElad LevyRaul NogueiraChristian SchumacherHenry Woo

Site Investigator

Universitätsklinikum DresdenUniversitätsmedizin GöttingenUniversitätsklinikum AachenCharité Berlin

Rüdiger von KummerMichael KnauthMartin WiesmannChristian Nolte

United States Europe

THERAPY Trial

THANK YOU

THERAPY Trial

ASPECTS AnalysisCore Lab Determined (ITT)

VariableIA + IV

Day 90 mRS 0-2IV Alone

Day 90 mRS 0-2p-value*

ASPECTS 0 to 4 0% (0/4)

33.3% (1/3)

0.2514

ASPECTS 5 to 1042.2%

(19/45)

30.2% (13/43)

*p-value from logistic regression treatment interaction**IA+IV group unable to read ASPECTS in 1 subject

THERAPY Trial

mTICIaIA + IV

Day 90 mRS 0-2p-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)

THERAPY Trial

GroupIA + IV

Day 90 mRS 0-2N = 50

IV AloneDay 90 mRS 0-2

N = 46p-valuea

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 LocationICA 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 LocationUS 36.4% (16/44) 27.9% (12/43) 0.9958Europe 50.0% (3/6) 66.7% (2/3)

a p-value from logistic regression treatment interaction

Pre-specified Subgroups (ITT)

THERAPY Trial

Intracranial ICA occlusion percentage

StudyIntracranial ICA

IA + IVIntracranial 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%

THERAPY Trial

IA + IV

IV Alone

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

6.0%

2.2%

20.0%

13.0%

12.0%

15.2%

16.0%

15.2%

30.0%

21.7%

4.0%

8.7%

12.0%

23.9%

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)

a

THERAPY Trial

IA + IV

IV Alone

0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0%

7.3%

2.4%

22.0%

12.2%

12.2%

14.6%

19.5%

17.1%

26.8%

19.5%

4.9%

9.8%

7.3%

24.4%

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