12/4/2017. Disclosures. Study organization. Stryker Medtronic Penumbra Viz Route 92. Data safety monitoring board Tudor G.

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1 12/4/2017 Update on Stroke Trials:Extending the Window DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo NP v1.0 Slide 1 of 26 Disclosures Stryker Medtronic Penumbra Viz Route 92 NP v1.0 Slide 2 of 26 Study organization Study principal investigators Data safety monitoring board Tudor G. Jovin, MD Wade Smith, MD - chair Raul Nogueira, MD Daryl Gress, MD Independent statisticians Berry Consultants Scott Berry PhD Todd Graves PhD Steven Hetts, MD Steering committee Roger Lewis, MD, PhD Blaise Baxter, MD Demetrius Lopes, MD Prof. Alain Bonafe Vitor Pereira, MD Anthony Furlan, MD Marc Ribo, MD Rishi Gupta, MD Jeffrey Saver, MD Prof. Olav Jansen Clinical events committee (CEC) Timothy Malisch, MD Ansaar Rai, MD Kevin Sheth, MD Core lab Neurovascular Research Imaging Core David Liebeskind, MD NP v1.0 Slide 3 of 26 1

2 Study background Current evidence suggests that benefit of thrombectomy rapidly decays over time and may no longer exist beyond 7.3 hours from stroke onset (or TLSW) 1 Indeed, the current AHA and ESO guidelines define a rigid therapeutic window of 6 hours as level 1a evidence 2,3 This treatment paradigm disregards individual variations in compensatory mechanisms for ischemia led by but not restricted to collateral flow. Growing evidence supports a physiologic rather than a purely time based approach where patients with Clinical-Core Mismatch (e.g. significant clinical deficits but still limited infarct size) may benefit from reperfusion regardless of time to treatment. 4 Wake-up strokes, strokes with unclear onset time, and witnessed late presenting strokes (> 6 hours) represent a large proportion of LVOS (~40%) yet no proven treatment options exist for this population. Outcomes = Collaterals Time 1 Saver et al, JAMA Powers et al, Stroke Wahlgren Int J Stroke 2016 et.al. 4 Jovin et.al, Stroke 2011 NP v1.0 Slide 4 of 26 Purpose of the DAWN Trial? The DAWN Trial was designed to compare the benefit of treatment with the Trevo Retriever vs. medical management alone within 6-24 hours after time last seen well (TSLW). The idea was that this trial would establish new options for an underserved patient population whose only option was medical management. NP v1.0 Slide 5 of 26 Study design Study design Patient population Target vessel Randomization Sites Sample size Multi-center, Bayesian adaptive-enrichment, prospective, randomized, open, masked assessment of endpoint trial Acute ischemic stroke (AIS) with large vessel occlusion Able to be randomized between six to 24 hours after time last known well Clinical imaging mismatch (CIM) defined by age, core, and NIHSS Intracranial ICA, M1 segment of the MCA 1:1 Trevo Retriever + medical management vs. medical management alone Up to 50 sites worldwide (30 US and 20 international) 500 maximum subjects: 250 in the treatment arm and 250 in the control arm. Minimum sample size is 150 subjects. Follow-up 24 hours (-6/+24), day 5-7/discharge, day 30 (± 14), and day 90 (± 14) NP v1.0 Slide 6 of 26 2

Study methods: workflow 6-24h NCCT/DWI: <1/3 MCA Territory CTA/MRA: ICA-T and/or MCA-M1 (Tandem Occlusions Allowed) Control 90-day mrs Informed Consent 1:1 Randomization: - CIM subgroup - ICA-T vs

NIHSS 20 + core <51cc Thrombectomy - U-W mrs - mrs 0-2 NP001713 v1.

utility-weighted mrs Nested dichotomous mrs 0-2 Early response at day 5-7/discharge, defined as a NIHSS drop of 10 points from baseline or NIHSS score 0 or 1 All cause mortality rates Median final

3 Study methods: workflow 6-24h NCCT/DWI: <1/3 MCA Territory CTA/MRA: ICA-T and/or MCA-M1 (Tandem Occlusions Allowed) Control 90-day mrs Informed Consent 1:1 Randomization: - CIM subgroup - ICA-T vs M vs 12-24h - Age 18 - NIHSS 10 - Pre-mRS TLSW to Randomization: 6-24h RAPID CTP/DWI CIM: A. 80 y/o: 1. NIHSS 10 + core <21cc B. <80 y/o: 2. NIHSS 10 + core <31cc 3. NIHSS 20 + core <51cc Thrombectomy - U-W mrs - mrs 0-2 NP v1.0 Slide 7 of 26 Study endpoints Primary endpoint Secondary endpoints Primary safety endpoint Secondary safety endpoint 90-day disability assessed by the modified Rankin scale (mrs) Assessed via utility-weighted mrs Nested dichotomous mrs 0-2 Early response at day 5-7/discharge, defined as a NIHSS drop of 10 points from baseline or NIHSS score 0 or 1 All cause mortality rates Median final infarct size at 24 (-6/+24) hours from randomization Revascularization rates at 24 (-6/+24) hours from randomization : reperfusion rates post device and post procedure by angiography core lab measurement of modified TICI > 2b Strokerelated mortality at 90 days Incidence of SICH, by ECASS III definition, within 24 (-6/+24) hours post randomization Incidence of neurological deterioration from baseline NIHSS score through day 5-7/discharge Incidence of procedure-related and device-related serious adverse events through 24 (-6/+24) hours post randomization NP v1.0 Slide 8 of 26 DAWN Trial utility-weighted mrs and enrichment Utility-weighted mrs Better captures health state transitions across the entire spectrum Patient-centered outcomes analysis mrs Weight Enrichment Designed to fine tune the patient population based on core infarct size Identify subgroups experiencing clinical benefit First futility/enrichment analysis at 150 subjects First efficacy analysis at 200 subjects Interim analysis after every 50 subjects up to 500 max 0-50 cc 0-45 cc 0-40 cc 0-35 cc0-30 cc NP v1.0 Slide 9 of 26 3

4 Trial enrollment rate and termination Site Status Sites Qualified 36 Contracts Executed 31 Sites Initiated 30 Sites Activated to Enroll 30 IRB/EC Approvals 31 Subjects Enrolled 206 Actual / Projected Enrollment Subjects Sep-14 Oct-14 Nov-14 Dec-14 Jan-15 Feb Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 Sep-15 Oct-15 Nov Dec Jan-16 Feb-16 Mar Apr May-16 Jun Jul-16 Aug-16 * Sep-16 Oct Nov-16 Dec Jan-17 Feb-17 Mar Apr-17 May-17 Jun-17 Jul Aug-17 Sep Oct-17 Nov-17 Dec-17 Enrollment stopped at DSMB recommendation. Actual Subjects Planned Subjects *Boundary for first enrichment not crossed. NP v1.0 Slide 10 of 26 Results NP v1.0 Slide 11 of 26 Randomization and follow-up * 30 day mrs carried forward in 4 pts 100% follow-up to 30 days NP v1.0 Slide 12 of 26 4

5 Demographics Age (years) (mean) or over (%) 23.4% 29.3% NIHSS, baseline (median, [IQR]) 17 [13-21] 17 [14-21] NIHSS (%) 72.9% 72.7% Sex, male (%) 39.3% 51.5% IV-tPA administered 4.7% 13.1% NP v1.0 Slide 13 of 26 Medical history Hypertension 77.6% 75.8% Atrial fibrillation* 40.2% 24.2% Diabetes mellitus 24.3% 31.3% Previous ischemic stroke or TIA 11.2% 11.1% * p=0.01 NP v1.0 Slide 14 of 26 Baseline imaging characteristics Baseline infarct volume by site RAPID (cc), median,[iqr] 7.6 [ ] 8.9 [ ] Patients with baseline MRI (%)* 43.0% 37.8% Patients with baseline CT/CTA/CTP(%)* 76.6% 76.5% * Patients may have both CTP and MRI NP v1.0 Slide 15 of 26 5

6 Baseline clot locations core lab adjudicated Clot location ICA 20.6% 19.2% M1 73.8% 74.7% M2 2.8% 3.0% NP v1.0 Slide 16 of 26 Workflow times and mode of stroke presentation Timelast seen well to randomization hours median [IQR] Time symptoms observed to randomization hours, median [IQR] Time last seen well to revascularization (TICI 2b/3) hours median [IQR] Mode of stroke presentation 12.2 (10.2, 16.3) 13.3 (9.4, 15.8) 4.8 [ ] 5.6 [ ] 13.6 [ ] NA Wake up stroke* 62.6% 47.5% Witnessed stroke 10.3% 14.1% Un-witnessed stroke 27.1% 38.4% * P=0.04 NP v1.0 Slide 17 of 26 Primary endpoints 90-day utlityweighted mrs Trevo MM Treatment benefit (95% CI) 5.5 ± ± (1.2, 3.1) Bayesianprobability of superiority >0.9999* 90-day mrs % 13.1% 35.5% (23.9%, 47.0%) >0.9999* *Similar to p< NNT for 90-day functional independence = 2.8 NP v1.0 Slide 18 of 26 6

Primary endpoints 48.6 % functional independence at 90 days 73% relative risk reduction of dependency in activities of daily life (ADL) 13.1 % functional independence at 90 days NP001713 *Similar v1.

7 Primary endpoints 48.6 % functional independence at 90 days 73% relative risk reduction of dependency in activities of daily life (ADL) 13.1 % functional independence at 90 days NP *Similar v1.0 to Slide p< of day mrs 0-2 by TLSW to randomization Trevo Retriever MM P-value 6-12h 55.1% 20.0% < h 43.1% 7.4% <0.001 Trevo Retriever MM NP v1.0 Slide 20 of 26 Procedural characteristics and outcomes Procedure duration (minutes) (median IQR) 56.0 [ ] Total number of Trevo devicepasses (median IQR) 2.0 [ ] Core lab adjudicatedticis Post procedure mtici 2B 84.1% *Protocol advised to stop after otici 2b achieved NP v1.0 Slide 21 of 26 7

8 Secondary endpoints Early dramatic response* 24-hour revascularization ƒ 100% 80% 60% 47.7% 2.5x more patients experienced >10 point decrease in NIHSS from baseline or NIHSS 0-1 within 5-7 days 100% 80% 60% 76.6% 100% relative improvement 40% 40% 36.4% 20% 0% 1 of every 2 patients Trevo Retriever (n=107) 19.2% Medical management (n=99) P< % 0% 3 of every 4 patients Trevo Retriever (n=107) Medical management (n=99) P<0.001 *defined as NIHSS drop of 10 from baseline or NIHSS 0 or 1 at day 5-7 or discharge (whichever is earlier) ƒ recanalization of the qualifying occlusive lesion on the 24-h follow-up CTA or MRA scans was also analyzed. Vessel occlusion status on CTA or MRA at 24 hours was characterized according to a scale ranging from 0 (no recanalization) to 1 (partial recanalization) to 2 (complete recanalization). Revascularization at 24 hours was defined as the presence of partial or complete recanalization. NP v1.0 Slide 22 of 26 Secondary endpoints Core infarct volume (cc) ~1cc infarct growth (median) 13cc infarct growth (median) 13x less infarct 22.0 growth in the Trevo Retriever group Trevo Retriever (n=107) P=0.003 Pre-treatment 24-hours post Pre-treatment 24-hours post 8.9 Medical management (p=99) 3x smaller infarct at 24-hours in the Trevo Retriever group NP v1.0 Slide 23 of 26 Other safety outcomes 100% 80% P=1.0 (no difference) P=0.3 (no difference) P<0.01 (statistically lesswith Trevo Retriever) Trevo Retriever (n-107) Medical management (n=99) 60% 40% 26.3% 20% 15.9% 18.2% 14.0% 5.6% 3.0% 3.7% 0% Stroke-related 90-day mortality sich (ECASS III) Neurological deterioration* ENT * defined as worsening 4 points in the National Institutes of Health Stroke Scale within 5 days after stroke not attributed to ICH or malignant cerebral edema. NP v1.0 Slide 24 of 26 8

9 Conclusions Thrombectomy with the Trevo Retriever in DAWN-eligible patients is associated with improvement in clinical outcomes across the entire range of utility weighted mrs and with higher rates of functional independence (mrs 0-2) compared to standard medical therapy (48.6% vs 13.1%, probability of superiority >0.999, NNT = 2.8) For every 100 patients treated with endovascular therapy, 49 will have a less disabled outcome as a result of treatment, including 36 who will be functionally independent The treatment effect size in DAWN is the highest out of any stroke trials to date and suggests that the presence of Clinical-Core Mismatch is a critical predictor of treatment effect independent of time to presentation Treatment effect persisted throughout 24 hours from TLKW; however, earlier treated patients do better Thrombectomy with the Trevo device in patients presenting beyond 6 hours of TLSW had comparable safety profile to thrombectomy performed within 6 hours NP v1.0 Slide 25 of 26 9

Study organization. Study principal investigators Tudor G. Jovin, MD Raul Nogueira, MD

Study organization. Study principal investigators Tudor G. Jovin, MD Raul Nogueira, MD DAWN STUDY- MAIN RESULTS DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo Tudor G. Jovin, MD Professor of Neurology