ESOC @ wagers TRAGE-III Tenecteplase for Ischemic Stroke Due to Large Vessel Occlusion at 4.5 to 24 Hours with Rentuslen Imaging Selection Yunyun Xiong and Yongjun Wang for the TRACE-Il investigators (NCT 05141305) Department of Neurology, Beijing Tiantan Hospital, Capital Medical University eso-conference.orgDisclosures ‘Competing)interests) > Dr. Schwamm serves as a scientific consultant regarding trial design and conduct to Genentech and Member of steering committee (TIMELESS NCT03785678); consultant on user interface design and usabllity to Lifelmage; and a member of a Data Safety Monitoring Boards (DSMB) for Penumbra (MIND NCT03342664). > Dr. Fisher serves as a consultant for Simcere USA and Lumosa; and a member of DSMB for Moleac. eS] elas > National Natural Science Foundation of China > Beijing Municipal Science & Technology Committee > China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou) supplied tenecteplase without charge ESOC @> aes caeTenecteplase in Ischemic Stroke Trials = NOR-TEST, Phase 3 Parsons, Phase 2b O.4mgfkg Tenecteplase ___AcT, Phase 3 0.25 maikg tenecteplase ‘was not superior to 0.25mg/kg tenecteplase_—_‘TRACE-2, Phase 3 was superior fo 0.1 mg/kg alteplase and showed a __isareasonable —_0.25mg/kg tenecteplase is, tenecteplase similar safety alternative o alteplase _non-inferior to alteplase Haley EC, Pilot dose- ATTEST, Phase 2 NOR-TEST 2 PartA, Phase 3 escalation study No diference between 0.4mg/kg Tenecteplase yeilded worse Tenecteplase doses of 0.25mgikg tenecteplase ‘safety and functional outcomes 0.1 to 0.4 mg/kg are safe and alteplase compared with alteplase in moderate or ischemic stroke severe stroke IC ‘we yote or srnone ESOC @ nae eso-conterence.orgLate Tenecteplase for Stroke Patients With Large Vessel Occlusion? ‘The WEW ENGLAND JOURNAL of MEDICINE ORIGINAL ARTICLE Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection Sore onthe Modified Rankin Seal 29 Day onl? 0) gems m6 is uss | ae Ta) (rezae}| eos) glade) (es Percenage of Pent: ‘THE voIce oF stROKE IweuROPE Esoc & TIMELESS 2. ‘A study of magingeterbn tous ontment + N=458 + EVT performed: ~77% * Comprehensive stroke center (median lytic to puncture 16min) * Shift analysis: aOR 1.13, 95% Cl 0.82-1.57 * sICH: 3.2% vs. 2.3% esorconference.org 10:701-711. N Engl J Med. 2024;Late Tenecteplase for Stroke Patients With | Large Vessel Occlusion? Global Thrombectomy Access + Median thrombectomy access was 2.79% global, and 21% in high income countries * Thrombectomy access is <1% in 27% of countries and 10% of countries have no thrombectomy access at all + The effect of late administration of tenecteplase in patients without immediate access to thrombectomy is currently unknown ce ca THE VOICE OF STROKE ESOC hahaa Circulation. 2023;147:1208-1220. _ese-conterenceorgLate Tenecteplase for Stroke Patients With & Large Vessel Occlusion? Global Thrombectomy Access + Median thrombectomy access was 2.79% global, and 21% in high income countries + Thrombectomy access is <1% in 27% of countries and 10% of countries have no thrombectomy access at all + The effect of late administration of tenecteplase in patients without immediate access to thrombectomy is currently unknown cenr {THe voice oF STROKE ESOC @& menor. Circulation. 2023;147:1208-1220. _-6s Mismatch volume: Hyperfusion volume-core volume Mismatch ratio: Hyperfusion volume/core volume NICE OF STROKE Neurol Ther. 2022;11:1777-1788. ESOC GB esr SSroke Voss Neural, 024.omn-2629-002064, _earconencearsKey Exclusion Criteria TRACE ll Gps + Intention to proceed to endovascular treatment + Allergy to tenecteplase + NIHSS consciousness score 1a >2, or epileptic seizure, hemiplegia after seizures (Todd's palsy) or other neurological/mental illness such that the patient is not able to cooperate or unwilling to cooperate + Any contraindication to intravenous thrombolysis + Multiple arterial occlusion (bilateral MCA occlusion, MCA occlusion accompanied with basilar occlusion, NB tandem carotid occlusion was eligible) THE VOICE OF STROKE ESOC > Newt csorconterenceargIntervention and Control TRACE: Geass Tenecteplase (0.25 mg/kg) is given as a single, intravenous bolus (within 510 s) immediately | on randomisation. Maximum dose is 25 mg. Aspirin combined with clopidogrel, aspirin alone, or clopidogrel alone after randomization at the discretion of local neurologists. | ESOC @ mame CoenOutcomes Primary/Outcome) MRS/score’S1/at 90 days (unadjusted) Secondary The ordinal distribution of mRS at 90 days: Outcomes MRS score $2 at 90 days Early neurological recovery at 72 hours (defined as a reduction of 28 points on NIHSS compared with baseline or a score of <1) Reperfusion at 24 hours (defined as >90% reduction in Tmax >6s lesion volume) Change from baseline to 7-day NIHSS score Safety Outcomes Symptomatic intracranial hemorrhage within 36 hours (ECASS II) Death from any cause Systemic bleeding within 90 days (GUSTO: moderate or severe bleeding) Adverse events or severe adverse events within 90 daysSample Size Aprespecified promising zone adaptive sample size re-estimation procedure (Mehta and Pocock)* Assumptions: Standard medical treatment group mRS 0-1: 25% Power: 80% One-sided alpha of 0.025 Attrition rate of 10% Minimum: 516 (12% difference), Maximum: 808 (9.5% difference) Interim analysis (258 patients) determined no sample size increase was required and the final sample size remained 516. ESOC GD maison srrore ns *Stat Med 2011;30:3267-3284.Results esac 953 Wer ecb ee fa inreereel henge ready recived erombolie stan exter 211 Were tended to reeed to enerselst ‘+50 1ad npedesiy in>172 CA team 2726 Were wb prem or winerpeabe CTP 20 id echemie stoke or moc fein in previous 3 months > 16Notmecingtrget mismatch profile ‘on CTP er MRIOMR prison ete beol ge 2802223 mat any kaw impairment inconuaion ‘S16 Point vnerael randomization 264 Were sped to tereteplae and 252 Wereassgnedo sandard meio treme andincaded inte I T 2 Were inca inthe fy popon 1252 Were inca inthe fy popusion TRAGE-IIl Time period: January, 2022, to November, 2023 Screening: 1469 patients Enrolled: 516 patients eso-conference.orgBaseline Characteristics GIES fenecteplase) TRAGE “II ess ‘Standard Medical Treatment: (N=264) (N=252) Median age (IQR) — yr 67 (58-75) 68 (59-76) Male sex — no. (%) 183 (69.3) 167 (66.3) Hypertension’ 177 (67.1) 180 (71.4) Diabetes mellitus 69 (26.1) 74 (28.2) Atrial fibrillation 49 (18.6) 48 (19.1) Median NIHSS score at admission — | 44 (7.45) 407-14) (]QR) Type of stroke onset — no. (%) Known onset time 4143 (54.2) 149 (59.1) Unwitnessed onset 20 (7.6) 19 (7.5) Wake-up stroke 101 (38.3) 84 (33.3)Baseline Characteri Cire etsttss Median volume of ischemic core (IQR) mi Median volume of perfusion lesion (QR) — mI stics Tener (N=264) 119.1 (79.8-177.2) 123.2 (74.6-180.1) 16.4 (5.7-28.4) — TRAGE-I @3- Renee ice rere tens (N=252) 14.9 (6.0-29.3) Occlusion site — no. (%) randomization — hr Internal carotid artery 87 (33.0) 84 (33.3) Middle cerebral artery — M1 119 (45.1) 130 (51.6) ‘Middle cerebral artery — M2 58 (22.0) 38 (15.1) Door-to-needle time — min. 139 (94-190) : Time from symptom onset to 422(85-160) 42.4 (8517.5) Endovascular treatment — no. (%) 4 (1.5) 5 (2.0)TRAGEMII Sa THEWOICE OF stROKE we eso-conferenceorgFree Primary Outcome TRACE-I] Gb=ges Modiied Rankin Seale Scoro we Tereza ” By ‘ose ESOC > was —Primary Outcome ‘Moained Rankin Seale Score . os ‘oat Pane On Con ONE Lecee Ten Seireelmeriee! Relative|Riskyy||P)Values (N=264) iTreatment(N=252) (95%1CI) mRS <1 at 90 days | 87 (33.0) 61 (24.2) 1.37 (1.04-1.81) |0.03 * Two-sided P value sac tHevoice or stRoKE €soc IWeunore eso-conference.rgSecondary Outcomes Standard) ee Tenses | |iiecrect Effect size (N=264) Treatment CaACiy (N=252) Ordinal distribution of mRS. 1.33 (0.98-1.81) 0.06 at 90 days MRS s2 at 90 days 115 (43.6) 84 (33.3) 1.31 (1.05-1.63) 0.02 Early neurological recovery at 72 hours (1-499) 40/250 (16.0) | 15/249 (6.0) 2.66 (1.51-4.69) 0.001 herr 290% at 24 hours | 4g/939 (20.1) | 27/229 (11.8) 4.70 (1.10-2.64) 0.02 ‘Change from baseline to 7-day Nise score -4 (6 to-1) -2(-5 to 0) -1.47 (-2.30 to-0.64) | 0.001. * Common odds ratio is shown for the ordinal score on mRS; B coefficient with its 95% Cl is shown for the outcome of NIHSS change from baseline to 7-day, and Relative Risks are shown for other outcomes.Safety Outcomes Safety outcomes Tenecteplase (N=264) (Standard NCL Treatment Relative Risk CAC Pyalue: (N=252)) SICH within 36 hours * | 8 (3.0) 20.8) 3.82 (0.82-17.87) 0.09 Death within 90 days | 35 (13.3) 33 (13.1) 1.01 (0.65-1.58) 0.96 ‘Severe or moderate | systemic bleeding 5(1.9) 20.8) 2.36 (0.46-12.09) 0.07 ‘Adverse events 134 (50.8) 129 (51.2) 0.99 (0.84-1.17) 0.89 Serious adverse events | 53 (20.1) 43,(17.1) 1.18 (0.82-1.69) 0.38 * ECASS Ill: any extravascular blood in the brain or within the cranium associated with clinical deterioration, defined by an increase of 4 points or more on the NIHSS from the baseline or within 36 hours; or that led to death and that was identified as the predominant cause of the neurological deterioration. ESOC @ maser ‘eso-conference.org— Subgroups TRA\ Ell Gees ‘subor0ur octets Tenecteplase Sunder Me pats Rink SHED motes) vera se weg een — aaraseasy, “oye ne a6) smeram Hoy sang suo resem ate x0 209) aH he wees, x nen wen + ssspeszon “a0 20 swan acon _— aes Ho 26 Rew 2038) —— assas2s Time rom symptom onset wesiment— hr 2 1 ney nen + waar o 28 3055) asa) — reross2a7, wate ms nen wen a renzn ree any m sen mare, — roreseaen decry —Mt py so) ee pa ra@s215 idl crea ary 22 6 non sau tse sac THEVOIEE OF TROKE Esoc meuwore eso-conference.org— Limitations TRACE mga + Open-label, blinded outcome + Results do not apply to patients who can immediately access thrombectomy * Trial was performed in China where patients have a lower proportion of atrial fibrillation than in Western countries oar THE VOICE OF STROKE €sac EUROPE eso-conferenceorgConclusions TRACE MII ges Tenecteplase reduced disability for Chinese patients with LVO 4.5-24h after onset | + No safety concerns — SICH 3% similar to TIMELESS and 0-4.5 hr trials — no difference in mortality The results apply to patients who cannot immediately access thrombectomy, including those requiring interhospital transfer in whom there is no guarantee they will remain eligible for EVT on arrivalomen) Acknowledgement TRACE Gem Thanks to TRACE-II trial participants, investigators, steering committee, DSMB, core lab and event adjudication committee. in revorce or sox ESOC @> nage éAcknowledgement TRAGE-Il @bngexs WYTRAGE-II Thank you —* ESOC