ESOC @ tee ‘Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation with Perfusion Imaging Selection within 4-5 hours of Onset (TASTE): a multicentre, randomised, controlled phase II non-inferiority trial 35 centres, 8 countries, 4 continents Coordinating Centre John Hunter Hospital, University of Newcastle, NSW, Australia aie Hunter New Englane INSW | Ucar Hosth NetworkAuthors Sa Mark W, Parsons, Vignan Yogendrakumar, Leonid Churilov, Carlos Garcia-Esperon, Bruce C.V, Campbell, Michelle L. Russell, Gagan Sharma, Chushuang Chen, Longting Lin, Beng Lim Chew, Felix C. Ng P, Akshay Deepak, Philip M.C. Choi, Timothy J. Klcinig, Dennis J. Cordato, Teddy Y. Wu, John N. Fink, Henry Ma, Thanh G. Phan, Hugh S. Markus, Carlos A. Molina, Chon-Haw Tsai, Jiunn-Tay Lee, Jiann-Shing Jeng, Daniel Strbian, Atte Meretoja, Juan F. Arenillas, Brian H. Buck, Michael J. Devlin, Helen Brown, Ken S. Butcher, Billy O’Brien, Arman Sabet, Tissa Wijeratne, Andrew Bivard, Rohan S. Grimley, Smriti Agarwal, Sunil K Munshi, Geoffrey A Donnan, Stephen M. Davis, Ferdinand Miteff, Neil J. Spratt, and Christopher R. Levi, for the TASTE Investigators. ESOC@> sexe ENS) ) ae Health Hunter New England Local Health NetworkDisclosures es * The main funder was a Government Grant from National Health and Medical Research Council of Australia. + Some additional funding, and some study drug, was supplied by the manufacturer (Bochringer Ingelheim) + The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Health con trevor a | ter New Engar ESOC @& NSW | CScsrfsih NotenDeclaration of interests es | Advisory Board for Metalyse in stroke. FN has received grants from the National Health and Medical Research MW is on a Bockiinger-Ingelh Council of Australia aud the National Heart Foundation of Australia. AM participates on an advisory board for Bochringer Ingelheim and is World ‘Stroke Organisation board member. HSM reports grants {rom the British Heart Foundation, the Medical Research Council, the Alzheimer's Society, and in-chief ofthe World Stroke Organisation journal, International Journal of Stoke. HM has received speaking the Stroke Association UK, and is the {ees from the Indonesian Stroke Society and reports travel support for investigator meetings. TGP has received speaking fees from Bayer, Boehringer Ingelheim, Pfizer, and BMS. JFA reports consulting fees from Amgen, Medtronic, and BMS-Pfizer reports speaking fees from Medwronic and BMS- Pfizer, reports travel support from Daiichi-Sankyo, participates on the advisory board for the WE-TRUST trial, and reports research grants from and Astra Zeneca. RSG has received travel support from Boehringer Ingelheim. SA bas reecived Spanish Ministry of Science, the European Commi funding from the UK Stroke Clinical Research Network. KSD is ia a spousal relationship with aa employee of Bochringer Ingelbeim and has recsived speaking fees from Bochringer Ingelheim and Astra Zeneca. All other authors report no disclosures. Ss ts | Health cenqn twevoice oF srnoxe mna® ) ANd | Fea ESOC @ wast’ (® INSW | Hunter New Enalend |—- Potential benefits of tenecteplase eas Higher clot binding = faster clot clearance Longer half-life = single bolus vs one hour infusion with alteplase = faster administration. esac @> meee | eaeeer Geese) Primary Outcome Haley 2010 _0.1,0.25, 0.4 mg/kg. 112 2 __ Safety/Efficacy Parsons 2012 0.1, 0.25 mg/kg 7s 2___ Reperfusion ATTEST 2015 0.25 me/kg. 104 2 Penumbra Salvage NOR-TEST 2017 0.40 mg/kg 1100 3 mRS at 90 days (superiority) EXTEND-IATNK 2018 0.25 ma/ke 202 Reperfusion TRACE 2021 0.1, 0.25, 0.32 mg/kg 236 Safety/Efficacy NOR-TEST-2A 2022 0.40 mg/kg 216 3 mRS at 90 days {non-inferiority) TASTE-A 2020.25 ma/kg 104 2___ Reperfusion ACT 2022 (0.25 mg/kg 1600 3 mRSat 90 days {non-inferiority) TRACE-2 2023 (0.25 me/ke 1430 3 mRS at 90 days (non-inferiority) ATTEST-2* 2023 0.25 mg/kg 1858 3 mRS at 90 days (non-inferiority) “Results presented at WSC 2023, publication pending Prior randomised trials of tenecteplase vs alteplase in sub-4.5 hour windowWhy is TASTE different? ee Core Volume: 16 ml (10%) DT3 Volume: 155 ml DT8 Volume: 10 ml Core Volume: 16 < 70 ml ? Yes Mismatch Volume: 155 > 15 ml ? Yes Mismatch Ratio: 9.7 > 1.8 ? Yes DT8 Volume: 10 < 100 ml? Yes Randomise Patient ? Yes in we voce oF staoxt ipsam ESOC @> west 8 SESSA eso-stroheorg/esoe202!Study Design - Summary @ Thrombolysis eligible patient stroke onset <4.5 hours* | *ifnota candidate for VT NCCT/CTP/CTA Core on DWI/CTP < 70 mL. + Penumbra Mismatch Ratio > 1.8 and > 15mL volume *Randomised to IV tPA (0.9 mg/kg) or IV TNK (0.25 mg/kg) Primary outcome = mRS 0-1 at 3 months (non-inferiority)* SCO me mom) "PROBE design [BE aceee ce strona ora/esezzeTASTE Analysis Plan - Sample Size Ga n + Recruitment began March 21, 2014 + Spanned the era of implementation of endovascular thrombectomy (also the era of Jay Z and Beyonce, | with possibly as many ups and downs) + 2017 -in response to decreasing LVO recruitment change from superiority to non-inferiority design + 2019 -in response to meta-analysis sample size increased to 728 patients = 90% power (one-sided non-inferiority alpha 0.025) to detect risk difference of 0.08 (26 % mRS 0-1 alteplase vs 34% tenecteplase) * 2021 - pre-planned interim at 546 patients = final sample size of 832 patients. ESOC > kame mE) )TASTE Analysis Plan: Non-inferiority 5 The primary endpoint was analysed for non-inferiority using both Intention To Treat and Per-Protocol principles, as recommended by EMA and FDA, and pre-specified. The absolute non-inferiority margin of 0.03 was based on the Emberson 2014 meta-analysis of alteplase compared to placebo. — Estimated weighted absolute effect (mRS 0-1) of alteplase vs placebo for anticipated TASTE population was 0.085 (95% Cl = 0.06-0.11) — Absolute non-inferiority margin of 0.03 = half of lower 95% Cl limit — Non-inferiority established if lower boundary of 95% Cl of the standardised risk difference* in achieving mRS 0-1 outcome between tenecteplase and alteplase arms was greater than -0.03 “Binary logistic regression model adjusted for age, baseline NIHSS, and premorbid mRS Tecwoceor sone = ESOC D> wesese” FS ete, eo tere nsreceozsTASTE Recruitment halted 20 Oct 2023 Sas + ATTEST-2 trial (presented WSC 2023) showed non-inferiority of tenecteplase to alteplase in a non-contrast CT population. + This result, in combination with non-inferior results from similar trials (to ATTEST-2) AcT and TRACE-2, lead to decision to cease recruitment in TASTE. + Final sample size of 680 participants. ) B ESOC > mame SEER eso-strokerg/esoc2024—— (Caesiato Tne Hiocated to Aitepase 38T) I TT Population oea39) Tr Popatavon r=3at) Per pretocol population (295) By wesaczorse ESOC @> mazar For PP analysis core imaging lab (blinded) reprocessed baseline CTP from all patients after enrolment closed and used batch analysis with latest version of MiStar software. All output was assessed by core lab for quality (artefact) and to ensure patients met the original mismatch criteria. Manual reprocessing performed including removal of clearly artefactual core/penumbra lesions where quality was deemed not interpretable. If manual reprocessing falled, or core lab core/penumbra volumes did not fulfill mismatch criteria, patient was excluded from PP analyses. eat SENSE exo-stroke.org/es0c2024Pa alec ed Cm Let} es } + we “9 a Ree ] © | 3) | xy (@) tue ete reprocessing and removal of : alk a rs Bucs Vv fe:17 YUL DEA es ee laayy Low contrast flow in white matter = artefact NRE BET ELC ut ull PYTac SCT et eet le) rarely pathophysiological Core/penumbramap Delay TimeFulfills mismatch criteria but with (scary) Images underlying the core/penumbra maps are averaged maps of all time points taken during CTP.= ‘contrast enhanced CT; (yet another advantage of doing CTP)oar a] (ED Mca) aE! 7 Bl 75 (65-82) 73(63-81) 716-11) 715-10) Baseline 202 (60%) 218 (54%) | 137 (40%) 123 (36%) demographics and workflow 285 (e¢x) 257 (87%) 7 ‘54 (15%) 44 (13%) times 249 (73%) 243 (71%) a 26 (8%) 27 (8%) ae ra CI 64 (19%) 71 (21%) (a ) [] E ti it i 79 (56-110) 83 (57-122) ses Enea 137 (112-181) 143 (119-190) cern eee 151(120-189) 155 (125-199) maa 7 (4-11) 7 (5-13) Enea en iene eee 65 (48-26) Dl7-8 (32-160) 460 (289-72-0) 36-3 (22:0-54-0) 5-9 (36-115) 6/337 (2%) 43/337 (13%) 55/337 (16%) 5} 54/337 (16%) A aoe eee ‘THE VOICE OF STROKE IneuRoPe SOC 94/337 (28%) 21/337 (6%) 49/337 (14%) 15/337 (486) 104/337 (31%) 61(23-12-0) 400 (25-6-67-9) 3141 (204-520) 63 (37-130) 4/340 (195) 155/340 (16%) 53/340 (16%) 152/340 (15%) 102/340 (30%) 14/340 (4%) 46/340 (13%) 14/340 (4%) 112/340 (33%) Baseline imaging characteristics exo-stroke.org/esoe2024Primary outcome ee ih Ee D er [MAGES Standardised Risk Difference 0-03 (One- 0-03 (0-031 to0-10) ‘eto: ROCIO | 55/555 yy) a00/seo ss) threshold ceBG) £0025}) Adjusted Odds Ratio 119 (085-165) Tiny a= ena (ote oae) Standardised Risk Difference 0-01 (One- sided non- 005 (-0-02 to 0-12) inferiority REI ORE GEICO 75/205 (59%) 171/306 (38%) threshold scale 0°1) {p0-025)) ‘Adjusted Odds Ratio 1-27 (0-90-4-81) [exces eso-stroke-ora/esoc2024 esac @> ween gz2Modified Rankin at 90 days a Tenecegiase Primary Efficacy Outcome Intention To “#3 Treat Population (n=675) Adjusted Generalised odds ratio 1-11 (0-93-1-32) esas “estoy Primary Efficacy Outcome Per Protocol Population (n=601) va Adjusted Generalised odds ratio 1-20 (0-90-1-60) Atepiase (ossoe) sit |Heatn ESOC @ neat meanness ESTEE) ) - - SEs = - EeAke teeuteelisyce ens an 23/335 (7%) 15/340 (4%) Gace ei sc POH Ase | 39/335 (12%) 28/340 (8%) e675) CREED | oss7 aye) o/sa0 cz) Geoaeanie (Ges) THEVOICE OF STROKE. mncuRoPC, esac & Maen LSS] = ===) Standardised Risk Difference 0-02 (-0-02 to 0-05) Key Safety Outcomes Adjusted Odds Ratio 1-42 (0-72-2-8a) Standardised Risk Difference 0-02 (-0-02 to 0-06) Adjusted Odds Ratio: 1-33 (0-78-2-28) Unadjusted Risk Difference: 001 (-0-01 to 0-03) Unadjusted Odds Ratio: 1:52 (055-4-16)7 caer Pavan tor ‘Suoproun pts (osmcn Interaction Forest Plot of the ‘el PPP ————— Primary Outcome, ee 116 ~~ 1690.72.39) Stratified by Pre- >to 0 = 4119/0781 Mid y =) a specified Patient Sub- vss LL groups (Intention-to- om = sar bl = teuea Treat population, n=675) a0 c.-/ 137 0@90,202) “ ——_ | rremsey on 133 ae 061,020,127) ccctnaaton (CAM Proimatea 108 1 e75(029,178) BE) isiaw2, M3 and beyond300 _ 198 (1.08, 3.19) our AeAPCAOIer 260 a en(oss. 155) ss yor of oe <_ —> rover Aepaso Favor Tenecolase ESOC > west |Risk Diff. Weight msn) ) Treatment Control Study Yes No Yes No wilh 95% Cl___(%) 2010 TNK-S28 5 16 13 18) 0.06 [-0.18, 031] 1.38 2012 TAAIS 18 7 10 15 | ——— 032/ 0.06, 058) 1.25 2015 ATTEST 13 34 10 39 + 0.07[-0.10, 024) 2.91 2O1BEXTENDIATNK 49 2 41. 60 i 0.08 [-0.06, 0.22] 4.53 2021 TRACE 35 22 35 2 || 4 — 0.02[-0.16, 0.20] 2.67 2022 AcT 296 506 266 499 a 0.02 [-0.03, 0.07] 37.54 2022 TASTE-A 23 32 20 29 = 0.01 [-0.18, 0.20) 236 2023 TRACE-2 439 266 405 291 a 0.04 -0.01, 0.09] 3226 2024 TASTE 91 144 188 152 + o.c2{-006, 0.08) 15:10 Overall 0.04 0.01, 0.08) Heterogeneity: Test of 0, = 6; Q(8) Test of = 0:2 = 2.37, p= 0.02 Random-elfects DerSimonian-Laird model SOC > wees Study-Level Meta-Analysis of Published Phase 2 and 3 trials (mRS 0-1 at 90 days) ‘NNT #25, This means that fr every 25 patents rested ‘win Tenectop Davent walhave excelent recovery af mone spec srewen KaseiTroalmont Control Risk Diff, Weight Study Yos No Yos No with 95% Cl___(%) 2010 TNK-S28 15 16 13 18 0.06 [-0.18, 0.31] 1.38 2012 TANS 18 7 10 15 0.32, 0.06, 0.58] 1.25 2015 ATTEST 13 34 10 39 0.07 [-0.10, 024] 2.91 201BEXTENDATNK 49 52 41 60 0.08 [-0.06, 022] 453 2021 TRACE 35 22 95 24 0.02[-0.16, 0.20) 267 2022 AcT 296 506 266 499 0.02{-0.03, 0.07) 37.54 2022 TASTE-A 23 32 20 29 0.01[-0.18, 0.20] 2.36 2023 TRACE-2 439 266 405 291 0.04-0.01, 0.09] 32.26 2024 TASTE 191 144 188 152 0.02 [-0.06, 0.03] 15.10 Overall 0.04 0.01, 0.05] Heterogeneity: warsProf Chung Hsu FA RBULEAOUR TEAM AR |Home'team (esate Rrra (and engine room of world No.1 ~ core brain imaging lab) Health Hunter New England Local Health Network]