Efficacy of Tenecteplase in Large Vessel Occlusion Stroke Within 24 Hours of Symptom Onset: The ETERNAL-LVO Randomized Controlled Trial
Vignan Yogendrakumar, Bruce Campbell, Leonid Churilov, Carlos García-Esperón, Philip Choi, Dennis Cordato, Niruta Dhimal, Liudmyla Olenko, Prodipta Guha, Gagan Sharma, Chushuang Chen, Amy McDonald, Vincent Thijs, Abul Mamun, Angela Dos Santos, Anna Balabanski, Timothy Kleinig, Kenneth Butcher, M. Devlin, Fintan O’Rourke, Geoffrey A. Donnan, Stephen M. Davis, Christopher Levi, Henry Ma, Mark Parsons, Nawaf Yassi, Bernard Yan, Michael Valente, Henry Zhao, Angelos Sharobeam, Laura Fisicchia, David M. Jackson, Peter Mitchell, Richard Dowling, Hannah Johns, Birendra Rokaha, Andrew Bivard, Ashley Park, Margaret Ma, Presaad Pillai, James Beharry, Helen M. Dewey, Tessa Busch, M.F. Chung, Narelle Stuart, Peter Park, Branko Borojevic, Joseph K. Wong, Channa Senanayake, Oneil G. Bhalala, Karen A. Robinson, Bailey McNamara, Edward Callaly, Tanya Frost, Karen Stephens, Pakeeran Siriratnam, Ross Cody, Tharani Chandran, Chris Linton, Nathaniel Lizak, Shelton Leung, Peter Tan, Dennis Young, Felix Ng, Gayleen Chappell, Thanh G. Phan, Marie Veronic Hervet, Carol Bendall, Jennifer Cranefield, Roy Drew, Neil J. Spratt, Beng Ghee Lim, Alvin Chew, Michelle Russell, Shu Ren, Julie Hennessy, Leon Edwards, Christopher Blair, Timmy Pham, Jasmeen Khan, Longting Lin, Rumbidzai Teramayi
Abstract
BACKGROUND: To assess the efficacy and safety of tenecteplase in patients presenting within 24 hours of symptom onset with a large vessel occlusion and target mismatch on perfusion computed tomography. METHODS: ETERNAL-LVO (Extending the Time Window for Tenecteplase by Effective Reperfusion in Patients With Large Vessel Occlusion) was a prospective, randomized, open-label, blinded end point, phase 3, superiority trial where adult participants with a large vessel occlusion, presenting within 24 hours of onset with salvageable tissue on computed tomography perfusion, were randomized to tenecteplase 0.25 mg/kg or standard care across 11 primary and comprehensive stroke centers in Australia. The primary outcome was the modified Rankin Scale score of 0 to 1 or return to baseline at 90 days via a modified Poisson regression model. Secondary outcomes include the modified Rankin Scale, considered as an ordinal variable, and symptomatic intracerebral hemorrhage. RESULTS: Following trial initiation, a supply shortage of the investigational product hindered recruitment. When supply resumed, phase 3 evidence had emerged supporting tenecteplase use within 4.5 hours of stroke onset, including large vessel occlusion. ETERNAL-LVO was, therefore, terminated early. Two hundred forty-two participants (median age: 73 years, 43% female, 79% undergoing EVT) were included in the modified intention-to-treat analysis; 120 received tenecteplase and 122 received standard care. No difference in the primary outcome was observed between the tenecteplase (n=44, 37%) and standard care (n=52, 43%; adjusted risk ratio, 0.90 [95% CI, 0.66–1.21]; P =0.48). No significant differences in an ordinal analysis of the modified Rankin Scale were observed between the 2 treatment groups. In a planned per-protocol analysis, the odds of improvement by 1 point in the modified Rankin Scale were doubled in the tenecteplase-treated transfer subgroup compared with standard care transfer patients (odds ratio, 2.61 [95% CI, 1.07–6.40]). Symptomatic intracerebral hemorrhage occurred in 5 (4%) participants assigned to tenecteplase and was present in 1 (1%) participant assigned to standard care. CONCLUSIONS: Treatment with tenecteplase did not increase the likelihood of a favorable functional outcome, but early stoppage of the study prevents definitive conclusions from being drawn. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04454788.