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In the Intravascular Cooling in the Treatment of Stroke (ICTuS) trial, awake stroke patients were successfully cooled using an endovascular cooling catheter and a novel antishivering regimen. In the ICTuS-L study, the combination of endovascular hypothermia and thrombolysis proved feasible; while hypothermia was associated with no increased risk of bleeding complications, there was an increased association with pneumonia. Despite efforts to expedite, cooling began on average six-hours after stroke onset. We designed a novel Phase 2\/3 trial to further test the safety of combined thrombolysis and endovascular hypothermia and to determine if the combination shows superiority compared with thrombolysis alone. ICTuS 2 ( n = 400) will assess four hypotheses, and if milestones are met, ICTuS 3 ( n = 1200) will begin as a seamless continuation for a total sample of 1600 patients. The ICTuS 2 milestones include ( 1 ) target temperature reached within six-hours of symptom onset; ( 2 ) no increased risk of pneumonia; ( 3 ) no increase in signs\/symptoms of fluid overload due to chilled saline infusions; and ( 4 ) sufficient recruitment to complete the trial on time. The ICTuS 2\/3 protocol contains novel features\u2013based on the previous ICTuS and ICTuS-L trials \u2013 designed to achieve these milestones. Innovations include scrupulous pneumonia surveillance, intravenous chilled saline immediately after randomization to induce rapid cooling, and a requirement for catheter placement within two-hours of thrombolysis. An Investigational Device Exemption has been obtained and an initial group of sites initiated. <\/jats:p>","DOI":"10.1111\/ijs.12151","type":"journal-article","created":{"date-parts":[[2013,11,11]],"date-time":"2013-11-11T02:46:53Z","timestamp":1384138013000},"page":"117-125","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":77,"title":["Endovascular Therapeutic Hypothermia for Acute Ischemic Stroke: ICTuS 2\/3 Protocol"],"prefix":"10.1177","volume":"9","author":[{"given":"Patrick D.","family":"Lyden","sequence":"first","affiliation":[{"name":"Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Hemmen","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, UCSD Stroke Center, University of California, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Grotta","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Texas \u2013 Houston Medical School, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Rapp","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, UCSD Stroke Center, University of California, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rema","family":"Raman","sequence":"additional","affiliation":[{"name":"Department of Family and Preventive Medicine, Division of Biostatistics and Bioinformatics, University of California, San Diego, CA, 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