Thrombolysis with Alteplase at 0·6 mg/kg for Acute FLAIR-Negative Stroke with Unknown Time of Onset: THAWS Randomized Controlled Trial

Background: The WAKE-UP trial recently revealed the efficacy of magnetic resonance imaging (MRI)-based intravenous thrombolysis with alteplase at 0·9 mg/kg in acute ischemic stroke patients with unknown time of onset. We assessed whether lower-dose alteplase at 0·6 mg/kg is efficacious and safe in patients under the same conditions. Methods: This was an investigator-initiated, multicenter, randomized, open-label, blinded-endpoint trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4·5 h (e.g., wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0·6 mg/kg or standard medical treatment if MRI showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on FLAIR. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Findings: Following the early stop and positive results of the WAKE-UP trial, this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age: 74·4±12·2 years; median National Institutes of Health Stroke Scale score: 7; interquartile range: 4-13). Favorable outcome was comparable between the alteplase group (32/68, 47·1%) and the control group (28/58, 48·3%) (relative risk (RR), 0·97; 95% confidence interval (CI), 0·68 to 1·41; p=0·892). Symptomatic intracranial hemorrhage within 22-36 h occurred in 1/71 (1·4%) and 0/60 (RR, infinity; 95%CI, 0·06 to infinity; p=1·0), respectively. Death at 90 days occurred in 2/71 (2·8%) and 2/60 (3·3%) (RR, 0·85; 95%CI, 0·06 to 12·58; p=1·0), respectively. Interpretation: No difference in favorable outcome was seen between alteplase and control groups among ischemic stroke patients with unknown time of onset. The safety of alteplase at 0·6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: This trial was registered with ClinicalTrials.gov NCT02002325 and UMIN 000011630. Funding Statement: This trial was funded mainly by the Japan Agency for Medical Research and Development (AMED) (JP16ek0210025h and JP18ek0210091h), and the Ministry of Health, Labour, and Welfare, and partly by the Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center (H23-4-3; maintenance of the administration infrastructure for international multicenter studies of clinical stroke; P. I., K. Toyoda), and the Mihara Cerebrovascular Disorder Research Promotion Fund. Declaration of Interests: MK reports honoraria from Bayer, BMS/Pfizer, Daiichi-Sankyo and Nippon Boehringer Ingelheim, scientific advisory board from Ono, and research supports from Takeda, Daiichi-Sankyo, Nippon Boehringer Ingelheim, Astellas, Pfizer and Shionogi, outside the submitted work. RI reports personal fees from Bayer, personal fees from Bristol-Myers Squibb, personal fees from Daiichi-Sankyo, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Stryker, personal fees from Medtronic, personal fees from Otsuka Pharmaceutical, personal fees from GE, grants from Tohoku Fukushi University, personal fees from Tanabe Mitsubishi , personal fees from Johnson and Johnson, outside the submitted work. TI reports grants from Ogaki Tokusyukai Hospital, grants from GlaxoSmithKline K.K., outside the submitted work. YN reports personal fees from Bayer, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, Mochida, Ono, and Takeda, outside the submitted work. YO reports personal fees from Boehringer Ingelheim, personal fees from Bayer, personal fees from Pfizer, personal fees from Daiichi-Sankyo, personal fees from Bristol Myer Squibb, personal fees from Otsuka, outside the submitted work. NS reports personal fees from Otsuka, outside the submitted work. SY reports personal fees from Medtronic, personal fees from Stryker, personal fees from Kaneka Medics, personal fees from Otsuka Pharmaceutical, during the conduct of the study; personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo, personal fees from Pfizer, personal fees from Bayer, personal fees from Sanofi, personal fees from Bristol-Meyers, outside the submitted work. TU reports personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from AstraZeneca K.K., personal fees from Bayer Pharmaceutical Co., Ltd., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Takeda Pharmaceutical Co., Ltd., personal fees from Mitsubishi-Tanabe Pharma Co., Ltd, personal fees from UCB Japan Co., Ltd., personal fees from Kowa Shinyaku Co., Ltd., personal fees from Sumitomo Dainippon Pharma Co., Ltd., personal fees from Astellas Pharma Inc., personal fees from AbbVie GK, personal fees from Medtronic Japan Co., Ltd., personal fees from Eisai Co., Ltd., personal fees from Daiichi Sankyo Co., Ltd., personal fees from CSL Behring, personal fees from Japanese Physical Therapy Association, outside the submitted work. MI reports grants from Shimadzu Corporation, grants and personal fees from Otsuka Pharmaceutical Company Ltd., personal fees from Daiichi Sankyo Company Ltd., personal fees from Pfizer Inc., personal fees from Eisai, outside the submitted work. TK reports personal fees from Bayer Yakuhin Ltd, grants and personal fees from Daiichi Sankyo Co Ltd, grants and personal fees from Chugai Pharmaceutical Co Ltd, grants from Takeda Pharmaceutical Co Ltd, grants from Eisai Co Ltd, grants from Astellas Pharma Inc, grants from MSD KK, grants from Mitsubishi Tanabe Pharma Co, outside the submitted work. Dr. Sasaki reports personal fees from Mitsubishi Tanabe, personal fees from Bayer, personal fees from Astellas, personal fees from Ono Pharma, personal fees from Mediphysics, personal fees from Actelion, personal fees from Ezai, personal fees from FujiFilm, personal fees from Daiichi Sankyo, personal fees from Nippon Boehlinger Ingelheim, personal fees from Otsuka, personal fees from Chugai, grants and personal fees from Hitachi, grants from Actelion, grants from GE Healthcare, outside the submitted work. KK reports personal fees（honoraria for lecture presentations） from Bayer Yakuhin. KM reports personal fees and other from Bayer Yakuhin, personal fees from Otsuka Pharmaceutical, personal fees from Boehringer-Ingelhaem, personal fees from Mitsubishi Tanabe Pharma Cooperation, outside the submitted work; and personal fees (honoraria for seminar presentation) and other (Advisory Board) from AstraZeneca; personal fees (honoraria for seminar presentation) from Pfizer, Japan Stryker, Dai-ichi Sankyo, Astellas Pharma, Nippon Chemiphar and Fuji Film RI Pharma; and other (Advisory Board) from CSL Behring, Medico's Hirata, EPS Corporation, HEALIOS K.K. and T-PEC Corporation. KT reports personal fees from Daiichi-Sankyo, personal fees from Bayer Yakuhin, personal fees from Brystol-Meyers-Squibb, personal fees from Nippon Behringer Ingerheim, outside the submitted work. None of the other authors have any conflicts of interest to declare. Ethics Approval Statement: The trial protocol was approved by the Ministry of Health, Labour, and Welfare, Japan to perform a treatment not covered by the national health insurance system. The trial was approved by the local ethics committee or institutional review board at each participating center. Patients or their relatives provided written informed consent according to ethical regulations.