Phase 2 Trial of TAK-755 for Acute Ischemic Stroke

Prior treatment

• Persistent blood pressure elevation (systolic ≥185 mmHg or diastolic ≥110 mm Hg) prior to randomization.
• History of prior stroke in the past 90 days.
• Major surgery or severe trauma in the past 14 days.
• Another clinically significant concomitant disease that may pose additional risks for the participant in the opinion of the investigator.
• Participation in other interventional clinical trials within the previous 90 days.
• Any prior administration of TAK-755.
• Baseline conditions (prior to the index AIS event) that prevent an understanding of the nature, scope, and possible consequences of the trial, in the judgment of the investigator. Current Stroke Management
• Any prior administration (intravenous or intra-arterial) of alteplase or tenecteplase for the index AIS event, as well as any prior administration of prourokinase or reteplase for the index AIS event in countries where approved.

Other illness

• Seizure at time of index AIS event onset.
• History of severe traumatic brain injury in the past 90 days.
• History of intracranial hemorrhage.
• History of intracranial neoplasm except for small meningioma.
• History of intracranial or intraspinal surgery within the past 90 days.
• Diagnosis of serious, advanced, or terminal illness with anticipated life expectancy of less than 1 year.
• History of cerebral amyloid angiopathy.
• History of systemic malignancy, except for locally excised basal cell or squamous cell skin carcinoma with clear margins.
  • Current Medical Conditions 24. Active, uncontrolled bleeding.
• Bleeding diathesis or any other conditions that would pose significant bleeding risk.
• Evidence of acute or chronic intracranial hemorrhage.
• Known life-threatening hypersensitivity reaction to TAK-755 or its components.

Lab values

• Blood glucose <50 mg/dL or >400 mg/dL.
• Evidence of intracranial tumor (except incidental, small meningioma), cerebral aneurysm, or arteriovenous malformation.
  • Laboratory 39. Platelet count <50,000/mm3.
  • Other 41. Identification by the investigator as being potentially unable or unwilling to cooperate with trial procedures.

Other

• Medical History 1. Weight >130 kg or <40 kg.
• Eligible for administration of intravenous thrombolysis (alteplase or tenecteplase, as well as prourokinase or reteplase in countries where approved) for the index AIS event, based on the site’s standard clinical guidelines and direct availability.
• Inability to undergo MRI or CT.
• Rapidly improving AIS symptoms.
• Chronic causative intracranial occlusion.
• Causative total occlusion of the extracranial ICA.
• Evidence of septic emboli or bacterial endocarditis.
• Pregnancy, lactation, or unable to comply with birth control methods or abstinence as specified in the protocol in the opinion of the investigator.
  • Imaging 33. Poor quality imaging that precludes interpretation according to trial protocol.
• Evidence of significant intracranial mass effect or midline shift.
• Evidence of occlusion in >1 vascular territory.
• Evidence of extensive early ischemic change estimated to be greater than one-third of the middle cerebral artery territory.
• Administration of caplacizumab in the past 30 days.
• Administration of von Willebrand factor-containing products in the past 14 days.

• Informed Consent 1. The participant or legally authorized representative has provided informed consent before the initiation of any trial procedures.
• Participants who are within 0 to 4.5 hours of stroke symptom onset at time of enrollment: Definition of Salvageable Brain Tissue, Part A and B • For sites that use perfusion imaging as part of SoC for this time window (CT perfusion or MR perfusion): – Initial ischemic core volume <70 cc. – Absolute volume of reversible ischemic tissue (penumbra) of ≥10 cc. – ASPECTS >6 (NCCT or DWI MRI). • For sites that do not use perfusion imaging as part of SoC for this time window or do not have perfusion imaging capability: – ASPECTS >6 (NCCT or DWI MRI). o ASPECTS: defined in Section 8.2.2.3.
  • Age 2. 18 to 80 years of age, inclusive, at the time of signing the informed consent form. See Section 13.4 for country-specific criteria
  • Clinical Characteristics 3. Clinical diagnosis of acute ischemic stroke (AIS).
• Onset of stroke symptoms within 24 hours of enrollment. Wake-up strokes may be included if Last Known Well is within 24 hours of enrollment; time of onset will be considered the time of Last Known Well.
• National Institutes of Health Stroke Scale score of 6 to 25, indicating moderate to severe stroke.
• Estimated Modified Rankin Scale score <2 prior to AIS presentation, signifying no significant disability.
• Signs and symptoms consistent with anterior circulation stroke.
  • Imaging 8. Evidence of causative AIS occlusion on imaging (intracranial internal carotid artery [ICA], M1, M2, M3, M4, A1, A2, A3), either based on vascular imaging, corresponding perfusion deficit, or acute DWI MRI lesion in corresponding vascular territory.
• Participants who are within >4.5 to 24 hours of stroke symptom onset at time of enrollment: Definition of Salvageable Brain Tissue • Part A and B: For sites that have perfusion imaging capability (computed tomography [CT] perfusion or magnetic resonance [MR] perfusion): – Initial ischemic core volume <70 cc. – Absolute volume of reversible ischemic tissue (penumbra) of ≥10 cc. – Alberta Stroke Programme Early CT Score (ASPECTS) >6 (non-contrast CT [NCCT] or diffusion weighted imaging [DWI] magnetic resonance imaging [MRI]). • Parts A and B: For sites that use MRI as part of screening: – Acute ischemic lesion visible on DWI but no marked parenchymal hyperintensity visible on FLAIR (DWI/FLAIR mismatch). – For large vessel occlusion (LVO; intracranial ICA, M1, M2 occlusions): ASPECTS >6 (DWI MRI). – For medium vessel occlusion (MVO; M3, M4 occlusions): ASPECTS >7 (DWI MRI). – For medium vessel occlusion (MVO; A1, A2, A3 occlusions): evidence of early ischemic change in less than one-third of corresponding anterior cerebral artery vascular territory (DWI MRI). • Part A Only: For sites that do not have MRI or perfusion imaging capability: – For large vessel occlusion (LVO; intracranial ICA, M1, M2 occlusions): ASPECTS >6 (NCCT). – For medium vessel occlusion (MVO; M3, M4 occlusions): ASPECTS >7 (NCCT). – For medium vessel occlusion (MVO; A1, A2, A3 occlusions): evidence of early ischemic change in less than one-third of corresponding anterior cerebral artery vascular territory (NCCT). – Presence of leptomeningeal collaterals that are visualized on single phase or multiphase CT angiography (CTA). o ASPECTS: defined in Section 8.2.2.3.