A multicenter, randomized, double-blinded, placebo-controlled phase III study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III)

• Authors: Wendy C. Ziai, Johns Hopkins University; Stanley Tuhrim, Mt Sinai School of Medicine; Karen Lane, Johns Hopkins University; Nichol McBee, Johns Hopkins University; Kennedy Lees, University of Glasgow; Jesse Dawson, University of Glasgow; Kenneth Butcher, University of Alberta; Paul Vespa, University of California Los Angeles; David Wright, Emory University; Penelope M. Keyl, Johns Hopkins University; A. David Mendelow, Newscastle General Hospital; Carlos Kase, Emory University; Christine Wijman, Stanford Medical Center; Marc Lapointe, Medical University of South Carolina; Sayona John, Rush University; Richard Thompson, Johns Hopkins Bloomberg School of Public Health; Carol Thompson, Johns Hopkins Bloomberg School of Public Health; Steven Mayo, Emissary International; Pat Reilly, Genentech Inc; Scott Janis, National Institute of Neurological Disorders and Stroke; Issam Awad, University of Chicago; Daniel F. Hanley, Johns Hopkins University
• Journal Title: International Journal of Stroke
• Volume: Volume 9, Number 4
• Publisher: Sage Publications Ltd | 2014-06-01, Pages 536-542
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/ijs.12097
• Subjects: Biology, Neuroscience
• Keywords: Science & Technology; Life Sciences & Biomedicine; Clinical Neurology; Peripheral Vascular Disease; Neurosciences & Neurology; Cardiovascular System & Cardiology; intracerebral haemorrhage; protocols; thrombolysis; stroke; randomized clinical trial; SPONTANEOUS INTRACEREBRAL HEMORRHAGE; BLOOD-CLOT; PLASMINOGEN-ACTIVATOR; FIBRINOLYTIC THERAPY; CEREBROSPINAL-FLUID; CANINE MODEL; UROKINASE; SAFETY; HYDROCEPHALUS; INFUSION

Abstract

Background: In adults, intraventricular thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) facilitates resolution of intraventricular haemorrhage (IVH), reduces intracranial pressure, decreases duration of cerebrospinal fluid diversion, and may ameliorate direct neural injury. We hypothesize that patients with small parenchymal haematoma volumes (<30cc) and relatively large IVH causing acute obstructive hydrocephalus would have improved clinical outcomes when given injections of low-dose rtPA to accelerate lysis and evacuation of IVH compared with placebo. Methods: The Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III trial is an investigator-initiated, phase III, randomized, multicenter, double-blind, placebo-controlled study comparing the use of external ventricular drainage (EVD) combined with intraventricular injection of rtPA to EVD plus intraventricular injection of normal saline (placebo) for the treatment of IVH. Patients with known symptom onset within 24h of the computed tomography scan confirmed IVH and third or fourth ventricle obstruction, with or without supratentorial intracerebral haemorrhage volume <30cc, who require EVD are screened with a computed tomography scan at least six hours after EVD placement and, if necessary, at consecutive 12-h intervals until stabilization of any intracranial bleeding has been established. Patients who meet clinical and imaging criteria (no ongoing coagulopathy and no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly) will be randomized to either intraventricular rtPA or placebo. Results: The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 180 days. Clinical secondary outcomes include additional modified Rankin Scale dichotomizations at 180 days (0-4 vs. 5-6), ordinal modified Rankin Scale (0-6), mortality and safety events at 30 days, mortality at 180 days, functional status measures, type and intensity of intensive care unit management, rate and extent of ventricular blood clot removal, and quality of life measures. © 2013 World Stroke Organization.