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CLEAR III Clinical Trial

CLEAR III is a 500-patient Phase-III randomized clinical trial using a recombinant tissue plasminogen activator to quickly remove this blood from the ventricles. It is the hope of the over 70 academic medical centers in this international clinical trial that this may prove to be a better way to treat this brain injury.

The primary aim of the study is to determine whether the rapid removal of intraventricular hemorrhage (IVH) with low-dose rTPA improves modified Rankin Scores over 12 months compared to subjects treated with best medical care alone. Earlier studies have shown that placing a small catheter into the ventricle and giving a series of doses of TPA through it can remove most of the blood within a few days. Although it seems logical and early results have been promising, physicians still do not definitively know if removing the blood quickly (as compared to the slow healing process that naturally occurs over a period of weeks to months in patients that initially survive the stroke) will result in a better outcome for the patient 6-12 months later. If this therapy can reduce the rate of death and improve the quality of life for these patients, it could significantly change the way intraventricular hemorrhage is treated around the world.

CLEAR-III is the culmination of 10 years of research over a number of investigational trials. The early clinical studies were supported by grants from the Food and Drug Administration (FDA) Office of Orphan Products Development, the American Heart Association and other organizations. Current funding for CLEAR III is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS) and from the Eleanor Naylor Dana Charitable Trust, the Jeffrey and Harriet Legum Endowment, and support from Genentech, Inc. Over 70 major hospitals and academic institutions are participating in this trial as clinical sites or support teams.

NIH/NINDS Cooperative Agreement: U01 NS062851-02 Identifier: NCT00784134

The Clot Lysis: Evaluating Accelerated Resolution of IVH trial examined whether irrigating the ventricular system with alteplase improved functional outcomes in patients with small intracerebral hemorrhage (ICH) and large intraventricular hemorrhage (IVH).

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 1).

Poor outcomes were associated with mass-related obstruction of the third ventricle from thalamic ICH in alteplase-treated patients and from IVH in saline-treated patients. Once the ventricular system is cleared with alteplase, obstruction of cerebral spinal fluid flow from thalamic hemorrhage might become important in functional recovery 2).

Of the 500 patients with IVH, Venous Thromboembolism (VTE) occurred in 59 patients (11.8%) within the first 30 d. VTE chemoprophylaxis was initiated in 412 (82.4%) patients, but before VTE diagnosis in only 401 (80.2%) at median of 4 d (interquartile range, 1-8) from IVH onset, and was not associated with intracranial bleeding or catheter tract hemorrhage. In the multivariate logistic regression analysis, infection within 30 d (odds ratio, 1.80; confidence interval, 1.03-3.17) was significantly associated with higher odds of VTE occurrence. Starting VTE chemoprophylaxis after 72 h was additionally associated with VTE occurrence after the first week.

Infection and delay in the timely initiation of VTE chemoprophylaxis were associated with VTE occurrence. VTE chemoprophylaxis in IVH appears safe and should not be delayed beyond standard care policies for ICH including when intraventricular catheter placement and thrombolytic therapy are performed 3).

Intraventricular thrombolysis marginally increases the overall risk of symptomatic hemorrhagic complications after IVH, and only during the treatment phase 4).

Catheter tract hemorrhage (CTH) incidence on initial catheter placement and during stabilization was relatively low, despite emergent placement in a high-risk population. Catheter placement accuracy was similar or better than convenience samples from the published literature. Decreasing the risk of CTH may be achieved with attention to catheter placement accuracy and placement in the operating room. Antiplatelet agent use was an independent risk factor for CTH 5).

Among patients with spontaneous IVH requiring emergency CSF diversion, those with early elevated intracranial pressure, high CSF output, and placement of more than one EVD are at increased odds of permanent ventricular shunting. Administration of intraventricular alteplase, early radiographic findings, and CSF measures were not useful predictors of permanent CSF diversion 6).

In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status 7).

Risks of bleeding and infection in the CLEAR III trial are comparable to those previously reported in EVD case series. Rates of new bleeds and bacterial meningitis/ventriculitis are very low despite multiple daily injections, blood in the ventricles, the use of thrombolysis in half the cases, and generalization to >60 trial sites 8).


Ziai WC, Tuhrim S, Lane K, McBee N, Lees K, Dawson J, Butcher K, Vespa P, Wright DW, Keyl PM, Mendelow AD, Kase C, Wijman C, Lapointe M, John S, Thompson R, Thompson C, Mayo S, Reilly P, Janis S, Awad I, Hanley DF; CLEAR III Investigators. A multicenter, randomized, double-blinded, placebo-controlled phase III study of Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III). Int J Stroke. 2014 Jun;9(4):536-42. doi: 10.1111/ijs.12097. Epub 2013 Aug 28. PubMed PMID: 24033910.
Ullman NL, Tahsili-Fahadan P, Thompson CB, Ziai WC, Hanley DF. Third Ventricle Obstruction by Thalamic Intracerebral Hemorrhage Predicts Poor Functional Outcome Among Patients Treated with Alteplase in the CLEAR III Trial. Neurocrit Care. 2019 Apr;30(2):380-386. doi: 10.1007/s12028-018-0610-0. PubMed PMID: 30251074; PubMed Central PMCID: PMC6420835.
CLEAR III Trial Investigators . Venous Thromboembolism After Intraventricular Hemorrhage: Results From the CLEAR III Trial. Neurosurgery. 2019 Mar 1;84(3):709-716. doi: 10.1093/neuros/nyy189. PubMed PMID: 29788198.
Fam MD, Stadnik A, Zeineddine HA, Girard R, Mayo S, Dlugash R, McBee N, Lane K, Mould WA, Ziai W, Hanley D, Awad IA. Symptomatic Hemorrhagic Complications in Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III Clinical Trial (CLEAR III): A Posthoc Root-Cause Analysis. Neurosurgery. 2018 Dec 1;83(6):1260-1268. doi: 10.1093/neuros/nyx587. PubMed PMID: 29294116; PubMed Central PMCID: PMC6454794.
Müller A, Mould WA, Freeman WD, McBee N, Lane K, Dlugash R, Thompson R, Nekoovaght-Tak S, Madan V, Ali H, Stadnik A, Awad I, Hanley D, Ziai WC; CLEAR investigators. The Incidence of Catheter Tract Hemorrhage and Catheter Placement Accuracy in the CLEAR III Trial. Neurocrit Care. 2018 Aug;29(1):23-32. doi: 10.1007/s12028-017-0492-6. PubMed PMID: 29294223; PubMed Central PMCID: PMC6086340.
Murthy SB, Awad I, Harnof S, Aldrich F, Harrigan M, Jallo J, Caron JL, Huang J, Camarata P, Lara LR, Dlugash R, McBee N, Eslami V, Hanley DF, Ziai WC; CLEAR III Trial Investigators. Permanent CSF shunting after intraventricular hemorrhage in the CLEAR III trial. Neurology. 2017 Jul 25;89(4):355-362. doi: 10.1212/WNL.0000000000004155. Epub 2017 Jun 28. PubMed PMID: 28659429; PubMed Central PMCID: PMC5574677.
Hanley DF, Lane K, McBee N, Ziai W, Tuhrim S, Lees KR, Dawson J, Gandhi D, Ullman N, Mould WA, Mayo SW, Mendelow AD, Gregson B, Butcher K, Vespa P, Wright DW, Kase CS, Carhuapoma JR, Keyl PM, Diener-West M, Muschelli J, Betz JF, Thompson CB, Sugar EA, Yenokyan G, Janis S, John S, Harnof S, Lopez GA, Aldrich EF, Harrigan MR, Ansari S, Jallo J, Caron JL, LeDoux D, Adeoye O, Zuccarello M, Adams HP Jr, Rosenblum M, Thompson RE, Awad IA; CLEAR III Investigators. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017 Feb 11;389(10069):603-611. doi: 10.1016/S0140-6736(16)32410-2. Epub 2017 Jan 10. PubMed PMID: 28081952; PubMed Central PMCID: PMC6108339.
Dey M, Stadnik A, Riad F, Zhang L, McBee N, Kase C, Carhuapoma JR, Ram M, Lane K, Ostapkovich N, Aldrich F, Aldrich C, Jallo J, Butcher K, Snider R, Hanley D, Ziai W, Awad IA; CLEAR III Trial Investigators. Bleeding and infection with external ventricular drainage: a systematic review in comparison with adjudicated adverse events in the ongoing Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-III IHV) trial. Neurosurgery. 2015 Mar;76(3):291-300; discussion 301. doi: 10.1227/NEU.0000000000000624. PubMed PMID: 25635887; PubMed Central PMCID: PMC4333009.
clear_iii_clinical_trial.txt · Last modified: 2019/08/14 20:34 by administrador