Clinical trial NCT00784134: Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III
Official title: Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Intraventricular Hemorrhage
Keywords: intraventricular hemorrhage thrombolysis
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Genentech, Inc.
name: Emissary International LLC
First posted: 2008-11-02
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The overall objective of this Phase III clinical trial is to obtain information from a population of 500 ICH subjects with intraventricular hemorrhage (IVH), representative of current clinical practice and national demographics of ICH regarding the benefit (or lack thereof) of IVH clot removal on subject function as measured by modified Rankin Scale (mRS). This application requests funding for five years to initiate a Phase III randomized clinical trial (RCT) testing the benefit of clot removal for intraventricular hemorrhage. The investigators propose to compare extraventricular drainage (EVD) use plus recombinant tissue plasminogen activator (rt-PA; Alteplase; Genentech, Inc., San Francisco, CA) with EVD+ placebo in the management and treatment of subjects with small intracerebral hemorrhage (ICH) and large intraventricular hemorrhage (IVH defined as ICH \< 30 cc and obstruction of the 3rd or 4th ventricles by intraventricular blood clot).


Eligibility criteria: Inclusion Criteria:

* Age 18-80
* Symptom onset less than 24 hrs prior to diagnostic CT scan
* Spontaneous ICH less than or equal to 30 cc or primary IVH
* IVH obstructing 3rd and/or 4th ventricles
* ICH clot stability at 6 hours or more post IVC placement
* IVH clot stability at 6 hours or more post IVC placement
* Catheter tract bleeding stability 6 hours or more post IVC placement
* EVD placed per standard medical care
* SBP less than 200 mmHg sustained for 6 hours prior to drug administration
* Able to randomize within 72 hours of diagnostic CT scan
* Historical Rankin of 0 or 1

Exclusion Criteria:

* Suspected or untreated ruptured cerebral aneurysm, AVM, or tumor
* Presence of a choroid plexus vascular malformation or Moyamoya
* Clotting disorders
* Platelet count less than 100,000, INR greater than 1.4
* Pregnancy
* Infratentorial hemorrhage
* SAH at clinical presentation
* ICH/IVH enlargement that cannot be stabilized in the treatment time window
* Ongoing internal bleeding
* Superficial or surface bleeding
* Prior enrollment in the study
* Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated
* Planned or simultaneous participation (between screening and Day-30) in another interventional medical investigation or clinical trial.
* No subject or legal representative to give written informed consent

Primary outcomes:
measure: Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis
timeFrame: 180 days
measure: Participant Score on the Modified Rankin Scale (mRS) - Ordinal Analysis
timeFrame: 180 days
measure: Participants With Modified Rankin Scale (mRS) <=4 - Dichotomized Analysis
timeFrame: 180 days
measure: Random Effects Assessment of Site Effect on Modified Rankin Scale (mRS) <= 3
timeFrame: 180 days
measure: Longitudinal Assessment of Participants With Modified Rankin Scale (mRS) <=3
timeFrame: 30 days and 180 days
Secondary outcomes:
measure: All Cause Mortality
timeFrame: 180 days
measure: Clot Removal (Amount of Residual Blood)
timeFrame: 72 hours
measure: Intensity of Critical Care Management - Hospital Days
timeFrame: 30 days
measure: Intensity of Critical Care Management - ICU Days
timeFrame: 30 days
measure: Intensity of Critical Care Management - ICP Management
timeFrame: 30 days
measure: Intensity of Critical Care Management - Mechanical Ventilation
timeFrame: 30 days
measure: Intensity of Critical Care Management - Pressors
timeFrame: 30 days
measure: Intensity of Critical Care Management - Shunts
timeFrame: 30 days
measure: Intensity of Critical Care Management - All Infections
timeFrame: 30 days
measure: Intensity of Critical Care Management - Pneumonia
timeFrame: 30 days
measure: Intensity of Critical Care Management - All Infections
timeFrame: 180 days
measure: Safety/Mortality - Mortality Within 30 Days
timeFrame: 30 days
measure: Safety/Mortality - Bacterial Brain Infections Within 30 Days
timeFrame: 30 days
measure: Safety/Mortality - Systematic Bleeds Within 72 Hours
timeFrame: 72 hours
measure: Safety/Mortality - Systematic Bleeds Within 30 Days
timeFrame: 30 days
measure: Adverse and Serious Adverse Events
timeFrame: 180 days
measure: Predicting Hazards of Death by Treatment Group
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (African-American)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (White)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Female)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Male)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (65 Years or Under)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (Over 65 Years)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Less Than 20ml)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (20-50ml)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Greater Than 50ml)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Thalamic)
timeFrame: 180 days
measure: Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Non-Thalamic)
timeFrame: 180 days
measure: Functional Status - Barthel Index
timeFrame: 180 days
measure: Functional Status - Participants With Extended Glasgow Outcome (eGOS) Score >=Upper Severe Disability
timeFrame: 180 days
measure: Functional Status - National Institutes of Health Stroke Scale (NIHSS)
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Strength
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Mobility
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Hand Function
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Activities of Daily Living
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Communication
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Thinking
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Emotion
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Participation
timeFrame: 180 days
measure: Quality of Life - Stroke Impact Scale (SIS) - Recovery
timeFrame: 180 days
measure: Quality of Life - EuroQol Visual Analogue Scale (EQ-VAS)
timeFrame: 180 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic, Arizona
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California - Keck School of Medicine
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medical Center
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Des Moines
country: United States
facility: Ruan Neurology Clinical and Research Center
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: Kansas University Medical Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Kansas City
country: United States
facility: St. Luke's Brain and Stroke Institute
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis University
state: Missouri
city: Springfield
country: United States
facility: Springfield Neurological and Spine Institute
state: Missouri
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Edison
country: United States
facility: New Jersey Neuroscience Institute at JFK
state: New Jersey
city: Buffalo
country: United States
facility: University of Buffalo
state: New York
city: Manhasset
country: United States
facility: Northshore University Hospital Long Island
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case-Western Reserve University Hospital
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Portland
country: United States
facility: Maine Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Stroke Center
state: Oregon
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: University of Texas, Southwestern, Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas, Houston
state: Texas
city: San Antonio
country: United States
facility: University of Texas, San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Joinville
country: Brazil
facility: Hospital Sao Jose, Joinville
state: Santa Catarina
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Hospital de Pronto Socorro de Porto Alegre
city: Ribeirão Preto
country: Brazil
facility: Hospital de Clinicas de Ribeirao Preto
city: Sao Paulo
country: Brazil
facility: Hospital Sao Paulo Universidade Federal de Sao Paulo / UNIFESP
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Montreal
country: Canada
facility: Montreal Neurological Institute at McGill University
state: Quebec
city: Erlangen
country: Germany
facility: University of Erlangen
city: Halle
country: Germany
facility: University of Halle
city: Heidelberg
country: Germany
facility: University of Heidelberg
city: Leipzig
country: Germany
facility: University of Leipzig
city: Mainz
country: Germany
facility: University of Mainz
city: Tübingen
country: Germany
facility: University of Tubingen
city: Szeged
country: Hungary
facility: University of Szeged
state: Csongrad
city: Budapest
country: Hungary
facility: Honved Korhaz
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Pecs
country: Hungary
facility: University of Pecs
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Hebrew University Hospital
city: Ramat-Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Barcelona
country: Spain
facility: Bellvitge Hospital
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Zurich
country: Switzerland
facility: University of Zurich
state: ZH
city: Bern
country: Switzerland
facility: University Hospital, Inselpital, Bern
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
state: Manchester
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle General Hospital
city: Southampton
country: United Kingdom
facility: University of Southampton Hospital
Study officials:
affiliation: Johns Hopkins University
name: Daniel F. Hanley, MD
role: STUDY_CHAIR
References:
citation: Roh DJ, Asonye IS, Carvalho Poyraz F, Magid-Bernstein JR, Joiner EF, Avadhani R, Awad I, Hanley DF, Ziai WC, Murthy SB. Intraventricular Hemorrhage Expansion in the CLEAR III Trial: A Post Hoc Exploratory Analysis. Stroke. 2022 Jun;53(6):1847-1853. doi: 10.1161/STROKEAHA.121.037438. Epub 2022 Jan 28.
citation: Hansen BM, Ullman N, Muschelli J, Norrving B, Dlugash R, Avadhani R, Awad I, Zuccarello M, Ziai WC, Hanley DF, Thompson RE, Lindgren A; MISTIE and CLEAR Investigators. Relationship of White Matter Lesions with Intracerebral Hemorrhage Expansion and Functional Outcome: MISTIE II and CLEAR III. Neurocrit Care. 2020 Oct;33(2):516-524. doi: 10.1007/s12028-020-00916-4.
citation: Porter AL, Ebot J, Lane K, Mooney LH, Lannen AM, Richie EM, Dlugash R, Mayo S, Brott TG, Ziai W, Freeman WD, Hanley DF. Enhancing the Informed Consent Process Using Shared Decision Making and Consent Refusal Data from the CLEAR III Trial. Neurocrit Care. 2020 Feb;32(1):340-347. doi: 10.1007/s12028-019-00860-y.
citation: Eslami V, Tahsili-Fahadan P, Rivera-Lara L, Gandhi D, Ali H, Parry-Jones A, Nelson LS, Thompson RE, Nekoobakht-Tak S, Dlugash R, McBee N, Awad I, Hanley DF, Ziai WC. Influence of Intracerebral Hemorrhage Location on Outcomes in Patients With Severe Intraventricular Hemorrhage. Stroke. 2019 Jul;50(7):1688-1695. doi: 10.1161/STROKEAHA.118.024187. Epub 2019 Jun 10.
citation: Fam MD, Zeineddine HA, Eliyas JK, Stadnik A, Jesselson M, McBee N, Lane K, Cao Y, Wu M, Zhang L, Thompson RE, John S, Ziai W, Hanley DF, Awad IA; CLEAR III Trial Investigators. CSF inflammatory response after intraventricular hemorrhage. Neurology. 2017 Oct 10;89(15):1553-1560. doi: 10.1212/WNL.0000000000004493. Epub 2017 Sep 8.
citation: 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.
citation: Webb AJ, Ullman NL, Morgan TC, Muschelli J, Kornbluth J, Awad IA, Mayo S, Rosenblum M, Ziai W, Zuccarrello M, Aldrich F, John S, Harnof S, Lopez G, Broaddus WC, Wijman C, Vespa P, Bullock R, Haines SJ, Cruz-Flores S, Tuhrim S, Hill MD, Narayan R, Hanley DF; MISTIE and CLEAR Investigators. Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III. Stroke. 2015 Sep;46(9):2470-6. doi: 10.1161/STROKEAHA.114.007343. Epub 2015 Aug 4.