Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III
NCT ID: NCT01827046
Last Updated: 2019-09-27
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
499 participants
INTERVENTIONAL
2013-12-30
2018-09-30
Brief Summary
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Detailed Description
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Efficacy: Demonstrate that minimally invasive surgery (MIS) plus recombinant tissue plasminogen activator (rt-PA) for three days improves functional outcome by a 12% increase in the modified Rankin Scale (mRS) score 0-3 compared to medically treated subjects assessed at 365 days.
Secondary Objective:
Demonstrate that the end of treatment volume and percent of ICH reduction from MIS+rt-PA is related to improved functional outcome, as compared to medically treated subjects.
Safety:
Demonstrate that early use of MIS+rt-PA for three days is safe for the treatment of ICH relative to rates of mortality, rebleeding, and infection in the medically treated subject at 30 days.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
SINGLE
Study Groups
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MIS plus rt-PA management
Subjects randomized to the Minimally Invasive Surgery (MIS) plus rt-PA management arm will undergo minimally invasive surgery followed by up to 9 doses of 1.0 mg of rt-PA (Activase/Alteplase/CathFlo) for intracerebral hemorrhage clot resolution.
rt-PA
Up to 9 doses of 1.0 mg of rt-PA will be administered through the catheter that was placed directly into the intracerebral hemorrhage using minimally invasive surgery.
Medical management
Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
No interventions assigned to this group
Interventions
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rt-PA
Up to 9 doses of 1.0 mg of rt-PA will be administered through the catheter that was placed directly into the intracerebral hemorrhage using minimally invasive surgery.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Stability CT scan done at least 6 hours after diagnostic CT showing clot stability (growth \< 5 mL as measured by ABC/2 method).
* Symptoms less than 24 hours prior to diagnostic CT (dCT) scan (an unknown time of onset is exclusionary).
* Ability to randomize between 12 and 72 hours after dCT.
* Systolic Blood Pressure (SBP) \< 180 mmHg sustained for six hours recorded closest to the time of randomization.
* Historical Rankin score of 0 or 1.
* Age ≥ 18 and older.
Exclusion Criteria
* Intraventricular hemorrhage (IVH) requiring treatment for IVH-related (casting) mass effect or shift due to trapped ventricle. External ventricular drain (EVD) to treat intracranial pressure (ICP) is allowed.
* Thalamic bleeds with apparent midbrain extension with third nerve palsy or dilated and non-reactive pupils. Other (supranuclear) gaze abnormalities are not exclusions. Note: Patients with a posterior fossa ICH or cerebellar hematomas are ineligible.
* Irreversible impaired brain stem function (bilateral fixed, dilated pupils and extensor motor posturing), GCS ≤ 4.
* Ruptured aneurysm, arteriovenous malformation (AVM), vascular anomaly, Moyamoya disease, hemorrhagic conversion of an ischemic infarct, recurrence of a recent (\< 1 year) hemorrhage diagnosed with radiographic imaging.
* Patients with unstable mass or evolving intracranial compartment syndrome.
* Platelet count \< 100,000; international normalized ratio (INR) \> 1.4.
* Any irreversible coagulopathy or known clotting disorder.
* Inability to sustain INR ≤ 1.4 using short- and long-active procoagulants (such as but not limited to NovoSeven, Fresh Frozen Plasma (FFP), and/or vitamin K).
* Subjects requiring long-term anti-coagulation are excluded. Reversal of anti-coagulation is permitted for medically stable patients who can realistically tolerate the short term risk of reversal. Patient must not require Coumadin (anticoagulation) during the first 30 days, and normalized coagulation parameters must be demonstrated, monitored closely and maintained during the period of brain instrumentation.
* Use of Dabigatran, Apixaban, and/or Rivaroxaban (or a similar medication from the similar medication class) prior to symptom onset.
* Internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts.
* Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures, etc.) or site of recent surgical intervention.
* Positive urine or serum pregnancy test in pre-menopausal female subjects without a documented history of surgical sterilization.
* Allergy/sensitivity to rt-PA.
* Prior enrollment in the study.
* Participation in a concurrent interventional medical investigation or clinical trial. Patients in observational, natural history, and/or epidemiological studies not involving an intervention are eligible.
* Not expected to survive to the day 365 visit due to co-morbidities and/or are do not resuscitate (DNR)/ do not intubate (DNI) status prior to randomization.
* Any concurrent serious illness that would interfere with the safety assessments including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, and hematologic disease.
* Patients with a mechanical heart valve. Presence of bio-prosthetic valve(s) is permitted.
* Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, or subacute bacterial endocarditis.
* Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated.
* Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
* In the investigator's opinion, the patient is unstable and would benefit from a specific intervention rather than supportive care plus or minus MIS+rt-PA removal of the ICH.
* Inability or unwillingness of subject or legal guardian/representative to give written informed consent.
18 Years
ALL
No
Sponsors
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National Institute of Neurological Disorders and Stroke (NINDS)
NIH
Genentech, Inc.
INDUSTRY
Emissary International LLC
INDUSTRY
Johns Hopkins University
OTHER
Responsible Party
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Principal Investigators
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Daniel F. Hanley, MD
Role: STUDY_CHAIR
Johns Hopkins University
Mario Zuccarello, MD
Role: PRINCIPAL_INVESTIGATOR
University of Cincinnati
Issam Awad, MD
Role: PRINCIPAL_INVESTIGATOR
University of Chicago
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Banner Good Samaritan Hospital
Phoenix, Arizona, United States
Barrow Neurological Institute
Phoenix, Arizona, United States
Mercy San Juan Medical Center
Carmichael, California, United States
Scripps Health
La Jolla, California, United States
University of California, Los Angeles
Los Angeles, California, United States
University of California, San Diego
San Diego, California, United States
Stanford University
Stanford, California, United States
Hartford Hospital
Hartford, Connecticut, United States
Yale University
New Haven, Connecticut, United States
Mayo Clinic, Jacksonville
Jacksonville, Florida, United States
Gwinnett Medical Center
Lawrenceville, Georgia, United States
Northwestern University
Chicago, Illinois, United States
Rush University
Chicago, Illinois, United States
University of Illinois at Chicago
Chicago, Illinois, United States
University of Chicago Medical Center
Chicago, Illinois, United States
Northshore University Health System, Evanston
Evanston, Illinois, United States
Loyola University Chicago
Maywood, Illinois, United States
University of Kansas Medical Center
Kansas City, Kansas, United States
University of Louisville
Louisville, Kentucky, United States
Maine Medical Center
Portland, Maine, United States
University of Maryland
Baltimore, Maryland, United States
Johns Hopkins University
Baltimore, Maryland, United States
University of Michigan
Ann Arbor, Michigan, United States
Henry Ford Heath System
Detroit, Michigan, United States
Hennepin County Medical Center
Minneapolis, Minnesota, United States
St. Luke's Hospital of Kansas City
Kansas City, Missouri, United States
Washington University
St Louis, Missouri, United States
Rutgers - Robert Wood Johnson Medical School
New Brunswick, New Jersey, United States
University of New Mexico
Albuquerque, New Mexico, United States
University of Buffalo
Buffalo, New York, United States
North Shore Long Island Jewish Health System
Manhasset, New York, United States
Mount Sinai Medical Center
New York, New York, United States
Weill Cornell Medical College
New York, New York, United States
State University of New York, Upstate Medical University
Syracuse, New York, United States
Albert Einstein College of Medicine - Montefiore Medical Center
The Bronx, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
Wake Forest University Baptist Medical Center
Winston-Salem, North Carolina, United States
University of Cincinnati Medical Center
Cincinnati, Ohio, United States
Miami Valley Hospital
Dayton, Ohio, United States
Providence Brain and Spine Institute
Portland, Oregon, United States
Abington Memorial Hospital
Abington, Pennsylvania, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States
Temple University School of Medicine
Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
University of Texas Southwestern at Dallas
Dallas, Texas, United States
University of Texas, Houston
Houston, Texas, United States
University of Texas at San Antonio
San Antonio, Texas, United States
Intermountain Neurosciences Institute
Murray, Utah, United States
University of Utah
Salt Lake City, Utah, United States
University of Virginia Medical Center
Charlottesville, Virginia, United States
Fairfax INOVA Hospital
Falls Church, Virginia, United States
Virginia Commonwealth University
Richmond, Virginia, United States
University of Wisconsin
Madison, Wisconsin, United States
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
Royal Adelaide Hospital
North Adelaide, South Australia, Australia
Royal Melbourne Hospital
Parkville, Victoria, Australia
University of Alberta
Edmonton, Alberta, Canada
McMaster University
Hamilton, Ontario, Canada
Montreal Neurological Institute, McGill University
Montreal, Quebec, Canada
Guangzhou First People's Hospital
Guangzhou, Guangdong, China
Bayi Brain Hospital, Beijing Military General Hospital
Beijing, , China
Southwest Hospital, Third Military Medical University
Chongqing, , China
University of Bonn
Bonn, , Germany
University of Heidelberg
Heidelberg, , Germany
University of Mainz
Mainz, , Germany
University of Munich
Munich, , Germany
University of Pecs
Pécs, Baranya, Hungary
University of Debrecen
Debrecen, , Hungary
University of Szeged
Szeged, , Hungary
The Chaim Sheba Medical Center at Tel Hashomer
Tel Litwinsky, Ramat-Gan, Israel
Rabin Medical Center
Petah Tikva, , Israel
Hospital Universitario Cruces
Barakaldo, Biscay, Spain
Vall d'Hebron University Hospital
Barcelona, , Spain
Hospital de la Santa Creu i Sant Pau
Barcelona, , Spain
Bellvitge
Barcelona, , Spain
Hospital Universitario Mutua de Terrassa
Barcelona, , Spain
Hospital Universitario Rio Hortega
Valladolid, , Spain
Salford Royal NHS Foundation Trust
Salford, Manchester, United Kingdom
South Glasgow University Hospital
Glasgow, , United Kingdom
Newcastle Royal Victoria Infirmary
Newcastle upon Tyne, , United Kingdom
University of Southampton Hospital
Southampton, , United Kingdom
Countries
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References
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Cooper DC, Abramson E, Ziai WC, Flaherty ML, Shah VA, Avadhani R, Ostapkovich N, Carhuapoma L, Awad I, Zuccarello M, Hanley D, Sansing LH. Intracerebral haemorrhage laterality and associations with mood and pain: a MISTIE III substudy. Stroke Vasc Neurol. 2025 Apr 18:svn-2024-003755. doi: 10.1136/svn-2024-003755. Online ahead of print.
Sun P, Badihian S, Avadhani R, Walborn N, Yarava A, Alimoradi D, Awad I, Hanley D, Murthy S, Ziai W. Does stereotactic thrombolysis with alteplase for intracerebral haemorrhage alter intraventricular haematoma volume? A secondary analysis of the MISTIE-III trial. J Neurol Neurosurg Psychiatry. 2024 Sep 17;95(10):892-898. doi: 10.1136/jnnp-2023-333032.
Bako AT, Potter T, Pan AP, Tannous J, Britz G, Ziai WC, Awad I, Hanley D, Vahidy FS. Minimally Invasive Surgery With Thrombolysis for Intracerebral Hemorrhage Evacuation: Bayesian Reanalysis of a Randomized Controlled Trial. Neurology. 2023 Oct 17;101(16):e1614-e1622. doi: 10.1212/WNL.0000000000207735. Epub 2023 Sep 8.
Magid-Bernstein JR, Li Y, Cho SM, Piran PJ, Roh DJ, Gupta A, Shoamanesh A, Merkler A, Zhang C, Avadhani R, Montano N, Iadecola C, Falcone GJ, Sheth KN, Qureshi AI, Rosand J, Goldstein J, Awad I, Hanley DF, Kamel H, Ziai WC, Murthy SB. Cerebral Microbleeds and Acute Hematoma Characteristics in the ATACH-2 and MISTIE III Trials. Neurology. 2022 Mar 8;98(10):e1013-e1020. doi: 10.1212/WNL.0000000000013247. Epub 2021 Dec 22.
Hanley DF, Thompson RE, Rosenblum M, Yenokyan G, Lane K, McBee N, Mayo SW, Bistran-Hall AJ, Gandhi D, Mould WA, Ullman N, Ali H, Carhuapoma JR, Kase CS, Lees KR, Dawson J, Wilson A, Betz JF, Sugar EA, Hao Y, Avadhani R, Caron JL, Harrigan MR, Carlson AP, Bulters D, LeDoux D, Huang J, Cobb C, Gupta G, Kitagawa R, Chicoine MR, Patel H, Dodd R, Camarata PJ, Wolfe S, Stadnik A, Money PL, Mitchell P, Sarabia R, Harnof S, Barzo P, Unterberg A, Teitelbaum JS, Wang W, Anderson CS, Mendelow AD, Gregson B, Janis S, Vespa P, Ziai W, Zuccarello M, Awad IA; MISTIE III Investigators. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019 Mar 9;393(10175):1021-1032. doi: 10.1016/S0140-6736(19)30195-3. Epub 2019 Feb 7.
Provided Documents
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Document Type: Statistical Analysis Plan
Document Type: Study Protocol
Other Identifiers
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ICH02
Identifier Type: OTHER
Identifier Source: secondary_id
NA_00080619
Identifier Type: -
Identifier Source: org_study_id
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