Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III

NCT01827046 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: NA_00080619U01NS080824ICH02
• Study Type: interventional
• Target: 499
• Locations: 9 countries
• Sites: 84

Brief Summary

A phase III, randomized, case-controlled, open-label, 500-subject clinical trial of minimally invasive surgery plus rt-PA in the treatment of intracerebral hemorrhage (ICH).

Conditions

Intracerebral Hemorrhage

Keywords

intracerebral hemorrhage; ICH; brain hemorrhage; minimally invasive surgery; rt-PA

Outcome Measures

Primary Outcomes (1)

• Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted)

  Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 365 days post-ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). Ictus refers to symptom onset. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death.

  Day 365

Secondary Outcomes (11)

• Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)

  Day 365

• All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)

  Day 365

• Clot Removal (Amount of Residual Blood)

  24 hours after last dose

• Patient Disposition: Home Days Over 365 Days Time From Ictus.

  During 365 days of follow-up

• Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)

  Day 365

Other Outcomes (6)

• Mortality and Safety Events: First-week (Operative) Mortality

  Day 7

• Mortality and Safety Events: All Cause Mortality

  Day 30

• Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose

  72 hours after last dose

Study Arms (2)

MIS plus rt-PA management

EXPERIMENTAL

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.

Drug: rt-PA

Medical management

NO INTERVENTION

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.

Interventions

rt-PA DRUG

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.

Also known as: Activase, Alteplase, CathFlo

MIS plus rt-PA management

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Spontaneous supratentorial ICH ≥ 30 mL diagnosed using radiographic imaging (computerized tomography (CT), computerized tomography angiography (CTA), etc.), with a Glasgow Coma Scale (GCS) ≤ 14 or a NIHSS ≥ 6.
• Stability CT scan done at least 6 hours after diagnostic CT showing clot stability (growth \< 5 mL as measured by ABC/2 method).
• 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.

You may not qualify if:

• Infratentorial hemorrhage.
• 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.
• 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.

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• Genentech, Inc.: collaborator
• Emissary International LLC: collaborator

Study Sites (84)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Banner Good Samaritan Hospital

Phoenix, Arizona, 85006, United States

Location

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

Mercy San Juan Medical Center

Carmichael, California, 95608, United States

Location

Scripps Health

La Jolla, California, 92037, United States

Location

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

University of California, San Diego

San Diego, California, 92103, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Hartford Hospital

Hartford, Connecticut, 06102, United States

Location

Yale University

New Haven, Connecticut, 06510, United States

Location

Mayo Clinic, Jacksonville

Jacksonville, Florida, 32224, United States

Location

Gwinnett Medical Center

Lawrenceville, Georgia, 30046, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Rush University

Chicago, Illinois, 60612, United States

Location

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Northshore University Health System, Evanston

Evanston, Illinois, 60201, United States

Location

Loyola University Chicago

Maywood, Illinois, 60305, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Maine Medical Center

Portland, Maine, 04102, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

University of Michigan

Ann Arbor, Michigan, 48190, United States

Location

Henry Ford Heath System

Detroit, Michigan, 48202, United States

Location

Hennepin County Medical Center

Minneapolis, Minnesota, 55415, United States

Location

St. Luke's Hospital of Kansas City

Kansas City, Missouri, 64111, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Rutgers - Robert Wood Johnson Medical School

New Brunswick, New Jersey, 08901, United States

Location

University of New Mexico

Albuquerque, New Mexico, 87131, United States

Location

University of Buffalo

Buffalo, New York, 14203, United States

Location

North Shore Long Island Jewish Health System

Manhasset, New York, 11030, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

State University of New York, Upstate Medical University

Syracuse, New York, 13210, United States

Location

Albert Einstein College of Medicine - Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States

Location

Miami Valley Hospital

Dayton, Ohio, 45409, United States

Location

Providence Brain and Spine Institute

Portland, Oregon, 97225, United States

Location

Abington Memorial Hospital

Abington, Pennsylvania, 19001, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

Temple University School of Medicine

Philadelphia, Pennsylvania, 19140, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

University of Texas Southwestern at Dallas

Dallas, Texas, 75390, United States

Location

University of Texas, Houston

Houston, Texas, 77030, United States

Location

University of Texas at San Antonio

San Antonio, Texas, 78229, United States

Location

Intermountain Neurosciences Institute

Murray, Utah, 84107, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

University of Virginia Medical Center

Charlottesville, Virginia, 22908, United States

Location

Fairfax INOVA Hospital

Falls Church, Virginia, 22042, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Royal Prince Alfred Hospital

Camperdown, New South Wales, 2015, Australia

Location

Royal Adelaide Hospital

North Adelaide, South Australia, 5006, Australia

Location

Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

University of Alberta

Edmonton, Alberta, T6G 2B7, Canada

Location

McMaster University

Hamilton, Ontario, L8L 2X2, Canada

Location

Montreal Neurological Institute, McGill University

Montreal, Quebec, H3A 2B4, Canada

Location

Guangzhou First People's Hospital

Guangzhou, Guangdong, 510180, China

Location

Bayi Brain Hospital, Beijing Military General Hospital

Beijing, 100700, China

Location

Southwest Hospital, Third Military Medical University

Chongqing, 400038, China

Location

University of Bonn

Bonn, 53127, Germany

Location

University of Heidelberg

Heidelberg, 69120, Germany

Location

University of Mainz

Mainz, D-55131, Germany

Location

University of Munich

Munich, 81925, Germany

Location

University of Pecs

Pécs, Baranya, 7623, Hungary

Location

University of Debrecen

Debrecen, 4032, Hungary

Location

University of Szeged

Szeged, 6720, Hungary

Location

The Chaim Sheba Medical Center at Tel Hashomer

Tel Litwinsky, Ramat-Gan, 52621, Israel

Location

Rabin Medical Center

Petah Tikva, Israel

Location

Hospital Universitario Cruces

Barakaldo, Biscay, 48903, Spain

Location

Vall d'Hebron University Hospital

Barcelona, 08035, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, 08041, Spain

Location

Bellvitge

Barcelona, 08907, Spain

Location

Hospital Universitario Mutua de Terrassa

Barcelona, Spain

Location

Hospital Universitario Rio Hortega

Valladolid, 47012, Spain

Location

Salford Royal NHS Foundation Trust

Salford, Manchester, M6 8HD, United Kingdom

Location

South Glasgow University Hospital

Glasgow, G51 4TF, United Kingdom

Location

Newcastle Royal Victoria Infirmary

Newcastle upon Tyne, United Kingdom

Location

University of Southampton Hospital

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (5)

• 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 Dec 23;10(6):734-742. doi: 10.1136/svn-2024-003755.

  PMID: 40250866 DERIVED

• 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.

  PMID: 38670789 DERIVED

• 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.

  PMID: 37684058 DERIVED

• 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.

  PMID: 34937780 DERIVED

• 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.

  PMID: 30739747 DERIVED

MeSH Terms

Conditions

Cerebral Hemorrhage; Intracranial Hemorrhages

Interventions

Tissue Plasminogen Activator

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Daniel F. Hanley
• Organization: Johns Hopkins University Division of Brain Injury Outcomes

dhanley@jhmi.edu

4106146996

Study Officials

• Daniel F. Hanley, MD

  Johns Hopkins University

  STUDY CHAIR

• Mario Zuccarello, MD

  University of Cincinnati

  PRINCIPAL INVESTIGATOR

• Issam Awad, MD

  University of Chicago

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2013
• First Posted: April 9, 2013
• Study Start: December 30, 2013
• Primary Completion: September 1, 2018
• Study Completion: September 1, 2018
• Last Updated: September 27, 2019
• Results First Posted: September 27, 2019

Record last verified: 2019-09

Locations

AU (3); DE (4); IL (2); CN (3); CA (3); GB (4); HU (3); ES (6); US (56)