Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation (MISTIE)

The purpose of this trial is to determine the safety of using a combination of minimally invasive surgery and clot lysis with rt-PA to remove intracerebral hemorrhage (ICH). The ICES arm of the trial will determine the safety of endoscopic surgery to remove ICH. All MISTIE intention to treat subjects represent the hypothesized test group. The ICES cohort is to be analyzed separately.

Study Overview

• Status: Completed
• Conditions: Intracerebral Hemorrhage
• Intervention / Treatment: Drug: MIS+Cathflo Activase (drug); Procedure: Intraoperative stereotactic CT-Guided Endoscopic Surgery

Detailed Description

The purpose of this trial is to determine the safety of using a combination of minimally invasive surgery and clot lysis with rt-PA to remove intracerebral hemorrhage (ICH). The procedure is to use image-based surgery (MRI or CT) to provide catheter access to ICH for the intervention, which is a one-time clot aspiration followed by instillation of rt-PA over 72 hours.

The Intraoperative stereotactic CT-guided Endoscopic Surgery (ICES) arm of the trial will determine the safety, feasibility and effectiveness of endoscopic surgery to remove ICH. This tests the first step of the MISTIE surgical procedure with an endoscope, not a rigid cannula.

We propose to test if these interventions facilitate more rapid and complete recovery of function and decreased mortality from this condition compared to conventional medical management without subjecting the patient to craniotomy. The specific objective of this trial is to test the safety of these interventions and assess their ability to remove blood clot from brain tissue.

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute at McGill University
• Germany
  • Heidelberg, Germany, 69117
    • University of Heidelberg
• United Kingdom
  • Newcastle, United Kingdom
    • Newcastle General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurosurgical Associates
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Palo Alto, California, United States, 94034
      • Stanford University
    • San Diego, California, United States, 92103
      • University of California, San Diego
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Mayo Clinic
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60612
      • Rush University
    • Evanston, Illinois, United States, 60201
      • Northshore University Health System
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Systems
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Bayview Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • New Jersey
    • Edison, New Jersey, United States, 08818
      • JFK Medical Center New Jersey
  • New York
    • New York, New York, United States, 10029
      • Mt. Sinai Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44106
      • Case Western University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas, Houston
    • San Antonio, Texas, United States, 78229
      • University of Texas HSC, San Antonio
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-80
• GCS < 14 or a NIHSS > or equal to 6
• Spontaneous supratentorial ICH > or equal to 20cc
• Symptoms less than 12 hours prior to diagnostic CT scan (an unknown time of symptom onset is exclusionary)
• Intention to initiate surgery within 48 hours after diagnostic CT
• First dose can be given within 54 hours after diagnostic CT (delays for post surgical stabilization of catheter bleeding or because of unanticipated surgical delay are acceptable with approved waiver from the coordinating center) (Does not apply to ICES Tier)
• Six-hour clot size equal to the most previous clot size + 5 cc (as determined by an additional CT scan at least 6 hours after the initial stability scan (A*B*C)/2 method)
• SBP < 200 mmHg sustained for 6 hours recorded closest to time of randomization
• Historical Rankin score of 0 or 1
• Negative pregnancy test

Exclusion Criteria:

• Infratentorial hemorrhage (any involvement of the midbrain or lower brainstem as demonstrated by radiograph or complete third nerve palsy)
• Patients with platelet count < 100,000, INR > 1.4, or an elevated PT or APTT (reversal of coumadin is permitted but the patient must not require coumadin during the acute hospitalization). Irreversible coagulopathy either due to medical condition or prior to randomization
• Clotting disorders
• 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 valve
• Patients with unstable mass or evolving intracranial compartment syndrome
• Ruptured aneurysm, AVM, vascular anomaly
• Greater than 80 years (higher incidence of amyloid)
• Under 18 years of ag e (high incidence of occult vascular malformation)
• Pregnant (positive pregnancy test) or lactating females (likelihood of altered coagulation function associated with the high estrogen/progesterone state)
• Irreversibly impaired brainstem function (bilateral fixed, dilated pupils and extensor motor posturing), GCS less than or equal to 4
• Historical Rankin score greater than or equal to 2
• Intraventricular hemorrhage requiring external ventricular drainage
• Internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts (Does not apply to ICES Tier)
• Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or site of recent surgical intervention (Does not apply to ICES Tier)
• Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, and subacute bacterial endocarditis (Does not apply to ICES Tier)
• In the investigator's opinion, the patient is unstable and would benefit from a specific intervention rather than supportive care plus or minus MIS+rtPA
• 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
• Participation in another simultaneous trial of ICH treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Medical Management; Standard of care medical management as per American Heart Association (AHA) guidelines.
Active Comparator: MISTIE Surgical Management; Minimally invasive surgery (MIS) with clot lysis with recombinant tissue plasminogen activator (rt-PA). MIS+Cathflo Activase (drug): The intervention is a comparison of the safety and preliminary effectiveness of investigational minimally invasive surgery to place a catheter into an intracerebral hemorrhage blood clot and subsequent administration in sequential tiers of 0.3 or 1.0mg of rt-PA, CathFlo®) through the catheter once every eight hours for up to 72 hours, in addition to best medical care. This includes 54 intent-to-treat patients, and excludes 27 pilots.	Drug: MIS+Cathflo Activase (drug); MIS+Cathflo Activase (drug): The intervention is a comparison of the safety and preliminary effectiveness of investigational minimally invasive surgery to place a catheter into an intracerebral hemorrhage blood clot and subsequent administration in sequential tiers of 0.3 or 1.0mg of rt-PA, CathFlo® through the catheter once every eight hours for up to 72 hours, in addition to best medical care.; Other Names: rtPA
Active Comparator: ICES Surgical Management; Intraoperative stereotactic CT-Guided Endoscopic Surgery Mechanical intracerebral hemorrhage removal via an endoscope utilizing the same operative-targeting arm as MISTIE arm. Best medical care was provided, but no rt-PA was administered. This includes 14 intent-to-treat patients, and excludes 4 pilots.	Procedure: Intraoperative stereotactic CT-Guided Endoscopic Surgery; Mechanical intracerebral hemorrhage removal via an endoscope utilizing the same operative targeting arm as MISTIE arm. No rt-PA administered, and in addition to best medical care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome Number 1: Rate of Mortality	Percentage of participants who died during the first 30 days after randomization.	30 days from randomization
Safety Outcome Number 2: Rate of Procedure-related Mortality	Percentage of participants who died during the first 7 days after randomization.	7 days from randomization
Safety Outcome Number 3: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis	Percentage of participants who had a bacterial brain infection (cerebritis, meningitis, ventriculitis) within 30 days of randomization.	30 days from randomization
Safety Outcome Number 4: Rate of Symptomatic Rebleeding	The difference in the rate of symptomatic rebleeding 72 hours post last dose.	72 hours post last dose
Efficacy Outcome Number 1: Dichotomized Modified Rankin Scale (mRS) at Day 180	Percentage of participants with dichotomized mRS score in 0-3 range. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead	180 days from randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ordinal Modified Rankin Scale (mRS) at Day 180	Ordinal distribution of the Modified Rankin Scale score at 180 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead.	180 days from randomization
Ordinal Modified Rankin Scale (mRS) at Day 365	Ordinal distribution of the Modified Rankin Scale score at 365 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead.	365 days from randomization
Clot Size Reduction by End of Treatment	The percentage of blood clot resolved by the end of treatment CT scan compared to the stability CT scan.	Time from randomization until end of treatment, up to 10 days
Post-operative Clot Size Reduction	The percentage of blood clot resolved by the end of treatment CT scan compared to the post-operative CT scan for surgical patients.	Time from post-operation until end of treatment, up to 10 days

Collaborators and Investigators

• Sponsor: Daniel Hanley
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Genentech, Inc.; Emissary International LLC
• Investigators: Study Chair: Daniel F. Hanley, MD, Johns Hopkins University; Principal Investigator: Mario Zuccarello, MD, University of Cincinnati; Principal Investigator: Paul Vespa, MD, University of California, Los Angeles

Publications and helpful links

General Publications

• 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.
• 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.
• Vespa P, Hanley D, Betz J, Hoffer A, Engh J, Carter R, Nakaji P, Ogilvy C, Jallo J, Selman W, Bistran-Hall A, Lane K, McBee N, Saver J, Thompson RE, Martin N; ICES Investigators. ICES (Intraoperative Stereotactic Computed Tomography-Guided Endoscopic Surgery) for Brain Hemorrhage: A Multicenter Randomized Controlled Trial. Stroke. 2016 Nov;47(11):2749-2755. doi: 10.1161/STROKEAHA.116.013837. Epub 2016 Oct 6. Erratum In: Stroke. 2017 Nov;48(11):e335.
• Hanley DF, Thompson RE, Muschelli J, Rosenblum M, McBee N, Lane K, Bistran-Hall AJ, Mayo SW, Keyl P, Gandhi D, Morgan TC, Ullman N, Mould WA, Carhuapoma JR, Kase C, Ziai W, Thompson CB, Yenokyan G, Huang E, Broaddus WC, Graham RS, Aldrich EF, Dodd R, Wijman C, Caron JL, Huang J, Camarata P, Mendelow AD, Gregson B, Janis S, Vespa P, Martin N, Awad I, Zuccarello M; MISTIE Investigators. Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial. Lancet Neurol. 2016 Nov;15(12):1228-1237. doi: 10.1016/S1474-4422(16)30234-4. Epub 2016 Oct 11.
• Muschelli J, Ullman NL, Sweeney EM, Eloyan A, Martin N, Vespa P, Hanley DF, Crainiceanu CM. Quantitative Intracerebral Hemorrhage Localization. Stroke. 2015 Nov;46(11):3270-3. doi: 10.1161/STROKEAHA.115.010369. Epub 2015 Oct 8.

Helpful Links

• Trial website

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: September 21, 2005
• First Submitted That Met QC Criteria: September 21, 2005
• First Posted (Estimate): September 23, 2005

Study Record Updates

• Last Update Posted (Estimate): June 18, 2015
• Last Update Submitted That Met QC Criteria: June 17, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator
• Other Study ID Numbers: ICH01; R01NS046309 (U.S. NIH Grant/Contract)