Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation

NCT00224770 | Completed Phase 2 Results DMC

• 2 other identifiers: ICH01R01NS046309
• Study Type: interventional
• Target: 141
• Locations: 4 countries
• Sites: 29

Brief Summary

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.

Conditions

Intracerebral Hemorrhage

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (4)

• Ordinal Modified Rankin Scale (mRS) at Day 180

  180 days from randomization

• Ordinal Modified Rankin Scale (mRS) at Day 365

  365 days from randomization

• Clot Size Reduction by End of Treatment

  Time from randomization until end of treatment, up to 10 days

• Post-operative Clot Size Reduction

  Time from post-operation until end of treatment, up to 10 days

Study Arms (3)

Medical Management

NO INTERVENTION

Standard of care medical management as per American Heart Association (AHA) guidelines.

MISTIE Surgical Management

ACTIVE COMPARATOR

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)

ICES Surgical Management

ACTIVE COMPARATOR

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

Interventions

MIS+Cathflo Activase (drug) 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.

Also known as: rtPA

MISTIE Surgical Management

Intraoperative stereotactic CT-Guided Endoscopic Surgery PROCEDURE

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.

ICES Surgical Management

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-80
• GCS \< 14 or a NIHSS \> or equal to 6
• Spontaneous supratentorial ICH \> or equal to 20cc
• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

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

Study Sites (29)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Barrow Neurosurgical Associates

Phoenix, Arizona, 85013, United States

Location

University of California Los Angeles

Los Angeles, California, 90095, United States

Location

Stanford University

Palo Alto, California, 94034, United States

Location

University of California, San Diego

San Diego, California, 92103, United States

Location

Hartford Hospital

Hartford, Connecticut, 06102, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007, United States

Location

Mayo Clinic

Jacksonville, Florida, 32216, United States

Location

Rush University

Chicago, Illinois, 60612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

NorthShore University Health System

Evanston, Illinois, 60201, United States

Location

University of Maryland Medical Systems

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University/Bayview Medical Center

Baltimore, Maryland, 21287, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

JFK Medical Center New Jersey

Edison, New Jersey, 08818, United States

Location

Mt. Sinai Medical Center

New York, New York, 10029, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

Case Western University

Cleveland, Ohio, 44106, United States

Location

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

Location

Temple University

Philadelphia, Pennsylvania, 19140, United States

Location

Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212, 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

University of Texas, Houston

Houston, Texas, 77030, United States

Location

University of Texas HSC, San Antonio

San Antonio, Texas, 78229, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

Montreal Neurological Institute at McGill University

Montreal, Quebec, H3A 2B4, Canada

Location

University of Heidelberg

Heidelberg, 69117, Germany

Location

Newcastle General Hospital

Newcastle, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 32026447 DERIVED

• 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.

  PMID: 27758940 DERIVED

• 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.

  PMID: 27751554 DERIVED

• 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.

  PMID: 26451031 DERIVED

• 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.

  PMID: 26243227 DERIVED

MeSH Terms

Conditions

Cerebral Hemorrhage

Interventions

Pharmaceutical Preparations

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr. Daniel F. Hanley
• Organization: Johns Hopkins University

dhanley@jhmi.edu

(410) 614-6996

Study Officials

• Daniel F. Hanley, MD

  Johns Hopkins University

  STUDY CHAIR

• Mario Zuccarello, MD

  University of Cincinnati

  PRINCIPAL INVESTIGATOR

• Paul Vespa, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: September 21, 2005
• First Posted: September 23, 2005
• Study Start: August 1, 2005
• Primary Completion: August 1, 2012
• Study Completion: April 1, 2013
• Last Updated: June 18, 2015
• Results First Posted: June 18, 2015

Record last verified: 2015-06

Locations

CA (1); GB (1); US (26); DE (1)