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

Intracerebral Hemorrhage Clinical Trial

— MISTIE-III  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01827046
• Other study ID #: NA_00080619
• Secondary ID: U01NS080824ICH02
• Status: Completed
• Phase: Phase 3
• Start date: December 30, 2013
• Est. completion date: September 2018

Study information

• Verified date: September 2019
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Description:

Primary Objectives:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 499
• Est. completion date: September 2018
• Est. primary completion date: September 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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).

• 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:

• 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.

• 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.

Related Conditions & MeSH terms

• Cerebral Hemorrhage
• Hemorrhage
• Intracerebral Hemorrhage

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Royal Adelaide Hospital	North Adelaide	South Australia
Australia	Royal Melbourne Hospital	Parkville	Victoria
Canada	University of Alberta	Edmonton	Alberta
Canada	McMaster University	Hamilton	Ontario
Canada	Montreal Neurological Institute, McGill University	Montreal	Quebec
China	Bayi Brain Hospital, Beijing Military General Hospital	Beijing
China	Southwest Hospital, Third Military Medical University	Chongqing
China	Guangzhou First People's Hospital	Guangzhou	Guangdong
Germany	University of Bonn	Bonn
Germany	University of Heidelberg	Heidelberg
Germany	University of Mainz	Mainz
Germany	University of Munich	Munich
Hungary	University of Debrecen	Debrecen
Hungary	University of Pecs	Pecs	Baranya County
Hungary	University of Szeged	Szeged
Israel	Rabin Medical Center	Petach Tikva
Israel	The Chaim Sheba Medical Center at Tel Hashomer	Tel Hashomer	Ramat-Gan
Spain	Hospital Universitario Cruces	Barakaldo	Biscay
Spain	Bellvitge	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitario Mutua de Terrassa	Barcelona
Spain	Vall d'Hebron University Hospital	Barcelona
Spain	Hospital Universitario Rio Hortega	Valladolid
United Kingdom	South Glasgow University Hospital	Glasgow
United Kingdom	Newcastle Royal Victoria Infirmary	Newcastle upon Tyne
United Kingdom	Salford Royal NHS Foundation Trust	Salford	Manchester
United Kingdom	University of Southampton Hospital	Southampton
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	University of New Mexico	Albuquerque	New Mexico
United States	University of Michigan	Ann Arbor	Michigan
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Albert Einstein College of Medicine - Montefiore Medical Center	Bronx	New York
United States	University of Buffalo	Buffalo	New York
United States	Mercy San Juan Medical Center	Carmichael	California
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Rush University	Chicago	Illinois
United States	University of Chicago Medical Center	Chicago	Illinois
United States	University of Illinois at Chicago	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	University of Texas Southwestern at Dallas	Dallas	Texas
United States	Miami Valley Hospital	Dayton	Ohio
United States	Henry Ford Heath System	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Northshore University Health System, Evanston	Evanston	Illinois
United States	Fairfax INOVA Hospital	Falls Church	Virginia
United States	Hartford Hospital	Hartford	Connecticut
United States	University of Texas, Houston	Houston	Texas
United States	Mayo Clinic, Jacksonville	Jacksonville	Florida
United States	St. Luke's Hospital of Kansas City	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Scripps Health	La Jolla	California
United States	Gwinnett Medical Center	Lawrenceville	Georgia
United States	University of California, Los Angeles	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	University of Wisconsin	Madison	Wisconsin
United States	North Shore Long Island Jewish Health System	Manhasset	New York
United States	Loyola University Chicago	Maywood	Illinois
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Intermountain Neurosciences Institute	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Rutgers - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	Mount Sinai Medical Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Temple University School of Medicine	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Banner Good Samaritan Hospital	Phoenix	Arizona
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Maine Medical Center	Portland	Maine
United States	Providence Brain and Spine Institute	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Washington University	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	University of Texas at San Antonio	San Antonio	Texas
United States	University of California, San Diego	San Diego	California
United States	Stanford University	Stanford	California
United States	State University of New York, Upstate Medical University	Syracuse	New York
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
Johns Hopkins University	Emissary International LLC, Genentech, Inc., National Institute of Neurological Disorders and Stroke (NINDS)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  China,  Germany,  Hungary,  Israel,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mortality and Safety Events: First-week (Operative) Mortality	Mortality and Safety events: By group comparison of mortality within the first 7 days post randomization.	Day 7
Other	Mortality and Safety Events: All Cause Mortality	By group comparison of mortality from all causes within the first 30 days post randomization.	Day 30
Other	Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose	By group comparison of the percentage of subjects experiencing one or more adjudicated symptomatic brain bleeding events within the first 30 days post randomization.	72 hours after last dose
Other	Mortality and Safety Events: Adjudicated Bacterial Brain Infection	By group comparison of the percentage of subjects experiencing one or more adjudicated brain bacterial infection events within the first 30 days post randomization.	Day 30
Other	Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days	By group comparison of the total number of adjudicated serious adverse events that occurred within the first 30 days post randomization.	Day 30
Other	Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus	By group comparison of the total number of adjudicated adverse events (AE) and serious adverse events (SAE) across all coded organ systems that occurred within the first 30 days post ictus.	Day 30
Primary	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	Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)	Dichotomized, cross-sectional extended Glasgow Outcome Scale (eGOS) score upper good recovery (UGR) through upper severe disability (US) vs. lower severe disability (LS) through death 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).; The eGOS 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 as: 1=Death, 2=Vegetative state, 3=Lower severe disability, 4=Upper severe disability, 5=Lower moderate disability, 6=Upper moderate disability, 7=Lower good recovery, 8=Upper good recovery. Dichotomous variable coding is as follows: 1=codes 4-8, 0=codes 1-3.	Day 365
Secondary	All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)	By group comparison of mortality from ictus to 365 days adjusted for baseline severity.	Day 365
Secondary	Clot Removal (Amount of Residual Blood)	Relationship between clot removal as an Area Under the Curve (AUC) clot-assessment that estimates the time-averaged clot volume from ictus to end of treatment (EOT i.e. 24 hours after last dose) as AUC clot exposure and functional outcome (proportion 0-3 Modified Rankin Scale (mRS)).	24 hours after last dose
Secondary	Patient Disposition: Home Days Over 365 Days Time From Ictus.	By group comparison of cumulative days at home during the 365 days post ictus.	During 365 days of follow-up
Secondary	Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)	Patient disposition: By group comparison of residential location at day 365 post ictus adjusted for baseline severity.; Good locations refers to home and rehabilitation; and bad locations refers to acute care, long-term care and death.	Day 365
Secondary	Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted)	Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 180 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).; 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 180
Secondary	Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted)	Dichotomized, cross-sectional extended Glasgow Outcome Scale (eGOS) score upper good recovery (UGR) through upper severe disability (US) vs. lower severe disability (LS) through death at 180 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).; The eGOS 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 as: 1=Death, 2=Vegetative state, 3=Lower severe disability, 4=Upper severe disability, 5=Lower moderate disability, 6=Upper moderate disability, 7=Lower good recovery, 8=Upper good recovery. Dichotomous variable coding is as follows: 1=codes 4-8, 0=codes 1-3.	Day 180
Secondary	Type and Intensity of ICU Management: ICU Days	By group comparison of cumulative number of days in the Intensive Care Unit (ICU) in a hospital	Up to 365 days
Secondary	Type and Intensity of ICU Management: Hospital Days	By group comparison of total number of days in the hospital	Up to 365 days
Secondary	EQ-VAS	By group comparison of EQ-VAS at day 365 post ictus. The EuroQol Visual Analogue Scale (EQ-VAS) is a self-reported measure of health status. It is a marked scale where subjects draw a line to indicate their health, with end points of 0 (the worst health you can imagine) and 100 (the best health you can imagine).	Day 365
Secondary	EuroQol 5 Dimensional Scale (EQ-5D)	By group comparison of EQ-5D at day 365 post ictus. The EuroQol 5 Dimensional Scale (Eq-5D) is a self-reported measure of health status. It is arranged to assess domains related to mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each domain, codes were 1=no problems, 2=some problems, 3=extreme problems, and 9=unknown. Having a problem in at least 1 domain was coded as 1 (originally represented by 2 or 3) and no problems as 0 (originally represented by 1) .	Day 365