Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III
- Registration Number
- NCT01827046
- Lead Sponsor
- Johns Hopkins University
- 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).
- Detailed 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 & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 499
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description MIS plus rt-PA management rt-PA 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.
- Primary Outcome Measures
Name Time Method Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted) Day 365 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.
- Secondary Outcome Measures
Name Time Method Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted) Day 365 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.Patient Disposition: Home Days Over 365 Days Time From Ictus. During 365 days of follow-up By group comparison of cumulative days at home during the 365 days post ictus.
Type and Intensity of ICU Management: ICU Days Up to 365 days By group comparison of cumulative number of days in the Intensive Care Unit (ICU) in a hospital
EQ-VAS Day 365 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).
EuroQol 5 Dimensional Scale (EQ-5D) Day 365 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) .
All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted) Day 365 By group comparison of mortality from ictus to 365 days adjusted for baseline severity.
Clot Removal (Amount of Residual Blood) 24 hours after last dose 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)).
Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted) Day 180 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.Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted) Day 365 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.Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted) Day 180 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 deathType and Intensity of ICU Management: Hospital Days Up to 365 days By group comparison of total number of days in the hospital
Trial Locations
- Locations (84)
Northwestern University
🇺🇸Chicago, Illinois, United States
University of Illinois at Chicago
🇺🇸Chicago, Illinois, United States
University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas, Houston
🇺🇸Houston, Texas, United States
North Shore Long Island Jewish Health System
🇺🇸Manhasset, New York, United States
University of Buffalo
🇺🇸Buffalo, New York, United States
State University of New York, Upstate Medical University
🇺🇸Syracuse, New York, United States
Bayi Brain Hospital, Beijing Military General Hospital
🇨🇳Beijing, China
Hospital de la Santa Creu i Sant Pau
🇪🇸Barcelona, Spain
University of Maryland
🇺🇸Baltimore, Maryland, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Albert Einstein College of Medicine - Montefiore Medical Center
🇺🇸Bronx, New York, United States
University of Munich
🇩🇪Munich, Germany
Miami Valley Hospital
🇺🇸Dayton, Ohio, United States
Washington University
🇺🇸Saint Louis, Missouri, United States
Intermountain Neurosciences Institute
🇺🇸Murray, Utah, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Vall d'Hebron University Hospital
🇪🇸Barcelona, Spain
University of Southampton Hospital
🇬🇧Southampton, United Kingdom
University of Heidelberg
🇩🇪Heidelberg, Germany
University of Bonn
🇩🇪Bonn, Germany
Rutgers - Robert Wood Johnson Medical School
🇺🇸New Brunswick, New Jersey, United States
Royal Prince Alfred Hospital
🇦🇺Camperdown, New South Wales, Australia
University of Debrecen
🇭🇺Debrecen, Hungary
Southwest Hospital, Third Military Medical University
🇨🇳Chongqing, China
Hospital Universitario Cruces
🇪🇸Barakaldo, Biscay, Spain
Royal Adelaide Hospital
🇦🇺North Adelaide, South Australia, Australia
Bellvitge
🇪🇸Barcelona, Spain
Hospital Universitario Mutua de Terrassa
🇪🇸Barcelona, Spain
South Glasgow University Hospital
🇬🇧Glasgow, United Kingdom
Newcastle Royal Victoria Infirmary
🇬🇧Newcastle upon Tyne, United Kingdom
University of New Mexico
🇺🇸Albuquerque, New Mexico, United States
University of Mainz
🇩🇪Mainz, Germany
Guangzhou First People's Hospital
🇨🇳Guangzhou, Guangdong, China
Mount Sinai Medical Center
🇺🇸New York, New York, United States
University of Texas Southwestern at Dallas
🇺🇸Dallas, Texas, United States
University of Szeged
🇭🇺Szeged, Hungary
Hospital Universitario Rio Hortega
🇪🇸Valladolid, Spain
University of California, San Diego
🇺🇸San Diego, California, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University of Texas at San Antonio
🇺🇸San Antonio, Texas, United States
Hennepin County Medical Center
🇺🇸Minneapolis, Minnesota, United States
Salford Royal NHS Foundation Trust
🇬🇧Salford, Manchester, United Kingdom
Abington Memorial Hospital
🇺🇸Abington, Pennsylvania, United States
Henry Ford Heath System
🇺🇸Detroit, Michigan, United States
Scripps Health
🇺🇸La Jolla, California, United States
Stanford University
🇺🇸Stanford, California, United States
Hartford Hospital
🇺🇸Hartford, Connecticut, United States
Mayo Clinic, Jacksonville
🇺🇸Jacksonville, Florida, United States
Rush University
🇺🇸Chicago, Illinois, United States
Northshore University Health System, Evanston
🇺🇸Evanston, Illinois, United States
Loyola University Chicago
🇺🇸Maywood, Illinois, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
University of Wisconsin
🇺🇸Madison, Wisconsin, United States
Montreal Neurological Institute, McGill University
🇨🇦Montreal, Quebec, Canada
University of Pecs
🇭🇺Pecs, Baranya County, Hungary
McMaster University
🇨🇦Hamilton, Ontario, Canada
University of Alberta
🇨🇦Edmonton, Alberta, Canada
The Chaim Sheba Medical Center at Tel Hashomer
🇮🇱Tel Hashomer, Ramat-Gan, Israel
Banner Good Samaritan Hospital
🇺🇸Phoenix, Arizona, United States
Maine Medical Center
🇺🇸Portland, Maine, United States
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
Royal Melbourne Hospital
🇦🇺Parkville, Victoria, Australia
Weill Cornell Medical College
🇺🇸New York, New York, United States
Rabin Medical Center
🇮🇱Petach Tikva, Israel
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Providence Brain and Spine Institute
🇺🇸Portland, Oregon, United States
Mercy San Juan Medical Center
🇺🇸Carmichael, California, United States
Gwinnett Medical Center
🇺🇸Lawrenceville, Georgia, United States
Temple University School of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
University of Virginia Medical Center
🇺🇸Charlottesville, Virginia, United States
Fairfax INOVA Hospital
🇺🇸Falls Church, Virginia, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Wake Forest University Baptist Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Yale University
🇺🇸New Haven, Connecticut, United States
University of Louisville
🇺🇸Louisville, Kentucky, United States
St. Luke's Hospital of Kansas City
🇺🇸Kansas City, Missouri, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States