Clinical trial NCT01827046: Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III
Official title: Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Intracerebral Hemorrhage
Keywords: intracerebral hemorrhage
ICH
brain hemorrhage
minimally invasive surgery
rt-PA
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Genentech, Inc.
name: Emissary International LLC
First posted: 2013-04-09
Enrollment: 499
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted)
timeFrame: Day 365
Secondary outcomes:
measure: Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)
timeFrame: Day 365
measure: All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)
timeFrame: Day 365
measure: Clot Removal (Amount of Residual Blood)
timeFrame: 24 hours after last dose
measure: Patient Disposition: Home Days Over 365 Days Time From Ictus.
timeFrame: During 365 days of follow-up
measure: Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)
timeFrame: Day 365
measure: Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted)
timeFrame: Day 180
measure: Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted)
timeFrame: Day 180
measure: Type and Intensity of ICU Management: ICU Days
timeFrame: Up to 365 days
measure: Type and Intensity of ICU Management: Hospital Days
timeFrame: Up to 365 days
measure: EQ-VAS
timeFrame: Day 365
measure: EuroQol 5 Dimensional Scale (EQ-5D)
timeFrame: Day 365
Other outcomes:
measure: Mortality and Safety Events: First-week (Operative) Mortality
timeFrame: Day 7
measure: Mortality and Safety Events: All Cause Mortality
timeFrame: Day 30
measure: Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose
timeFrame: 72 hours after last dose
measure: Mortality and Safety Events: Adjudicated Bacterial Brain Infection
timeFrame: Day 30
measure: Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days
timeFrame: Day 30
measure: Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus
timeFrame: Day 30
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner Good Samaritan Hospital
state: Arizona
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Carmichael
country: United States
facility: Mercy San Juan Medical Center
state: California
city: La Jolla
country: United States
facility: Scripps Health
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Lawrenceville
country: United States
facility: Gwinnett Medical Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Evanston
country: United States
facility: Northshore University Health System, Evanston
state: Illinois
city: Maywood
country: United States
facility: Loyola University Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Heath System
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Kansas City
country: United States
facility: St. Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers - Robert Wood Johnson Medical School
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Bronx
country: United States
facility: Albert Einstein College of Medicine - Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: University of Buffalo
state: New York
city: Manhasset
country: United States
facility: North Shore Long Island Jewish Health System
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Syracuse
country: United States
facility: State University of New York, Upstate Medical University
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Portland
country: United States
facility: Providence Brain and Spine Institute
state: Oregon
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University School of Medicine
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas, Houston
state: Texas
city: San Antonio
country: United States
facility: University of Texas at San Antonio
state: Texas
city: Murray
country: United States
facility: Intermountain Neurosciences Institute
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Medical Center
state: Virginia
city: Falls Church
country: United States
facility: Fairfax INOVA Hospital
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: North Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Institute, McGill University
state: Quebec
city: Guangzhou
country: China
facility: Guangzhou First People's Hospital
state: Guangdong
city: Beijing
country: China
facility: Bayi Brain Hospital, Beijing Military General Hospital
city: Chongqing
country: China
facility: Southwest Hospital, Third Military Medical University
city: Bonn
country: Germany
facility: University of Bonn
city: Heidelberg
country: Germany
facility: University of Heidelberg
city: Mainz
country: Germany
facility: University of Mainz
city: Munich
country: Germany
facility: University of Munich
city: Pecs
country: Hungary
facility: University of Pecs
state: Baranya County
city: Debrecen
country: Hungary
facility: University of Debrecen
city: Szeged
country: Hungary
facility: University of Szeged
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center at Tel Hashomer
state: Ramat-Gan
city: Petach Tikva
country: Israel
facility: Rabin Medical Center
city: Barakaldo
country: Spain
facility: Hospital Universitario Cruces
state: Biscay
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Bellvitge
city: Barcelona
country: Spain
facility: Hospital Universitario Mutua de Terrassa
city: Valladolid
country: Spain
facility: Hospital Universitario Rio Hortega
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
state: Manchester
city: Glasgow
country: United Kingdom
facility: South Glasgow University Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle Royal Victoria Infirmary
city: Southampton
country: United Kingdom
facility: University of Southampton Hospital
Study officials:
affiliation: Johns Hopkins University
name: Daniel F. Hanley, MD
role: STUDY_CHAIR
affiliation: University of Cincinnati
name: Mario Zuccarello, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Issam Awad, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.