Clinical trial NCT00224770: Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation
Official title: Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Intracerebral Hemorrhage
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: 2005-09-23
Enrollment: 141
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety Outcome Number 1: Rate of Mortality
timeFrame: 30 days from randomization
measure: Safety Outcome Number 2: Rate of Procedure-related Mortality
timeFrame: 7 days from randomization
measure: Safety Outcome Number 3: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis
timeFrame: 30 days from randomization
measure: Safety Outcome Number 4: Rate of Symptomatic Rebleeding
timeFrame: 72 hours post last dose
measure: Efficacy Outcome Number 1: Dichotomized Modified Rankin Scale (mRS) at Day 180
timeFrame: 180 days from randomization
Secondary outcomes:
measure: Ordinal Modified Rankin Scale (mRS) at Day 180
timeFrame: 180 days from randomization
measure: Ordinal Modified Rankin Scale (mRS) at Day 365
timeFrame: 365 days from randomization
measure: Clot Size Reduction by End of Treatment
timeFrame: Time from randomization until end of treatment, up to 10 days
measure: Post-operative Clot Size Reduction
timeFrame: Time from post-operation until end of treatment, up to 10 days
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurosurgical Associates
state: Arizona
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Chicago
country: United States
facility: Rush University
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Evanston
country: United States
facility: NorthShore University Health System
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Systems
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University/Bayview Medical Center
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Edison
country: United States
facility: JFK Medical Center New Jersey
state: New Jersey
city: New York
country: United States
facility: Mt. Sinai Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Case Western University
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
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: Houston
country: United States
facility: University of Texas, Houston
state: Texas
city: San Antonio
country: United States
facility: University of Texas HSC, San Antonio
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Montreal
country: Canada
facility: Montreal Neurological Institute at McGill University
state: Quebec
city: Heidelberg
country: Germany
facility: University of Heidelberg
city: Newcastle
country: United Kingdom
facility: Newcastle General 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 California, Los Angeles
name: Paul Vespa, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.