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

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01827046
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Genentech, Inc. (Industry), Emissary International LLC (Industry)
• Enrollment: 499
• Locations: 84
• Arms: 2
• Actual Duration (Months): 56
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Intracerebral Hemorrhage	Drug: rt-PA	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 499 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III
• Actual Study Start Date: Dec 30, 2013
• Actual Primary Completion Date: Sep 1, 2018
• Actual Study Completion Date: Sep 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MIS plus rt-PA management 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.	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.; Other Names: Activase Alteplase CathFlo
No Intervention: Medical management Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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)).

4. 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.

5. 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.

6. 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 death

7. 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.

8. 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

9. Type and Intensity of ICU Management: Hospital Days [Up to 365 days]

   By group comparison of total number of days in the hospital

10. 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).

11. 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) .

Other Outcome Measures

1. Mortality and Safety Events: First-week (Operative) Mortality [Day 7]

   Mortality and Safety events: By group comparison of mortality within the first 7 days post randomization.

2. Mortality and Safety Events: All Cause Mortality [Day 30]

   By group comparison of mortality from all causes within the first 30 days post randomization.

3. Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose [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.

4. Mortality and Safety Events: Adjudicated Bacterial Brain Infection [Day 30]

   By group comparison of the percentage of subjects experiencing one or more adjudicated brain bacterial infection events within the first 30 days post randomization.

5. Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days [Day 30]

   By group comparison of the total number of adjudicated serious adverse events that occurred within the first 30 days post randomization.

6. Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus [Day 30]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Banner Good Samaritan Hospital	Phoenix	Arizona	United States	85006
3	Barrow Neurological Institute	Phoenix	Arizona	United States	85013
4	Mercy San Juan Medical Center	Carmichael	California	United States	95608
5	Scripps Health	La Jolla	California	United States	92037
6	University of California, Los Angeles	Los Angeles	California	United States	90095
7	University of California, San Diego	San Diego	California	United States	92103
8	Stanford University	Stanford	California	United States	94305
9	Hartford Hospital	Hartford	Connecticut	United States	06102
10	Yale University	New Haven	Connecticut	United States	06510
11	Mayo Clinic, Jacksonville	Jacksonville	Florida	United States	32224
12	Gwinnett Medical Center	Lawrenceville	Georgia	United States	30046
13	Northwestern University	Chicago	Illinois	United States	60611
14	Rush University	Chicago	Illinois	United States	60612
15	University of Illinois at Chicago	Chicago	Illinois	United States	60612
16	University of Chicago Medical Center	Chicago	Illinois	United States	60637
17	Northshore University Health System, Evanston	Evanston	Illinois	United States	60201
18	Loyola University Chicago	Maywood	Illinois	United States	60305
19	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
20	University of Louisville	Louisville	Kentucky	United States	40202
21	Maine Medical Center	Portland	Maine	United States	04102
22	University of Maryland	Baltimore	Maryland	United States	21201
23	Johns Hopkins University	Baltimore	Maryland	United States	21287
24	University of Michigan	Ann Arbor	Michigan	United States	48190
25	Henry Ford Heath System	Detroit	Michigan	United States	48202
26	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
27	St. Luke's Hospital of Kansas City	Kansas City	Missouri	United States	64111
28	Washington University	Saint Louis	Missouri	United States	63110
29	Rutgers - Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08901
30	University of New Mexico	Albuquerque	New Mexico	United States	87131
31	Albert Einstein College of Medicine - Montefiore Medical Center	Bronx	New York	United States	10467
32	University of Buffalo	Buffalo	New York	United States	14203
33	North Shore Long Island Jewish Health System	Manhasset	New York	United States	11030
34	Mount Sinai Medical Center	New York	New York	United States	10029
35	Weill Cornell Medical College	New York	New York	United States	10065
36	State University of New York, Upstate Medical University	Syracuse	New York	United States	13210
37	Duke University Medical Center	Durham	North Carolina	United States	27710
38	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
39	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
40	Miami Valley Hospital	Dayton	Ohio	United States	45409
41	Providence Brain and Spine Institute	Portland	Oregon	United States	97225
42	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
43	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
44	Temple University School of Medicine	Philadelphia	Pennsylvania	United States	19140
45	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
46	Medical University of South Carolina	Charleston	South Carolina	United States	29425
47	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
48	University of Texas Southwestern at Dallas	Dallas	Texas	United States	75390
49	University of Texas, Houston	Houston	Texas	United States	77030
50	University of Texas at San Antonio	San Antonio	Texas	United States	78229
51	Intermountain Neurosciences Institute	Murray	Utah	United States	84107
52	University of Utah	Salt Lake City	Utah	United States	84132
53	University of Virginia Medical Center	Charlottesville	Virginia	United States	22908
54	Fairfax INOVA Hospital	Falls Church	Virginia	United States	22042
55	Virginia Commonwealth University	Richmond	Virginia	United States	23298
56	University of Wisconsin	Madison	Wisconsin	United States	53792
57	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2015
58	Royal Adelaide Hospital	North Adelaide	South Australia	Australia	5006
59	Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
60	University of Alberta	Edmonton	Alberta	Canada	T6G 2B7
61	McMaster University	Hamilton	Ontario	Canada	L8L 2X2
62	Montreal Neurological Institute, McGill University	Montreal	Quebec	Canada	H3A 2B4
63	Guangzhou First People's Hospital	Guangzhou	Guangdong	China	510180
64	Bayi Brain Hospital, Beijing Military General Hospital	Beijing		China	100700
65	Southwest Hospital, Third Military Medical University	Chongqing		China	400038
66	University of Bonn	Bonn		Germany	53127
67	University of Heidelberg	Heidelberg		Germany	69120
68	University of Mainz	Mainz		Germany	D-55131
69	University of Munich	Munich		Germany	81925
70	University of Pecs	Pecs	Baranya County	Hungary	7623
71	University of Debrecen	Debrecen		Hungary	4032
72	University of Szeged	Szeged		Hungary	6720
73	The Chaim Sheba Medical Center at Tel Hashomer	Tel Hashomer	Ramat-Gan	Israel	52621
74	Rabin Medical Center	Petach Tikva		Israel
75	Hospital Universitario Cruces	Barakaldo	Biscay	Spain	48903
76	Vall d'Hebron University Hospital	Barcelona		Spain	08035
77	Hospital de la Santa Creu i Sant Pau	Barcelona		Spain	08041
78	Bellvitge	Barcelona		Spain	08907
79	Hospital Universitario Mutua de Terrassa	Barcelona		Spain
80	Hospital Universitario Rio Hortega	Valladolid		Spain	47012
81	Salford Royal NHS Foundation Trust	Salford	Manchester	United Kingdom	M6 8HD
82	South Glasgow University Hospital	Glasgow		United Kingdom	G51 4TF
83	Newcastle Royal Victoria Infirmary	Newcastle upon Tyne		United Kingdom
84	University of Southampton Hospital	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

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

Investigators

• Study Chair: Daniel F. Hanley, MD, Johns Hopkins University
• Principal Investigator: Mario Zuccarello, MD, University of Cincinnati
• Principal Investigator: Issam Awad, MD, University of Chicago

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 25, 2018
• Study Protocol - Apr 14, 2015

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT01827046
• Other Study ID Numbers: NA_00080619; U01NS080824; ICH02
• First Posted: Apr 9, 2013
• Last Update Posted: Sep 27, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Johns Hopkins University: intracerebral hemorrhage; ICH; brain hemorrhage; minimally invasive surgery; rt-PA
• Additional relevant MeSH terms: Cerebral Hemorrhage; Hemorrhage; Tissue Plasminogen Activator

Study Results

Participant Flow

Recruitment Details	Recruitment and randomization occurred at 78 hospitals in USA, Canada, Europe, Australia, and Asia

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the Minimally Invasive Surgery (MIS) plus recombinant tissue plasminogen activator (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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Period Title: Overall Study
STARTED	250	249
COMPLETED	249	240
NOT COMPLETED	1	9

Baseline Characteristics

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management	Total
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.	Total of all reporting groups
Overall Participants	250	249	499
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	62	62	62
Sex: Female, Male (Count of Participants)
Female	91 36.4%	103 41.4%	194 38.9%
Male	159 63.6%	146 58.6%	305 61.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	34 13.6%	34 13.7%	68 13.6%
Not Hispanic or Latino	216 86.4%	215 86.3%	431 86.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	1 0.4%	2 0.4%
Asian	12 4.8%	18 7.2%	30 6%
Native Hawaiian or Other Pacific Islander	0 0%	3 1.2%	3 0.6%
Black or African American	46 18.4%	41 16.5%	87 17.4%
White	190 76%	184 73.9%	374 74.9%
More than one race	0 0%	2 0.8%	2 0.4%
Unknown or Not Reported	1 0.4%	0 0%	1 0.2%
Region of Enrollment (participants) [Number]
Australia	2 0.8%	2 0.8%	4 0.8%
Canada	3 1.2%	4 1.6%	7 1.4%
China	5 2%	5 2%	10 2%
Europe	41 16.4%	44 17.7%	85 17%
United States	199 79.6%	194 77.9%	393 78.8%
Tobacco use (Count of Participants)
Count of Participants [Participants]	50 20%	39 15.7%	89 17.8%
Cocaine use (Count of Participants)
Count of Participants [Participants]	11 4.4%	9 3.6%	20 4%
On anticoagulants (Count of Participants)
Count of Participants [Participants]	24 9.6%	10 4%	34 6.8%
Hormone replacement therapy (Count of Participants)
Count of Participants [Participants]	1 0.4%	3 1.2%	4 0.8%
Hyperlipidaemia medication compliant (Count of Participants)
Count of Participants [Participants]	96 38.4%	93 37.3%	189 37.9%
Antiplatelet therapy (Count of Participants)
Count of Participants [Participants]	67 26.8%	77 30.9%	144 28.9%
Diabetes (Count of Participants)
Count of Participants [Participants]	72 28.8%	67 26.9%	139 27.9%
Hypertension (Count of Participants)
Count of Participants [Participants]	241 96.4%	240 96.4%	481 96.4%
Other cardiovascular disease (Count of Participants)
Count of Participants [Participants]	38 15.2%	34 13.7%	72 14.4%
GCS score at randomization (Count of Participants)
3-8	64 25.6%	63 25.3%	127 25.5%
9-12	111 44.4%	108 43.4%	219 43.9%
13-15	75 30%	78 31.3%	153 30.7%
NIHSS score at randomization (Units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Units on a scale]	19	19	19
Diagnostic CT at presentation - IntraCerebral Hemorrhage (ICH) volume (mL) (mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL]	42.7	41.5	41.8
Diagnostic CT at presentation - IntraVentricular Hemorrhage (IVH) volume (mL) (mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL]	0	0	0
Stability CT(last CT before randomization) IntraCerebral Hemorrhage (ICH) volume (mL) (mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL]	45.8	45.3	45.6
Stability CT(last CT before randomization) IntraVentricular Hemorrhage (IVH) volume (mL) (mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mL]	0.3	0.4	0.4
Ventilated at randomization (Count of Participants)
Count of Participants [Participants]	107 42.8%	102 41%	209 41.9%
Blood pressure at presentation (mm Hg) [Median (Inter-Quartile Range) ]
Systolic BP (mm Hg)	177	176	177
Diastolic BP (mm Hg)	99	98	98
Blood pressure at randomization (mm Hg) [Median (Inter-Quartile Range) ]
Systolic BP (mm Hg)	138	138	138
Diastolic BP (mm Hg)	70	69	69
Time from stroke to diagnostic CT (h) (Hours) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Hours]	2.2	1.9	2.0
Time from stroke to stability CT (h) (Hours) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Hours]	36.4	36.3	36.3
Clot location (Count of Participants)
Deep	163 65.2%	144 57.8%	307 61.5%
Lobar	87 34.8%	105 42.2%	192 38.5%
mRS score before stroke (Count of Participants)
0	230 92%	233 93.6%	463 92.8%
1	20 8%	16 6.4%	36 7.2%

Outcome Measures

1. Primary Outcome

Title	Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted)
Description	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.
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

Includes participants with mRS scores available at day 365. Number and proportions reported refer to number of participants and proportions with Modified Rankin Score 0-3

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	249	240
mRS 0-3	110 44%	100 40.2%
mRS 4-6	139 55.6%	140 56.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.73
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	2
	Confidence Interval	(2-Sided) 95%; -6.8 to 10.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments	Adjusted for age, GCS, stability ICH volume, stability IVH volume, ICH deep location
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Multivariate logit model
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	4
	Confidence Interval	(2-Sided) 95%; -4 to 12
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)
Description	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.
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

Those with non-missing mRS scores at 365 days post ictus

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	244	234
eGOS UGR-US (4-8)	94 37.6%	84 33.7%
eGOS LS-Death (1-3)	150 60%	150 60.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Multivariate logit model
	Comments	Adjusted for age, GCS, stability ICH volume, stability IVH volume and ICH deep location
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)
Description	By group comparison of mortality from ictus to 365 days adjusted for baseline severity.
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Count of Participants [Participants]	48 19.2%	62 24.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.037
	Comments
	Method	Adjusted Cox proportional Hazard
	Comments	Adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location, diabetes, cardiovascular disease and race.
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Clot Removal (Amount of Residual Blood)
Description	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)).
Time Frame	24 hours after last dose

Outcome Measure Data

Analysis Population Description

Includes patients who survived through the dosing period

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	246	239
mRS 0-3	2.69 (1.11)	4.11 (1.35)
mRS 4-6	3.32 (1.33)	5.26 (1.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Logit model
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Multivariate logit model
	Comments	Adjusted for age, GCS, stability IVH volume, and ICH deep location
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Patient Disposition: Home Days Over 365 Days Time From Ictus.
Description	By group comparison of cumulative days at home during the 365 days post ictus.
Time Frame	During 365 days of follow-up

Outcome Measure Data

Analysis Population Description

Includes only patients with cumulative home days at any time during the 365 days of follow-up.

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	166	157
Median (Inter-Quartile Range) [Days]	306	300

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)
Description	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.
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Good Location	163 65.2%	151 60.6%
Bad location	87 34.8%	98 39.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted)
Description	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
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

Includes patients who were not lost to followup at day 180

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	243
mRS 0-3	99 39.6%	93 37.3%
mRS 4-6	151 60.4%	150 60.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Multivariate logit model
	Comments	Adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted)
Description	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.
Time Frame	Day 180

Outcome Measure Data

Analysis Population Description

Patients were included if they were not lost to followup at day 180

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	243
eGOS UGR-US (4-8)	81 32.4%	76 30.5%
eGOS LS-Death (1-3)	169 67.6%	167 67.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	Multivariate logit model
	Comments	Adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Type and Intensity of ICU Management: ICU Days
Description	By group comparison of cumulative number of days in the Intensive Care Unit (ICU) in a hospital
Time Frame	Up to 365 days

Outcome Measure Data

Analysis Population Description

Includes patients with cumulative ICU days during the 365 days of follow-up

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	240	238
Median (Inter-Quartile Range) [Days]	10	10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Median test
	Comments

10. Secondary Outcome

Title	Type and Intensity of ICU Management: Hospital Days
Description	By group comparison of total number of days in the hospital
Time Frame	Up to 365 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Median (Inter-Quartile Range) [Days]	17	17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	Median test
	Comments

11. Secondary Outcome

Title	EQ-VAS
Description	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).
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

Includes patients who survived or were not lost to followup through 365 days

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	183	164
Median (Inter-Quartile Range) [score on a scale]	70	70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.66
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

12. Secondary Outcome

Title	EuroQol 5 Dimensional Scale (EQ-5D)
Description	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) .
Time Frame	Day 365

Outcome Measure Data

Analysis Population Description

Patients were included if they survived or were not lost to followup through 365 days

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	192	170
Any problem	176 70.4%	155 62.2%
No problem	16 6.4%	15 6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Chi-squared
	Comments

13. Other Pre-specified Outcome

Title	Mortality and Safety Events: First-week (Operative) Mortality
Description	Mortality and Safety events: By group comparison of mortality within the first 7 days post randomization.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Count of Participants [Participants]	2 0.8%	10 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Chi-squared
	Comments

14. Other Pre-specified Outcome

Title	Mortality and Safety Events: All Cause Mortality
Description	By group comparison of mortality from all causes within the first 30 days post randomization.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Count of Participants [Participants]	23 9.2%	37 14.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Chi-squared
	Comments

15. Other Pre-specified Outcome

Title	Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose
Description	By group comparison of the percentage of subjects experiencing one or more adjudicated symptomatic brain bleeding events within the first 30 days post randomization.
Time Frame	72 hours after last dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Count of Participants [Participants]	6 2.4%	3 1.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Chi-squared
	Comments

16. Other Pre-specified Outcome

Title	Mortality and Safety Events: Adjudicated Bacterial Brain Infection
Description	By group comparison of the percentage of subjects experiencing one or more adjudicated brain bacterial infection events within the first 30 days post randomization.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Count of Participants [Participants]	2 0.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	Chi-squared
	Comments

17. Other Pre-specified Outcome

Title	Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days
Description	By group comparison of the total number of adjudicated serious adverse events that occurred within the first 30 days post randomization.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Number [Number of events]	123	136

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MIS Plus Rt-PA Management, Medical Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Chi-squared
	Comments

18. Other Pre-specified Outcome

Title	Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus
Description	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.
Time Frame	Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MIS Plus Rt-PA Management	Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.	Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
Measure Participants	250	249
Serious Adverse Events	123	136
Adverse Events	477	378

Adverse Events

Time Frame	30 days post-ictus
Arm/Group Title	MIS Plus Rt-PA Management		Medical Management
Arm/Group Description	Subjects randomized to the 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. 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.		Subjects randomized to medical management will receive the standard medical therapies for the treatment of intracerebral hemorrhage, which includes ICU care only and no planned surgical intervention.
All Cause Mortality
	MIS Plus Rt-PA Management		Medical Management
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/250 (19.2%)		62/249 (24.9%)
Serious Adverse Events
	MIS Plus Rt-PA Management		Medical Management
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	75/250 (30%)		84/249 (33.7%)
Cardiac disorders
Cardiac disorders	3/250 (1.2%)	4	1/249 (0.4%)	2
Gastrointestinal disorders
Gastrointestinal disorders	3/250 (1.2%)	4	4/249 (1.6%)	6
General disorders
General disorders and administration site conditions	13/250 (5.2%)	13	26/249 (10.4%)	27
Infections and infestations
Non-neurological infections	2/250 (0.8%)	5	4/249 (1.6%)	8
Injury, poisoning and procedural complications
Injury, Poisoning and procedural complications	3/250 (1.2%)	3	0/249 (0%)	0
Metabolism and nutrition disorders
Metabolism and nutrition disorders	1/250 (0.4%)	1	0/249 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms(Benign, malignant or unspecified	1/250 (0.4%)	1	0/249 (0%)	0
Nervous system disorders
Nervous system disorders	17/250 (6.8%)	41	33/249 (13.3%)	62
Psychiatric disorders
Psychiatric disorders	0/250 (0%)	0	1/249 (0.4%)	2
Renal and urinary disorders
Renal and urinary disorders	0/250 (0%)	0	1/249 (0.4%)	4
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disirders	26/250 (10.4%)	40	14/249 (5.6%)	25
Vascular disorders
Vascular disorders	6/250 (2.4%)	11	0/249 (0%)	0
Other (Not Including Serious) Adverse Events
	MIS Plus Rt-PA Management		Medical Management
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	205/250 (82%)		169/249 (67.9%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders	2/250 (0.8%)	3	0/249 (0%)	0
Cardiac disorders
Cardiac disorders	3/250 (1.2%)	15	5/249 (2%)	11
Gastrointestinal disorders
Gastrointestinal disorders	5/250 (2%)	12	7/249 (2.8%)	17
General disorders
General disorders and administration site conditions	17/250 (6.8%)	53	12/249 (4.8%)	42
Hepatobiliary disorders
Hepatobiliary disorders	0/250 (0%)	0	2/249 (0.8%)	2
Immune system disorders
Immune system disorders	0/250 (0%)	0	1/249 (0.4%)	1
Infections and infestations
Infections, non-neurologic	9/250 (3.6%)	16	25/249 (10%)	41
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications	1/250 (0.4%)	4	2/249 (0.8%)	3
Investigations
Investigations	1/250 (0.4%)	12	7/249 (2.8%)	20
Metabolism and nutrition disorders
Metabolism and nutrition disorders	3/250 (1.2%)	17	6/249 (2.4%)	20
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	2/250 (0.8%)	3	0/249 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms: benign, malignant, Unspecified (incl cysts and polyps)	1/250 (0.4%)	1	1/249 (0.4%)	2
Nervous system disorders
Nervous system disorders	108/250 (43.2%)	216	47/249 (18.9%)	107
Psychiatric disorders
Psychiatric disorders	6/250 (2.4%)	14	5/249 (2%)	13
Renal and urinary disorders
Renal and urinary disorders	3/250 (1.2%)	5	2/249 (0.8%)	5
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	30/250 (12%)	67	33/249 (13.3%)	62
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders	0/250 (0%)	0	1/249 (0.4%)	3
Vascular disorders
Vascular disorders	14/250 (5.6%)	39	13/249 (5.2%)	29

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.