Intracerebral Hemorrhage
Conditions
Keywords
intracerebral hemorrhage, ICH, brain hemorrhage, minimally invasive surgery, rt-PA
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.
Interventions
DRUGrt-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.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Genentech, Inc.
Emissary International LLC
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted) | Day 365 | By group comparison of mortality from ictus to 365 days adjusted for baseline severity. |
| Clot Removal (Amount of Residual Blood) | 24 hours after last dose | Relationship between clot removal as an Area Under the Curve (AUC) clot-assessment that estimates the time-averaged clot volume from ictus to end of treatment (EOT i.e. 24 hours after last dose) as AUC clot exposure and functional outcome (proportion 0-3 Modified Rankin Scale (mRS)). |
| 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. |
| Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted) | Day 365 | Patient disposition: By group comparison of residential location at day 365 post ictus adjusted for baseline severity. Good locations refers to home and rehabilitation; and bad locations refers to acute care, long-term care and death. |
| Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted) | Day 180 | Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 180 days post-ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death |
| 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. |
| 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 |
| Type and Intensity of ICU Management: Hospital Days | Up to 365 days | By group comparison of total number of days in the hospital |
| EQ-VAS | Day 365 | By group comparison of EQ-VAS at day 365 post ictus. The EuroQol Visual Analogue Scale (EQ-VAS) is a self-reported measure of health status. It is a marked scale where subjects draw a line to indicate their health, with end points of 0 (the worst health you can imagine) and 100 (the best health you can imagine). |
| EuroQol 5 Dimensional Scale (EQ-5D) | Day 365 | By group comparison of EQ-5D at day 365 post ictus. The EuroQol 5 Dimensional Scale (Eq-5D) is a self-reported measure of health status. It is arranged to assess domains related to mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each domain, codes were 1=no problems, 2=some problems, 3=extreme problems, and 9=unknown. Having a problem in at least 1 domain was coded as 1 (originally represented by 2 or 3) and no problems as 0 (originally represented by 1) . |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Mortality and Safety Events: All Cause Mortality | Day 30 | By group comparison of mortality from all causes within the first 30 days post randomization. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, Canada, China, Germany, Hungary, Israel, Spain, United Kingdom, United States
Participant flow
Recruitment details
Recruitment and randomization occurred at 78 hospitals in USA, Canada, Europe, Australia, and Asia
Participants by arm
| Arm | Count |
|---|---|
| MIS Plus Rt-PA Management 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. | 250 |
| 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. | 249 |
| Total | 499 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Medical Management | Total | MIS Plus Rt-PA Management |
|---|---|---|---|
| Age, Continuous | 62 years | 62 years | 62 years |
| Antiplatelet therapy | 77 Participants | 144 Participants | 67 Participants |
| Blood pressure at presentation Diastolic BP (mm Hg) | 98 mm Hg | 98 mm Hg | 99 mm Hg |
| Blood pressure at presentation Systolic BP (mm Hg) | 176 mm Hg | 177 mm Hg | 177 mm Hg |
| Blood pressure at randomization Diastolic BP (mm Hg) | 69 mm Hg | 69 mm Hg | 70 mm Hg |
| Blood pressure at randomization Systolic BP (mm Hg) | 138 mm Hg | 138 mm Hg | 138 mm Hg |
| Clot location Deep | 144 Participants | 307 Participants | 163 Participants |
| Clot location Lobar | 105 Participants | 192 Participants | 87 Participants |
| Cocaine use | 9 Participants | 20 Participants | 11 Participants |
| Diabetes | 67 Participants | 139 Participants | 72 Participants |
| Diagnostic CT at presentation - IntraCerebral Hemorrhage (ICH) volume (mL) | 41.5 mL | 41.8 mL | 42.7 mL |
| Diagnostic CT at presentation - IntraVentricular Hemorrhage (IVH) volume (mL) | 0 mL | 0 mL | 0 mL |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 68 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 215 Participants | 431 Participants | 216 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| GCS score at randomization 13-15 | 78 Participants | 153 Participants | 75 Participants |
| GCS score at randomization 3-8 | 63 Participants | 127 Participants | 64 Participants |
| GCS score at randomization 9-12 | 108 Participants | 219 Participants | 111 Participants |
| Hormone replacement therapy | 3 Participants | 4 Participants | 1 Participants |
| Hyperlipidaemia medication compliant | 93 Participants | 189 Participants | 96 Participants |
| Hypertension | 240 Participants | 481 Participants | 241 Participants |
| mRS score before stroke 0 | 233 Participants | 463 Participants | 230 Participants |
| mRS score before stroke 1 | 16 Participants | 36 Participants | 20 Participants |
| NIHSS score at randomization | 19 Units on a scale | 19 Units on a scale | 19 Units on a scale |
| On anticoagulants | 10 Participants | 34 Participants | 24 Participants |
| Other cardiovascular disease | 34 Participants | 72 Participants | 38 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 18 Participants | 30 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants | 87 Participants | 46 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 184 Participants | 374 Participants | 190 Participants |
| Region of Enrollment Australia | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Canada | 4 participants | 7 participants | 3 participants |
| Region of Enrollment China | 5 participants | 10 participants | 5 participants |
| Region of Enrollment Europe | 44 participants | 85 participants | 41 participants |
| Region of Enrollment United States | 194 participants | 393 participants | 199 participants |
| Sex: Female, Male Female | 103 Participants | 194 Participants | 91 Participants |
| Sex: Female, Male Male | 146 Participants | 305 Participants | 159 Participants |
| Stability CT(last CT before randomization) IntraCerebral Hemorrhage (ICH) volume (mL) | 45.3 mL | 45.6 mL | 45.8 mL |
| Stability CT(last CT before randomization) IntraVentricular Hemorrhage (IVH) volume (mL) | 0.4 mL | 0.4 mL | 0.3 mL |
| Time from stroke to diagnostic CT (h) | 1.9 Hours | 2.0 Hours | 2.2 Hours |
| Time from stroke to stability CT (h) | 36.3 Hours | 36.3 Hours | 36.4 Hours |
| Tobacco use | 39 Participants | 89 Participants | 50 Participants |
| Ventilated at randomization | 102 Participants | 209 Participants | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 48 / 250 | 62 / 249 |
| other Total, other adverse events | 205 / 250 | 169 / 249 |
| serious Total, serious adverse events | 75 / 250 | 84 / 249 |
Outcome results
Primary
Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted)
Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 365 days post-ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). Ictus refers to symptom onset. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death.
Time frame: Day 365
Population: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIS Plus Rt-PA Management | Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted) | mRS 0-3 | 110 Participants |
| MIS Plus Rt-PA Management | Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted) | mRS 4-6 | 139 Participants |
| Medical Management | Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted) | mRS 0-3 | 100 Participants |
| Medical Management | Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted) | mRS 4-6 | 140 Participants |
p-value: 0.7395% CI: [-6.8, 10.7]Chi-squared
Comparison: Adjusted for age, GCS, stability ICH volume, stability IVH volume, ICH deep locationp-value: 0.3395% CI: [-4, 12]Multivariate logit model
Secondary
All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)
By group comparison of mortality from ictus to 365 days adjusted for baseline severity.
Time frame: Day 365
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIS Plus Rt-PA Management | All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted) | 48 Participants |
| Medical Management | All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted) | 62 Participants |
p-value: 0.08Log Rank
p-value: 0.03795% CI: [0.45, 0.98]Adjusted Cox proportional Hazard
Secondary
Clot Removal (Amount of Residual Blood)
Relationship between clot removal as an Area Under the Curve (AUC) clot-assessment that estimates the time-averaged clot volume from ictus to end of treatment (EOT i.e. 24 hours after last dose) as AUC clot exposure and functional outcome (proportion 0-3 Modified Rankin Scale (mRS)).
Time frame: 24 hours after last dose
Population: Includes patients who survived through the dosing period
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MIS Plus Rt-PA Management | Clot Removal (Amount of Residual Blood) | mRS 0-3 | 2.69 10mL x days | Standard Deviation 1.11 |
| MIS Plus Rt-PA Management | Clot Removal (Amount of Residual Blood) | mRS 4-6 | 3.32 10mL x days | Standard Deviation 1.33 |
| Medical Management | Clot Removal (Amount of Residual Blood) | mRS 0-3 | 4.11 10mL x days | Standard Deviation 1.35 |
| Medical Management | Clot Removal (Amount of Residual Blood) | mRS 4-6 | 5.26 10mL x days | Standard Deviation 1.82 |
p-value: <0.00195% CI: [0.62, 0.8]Logit model
p-value: <0.00195% CI: [0.59, 0.78]Multivariate logit model
Secondary
Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted)
Dichotomized, adjudicated, cross-sectional modified Rankin Scale (mRS) score 0-3 vs. 4-6 at 180 days post-ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death
Time frame: Day 180
Population: Includes patients who were not lost to followup at day 180
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIS Plus Rt-PA Management | Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted) | mRS 0-3 | 99 Participants |
| MIS Plus Rt-PA Management | Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted) | mRS 4-6 | 151 Participants |
| Medical Management | Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted) | mRS 0-3 | 93 Participants |
| Medical Management | Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted) | mRS 4-6 | 150 Participants |
p-value: 0.7695% CI: [-0.1, 0.07]Chi-squared
p-value: 0.3195% CI: [0.81, 1.94]Multivariate logit model
Secondary
Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted)
Dichotomized, cross-sectional extended Glasgow Outcome Scale (eGOS) score upper good recovery (UGR) through upper severe disability (US) vs. lower severe disability (LS) through death at 180 days post ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). The eGOS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored as: 1=Death, 2=Vegetative state, 3=Lower severe disability, 4=Upper severe disability, 5=Lower moderate disability, 6=Upper moderate disability, 7=Lower good recovery, 8=Upper good recovery. Dichotomous variable coding is as follows: 1=codes 4-8, 0=codes 1-3.
Time frame: Day 180
Population: Patients were included if they were not lost to followup at day 180
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIS Plus Rt-PA Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted) | eGOS UGR-US (4-8) | 81 Participants |
| MIS Plus Rt-PA Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted) | eGOS LS-Death (1-3) | 169 Participants |
| Medical Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted) | eGOS UGR-US (4-8) | 76 Participants |
| Medical Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted) | eGOS LS-Death (1-3) | 167 Participants |
p-value: 0.7995% CI: [-0.07, 0.09]Chi-squared
p-value: 0.3595% CI: [0.79, 1.97]Multivariate logit model
Secondary
Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)
Dichotomized, cross-sectional extended Glasgow Outcome Scale (eGOS) score upper good recovery (UGR) through upper severe disability (US) vs. lower severe disability (LS) through death at 365 days post ictus, adjusting for baseline (pre-randomization) variables used in covariate adaptive randomization as well as the clinically established severity variables IVH size and ICH location (lobar or deep). The eGOS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored as: 1=Death, 2=Vegetative state, 3=Lower severe disability, 4=Upper severe disability, 5=Lower moderate disability, 6=Upper moderate disability, 7=Lower good recovery, 8=Upper good recovery. Dichotomous variable coding is as follows: 1=codes 4-8, 0=codes 1-3.
Time frame: Day 365
Population: Those with non-missing mRS scores at 365 days post ictus
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIS Plus Rt-PA Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted) | eGOS UGR-US (4-8) | 94 Participants |
| MIS Plus Rt-PA Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted) | eGOS LS-Death (1-3) | 150 Participants |
| Medical Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted) | eGOS UGR-US (4-8) | 84 Participants |
| Medical Management | Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted) | eGOS LS-Death (1-3) | 150 Participants |
p-value: 0.5595% CI: [-0.06, 0.11]Chi-squared
p-value: 0.2795% CI: [0.82, 1.97]Multivariate logit model
Secondary
EQ-VAS
By group comparison of EQ-VAS at day 365 post ictus. The EuroQol Visual Analogue Scale (EQ-VAS) is a self-reported measure of health status. It is a marked scale where subjects draw a line to indicate their health, with end points of 0 (the worst health you can imagine) and 100 (the best health you can imagine).
Time frame: Day 365
Population: Includes patients who survived or were not lost to followup through 365 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MIS Plus Rt-PA Management | EQ-VAS | 70 score on a scale |
| Medical Management | EQ-VAS | 70 score on a scale |
p-value: 0.66Wilcoxon (Mann-Whitney)
Secondary
EuroQol 5 Dimensional Scale (EQ-5D)
By group comparison of EQ-5D at day 365 post ictus. The EuroQol 5 Dimensional Scale (Eq-5D) is a self-reported measure of health status. It is arranged to assess domains related to mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each domain, codes were 1=no problems, 2=some problems, 3=extreme problems, and 9=unknown. Having a problem in at least 1 domain was coded as 1 (originally represented by 2 or 3) and no problems as 0 (originally represented by 1) .
Time frame: Day 365
Population: Patients were included if they survived or were not lost to followup through 365 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIS Plus Rt-PA Management | EuroQol 5 Dimensional Scale (EQ-5D) | Any problem | 176 Participants |
| MIS Plus Rt-PA Management | EuroQol 5 Dimensional Scale (EQ-5D) | No problem | 16 Participants |
| Medical Management | EuroQol 5 Dimensional Scale (EQ-5D) | Any problem | 155 Participants |
| Medical Management | EuroQol 5 Dimensional Scale (EQ-5D) | No problem | 15 Participants |
p-value: 0.87Chi-squared
Secondary
Patient Disposition: Home Days Over 365 Days Time From Ictus.
By group comparison of cumulative days at home during the 365 days post ictus.
Time frame: During 365 days of follow-up
Population: Includes only patients with cumulative home days at any time during the 365 days of follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MIS Plus Rt-PA Management | Patient Disposition: Home Days Over 365 Days Time From Ictus. | 306 Days |
| Medical Management | Patient Disposition: Home Days Over 365 Days Time From Ictus. | 300 Days |
p-value: 0.78Wilcoxon (Mann-Whitney)
Secondary
Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)
Patient disposition: By group comparison of residential location at day 365 post ictus adjusted for baseline severity. Good locations refers to home and rehabilitation; and bad locations refers to acute care, long-term care and death.
Time frame: Day 365
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIS Plus Rt-PA Management | Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted) | Good Location | 163 Participants |
| MIS Plus Rt-PA Management | Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted) | Bad location | 87 Participants |
| Medical Management | Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted) | Good Location | 151 Participants |
| Medical Management | Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted) | Bad location | 98 Participants |
p-value: 0.3495% CI: [-0.04, 0.11]Chi-squared
Secondary
Type and Intensity of ICU Management: Hospital Days
By group comparison of total number of days in the hospital
Time frame: Up to 365 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MIS Plus Rt-PA Management | Type and Intensity of ICU Management: Hospital Days | 17 Days |
| Medical Management | Type and Intensity of ICU Management: Hospital Days | 17 Days |
p-value: 0.75Median test
Secondary
Type and Intensity of ICU Management: ICU Days
By group comparison of cumulative number of days in the Intensive Care Unit (ICU) in a hospital
Time frame: Up to 365 days
Population: Includes patients with cumulative ICU days during the 365 days of follow-up
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MIS Plus Rt-PA Management | Type and Intensity of ICU Management: ICU Days | 10 Days |
| Medical Management | Type and Intensity of ICU Management: ICU Days | 10 Days |
p-value: 0.46Median test
Other Pre-specified
Mortality and Safety Events: Adjudicated Bacterial Brain Infection
By group comparison of the percentage of subjects experiencing one or more adjudicated brain bacterial infection events within the first 30 days post randomization.
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIS Plus Rt-PA Management | Mortality and Safety Events: Adjudicated Bacterial Brain Infection | 2 Participants |
| Medical Management | Mortality and Safety Events: Adjudicated Bacterial Brain Infection | 0 Participants |
p-value: 0.16Chi-squared
Other Pre-specified
Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose
By group comparison of the percentage of subjects experiencing one or more adjudicated symptomatic brain bleeding events within the first 30 days post randomization.
Time frame: 72 hours after last dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIS Plus Rt-PA Management | Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose | 6 Participants |
| Medical Management | Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose | 3 Participants |
p-value: 0.32Chi-squared
Other Pre-specified
Mortality and Safety Events: All Cause Mortality
By group comparison of mortality from all causes within the first 30 days post randomization.
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIS Plus Rt-PA Management | Mortality and Safety Events: All Cause Mortality | 23 Participants |
| Medical Management | Mortality and Safety Events: All Cause Mortality | 37 Participants |
p-value: 0.05Chi-squared
Other Pre-specified
Mortality and Safety Events: First-week (Operative) Mortality
Mortality and Safety events: By group comparison of mortality within the first 7 days post randomization.
Time frame: Day 7
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIS Plus Rt-PA Management | Mortality and Safety Events: First-week (Operative) Mortality | 2 Participants |
| Medical Management | Mortality and Safety Events: First-week (Operative) Mortality | 10 Participants |
p-value: 0.02Chi-squared
Other Pre-specified
Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus
By group comparison of the total number of adjudicated adverse events (AE) and serious adverse events (SAE) across all coded organ systems that occurred within the first 30 days post ictus.
Time frame: Day 30
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MIS Plus Rt-PA Management | Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus | Serious Adverse Events | 123 Number of events |
| MIS Plus Rt-PA Management | Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus | Adverse Events | 477 Number of events |
| Medical Management | Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus | Serious Adverse Events | 136 Number of events |
| Medical Management | Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus | Adverse Events | 378 Number of events |
Other Pre-specified
Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days
By group comparison of the total number of adjudicated serious adverse events that occurred within the first 30 days post randomization.
Time frame: Day 30
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MIS Plus Rt-PA Management | Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days | 123 Number of events |
| Medical Management | Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days | 136 Number of events |
p-value: 0.01Chi-squared