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CompletedNCT01827046MISTIE-IIIUpdated Sep 27, 2019Results posted

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

A Phase 3 interventional study of rt-PA in Intracerebral Hemorrhage, sponsored by Johns Hopkins University. Completed at 84 sites in 9 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-09-27.

Sponsored by Johns Hopkins University · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
499
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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).

Read the 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.

02

Conditions studied

  • Intracerebral Hemorrhage

Keywords

  • intracerebral hemorrhage
  • ICH
  • brain hemorrhage
  • minimally invasive surgery
  • rt-PA
03

In context

Cerebral Hemorrhage

476 studies on the registry are indexed under Cerebral Hemorrhage; 181 are open to participants now.

This study's enrollment of 499 is above the median of 100 across 287 interventional studies indexed under Cerebral Hemorrhage.

Browse Cerebral Hemorrhage studies →

Lead sponsor

Johns Hopkins University is the lead sponsor of 1,783 studies on the registry; 313 are open to participants now.

Of its 203 completed or terminated interventional studies of FDA-regulated products, 140 (69%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
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

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.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Single (Outcomes assessor)
Enrollment
499 participants (actual)

Study arms

  • 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

  • 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.

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.

    Also known as: Activase, Alteplase, CathFlo

06

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

Other outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  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

    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

07

Results

Posted Sep 27, 2019

Participant flow

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

Participant flow — Overall Study
MilestoneMIS Plus Rt-PA ManagementMedical Management
Started250249
Completed249240
Not completed19
Withdrew: Lost to follow-up15
Withdrew: Withdrawal by subject04

Outcome measures

PrimaryDichotomized, 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
Reported as:
Count of participants · Participants
Dichotomized, Adjudicated Modified Rankin Scale Score 0-3 vs. 4-6 at 365 Days Post Ictus (Adjusted)
ParticipantsMIS Plus Rt-PA ManagementMedical Management
mRS 0-3110100
mRS 4-6139140
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.73 · Risk difference (rd): 2 · 95% CI -6.8 to 10.7
  • MIS Plus Rt-PA Management vs Medical Management · Multivariate logit model · p = 0.33 · Risk difference (rd): 4 · 95% CI -4 to 12
SecondaryDichotomized 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
Reported as:
Count of participants · Participants
Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 365 Days Post Ictus (Adjusted)
ParticipantsMIS Plus Rt-PA ManagementMedical Management
eGOS UGR-US (4-8)9484
eGOS LS-Death (1-3)150150
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.55 · Risk difference (rd): 0.03 · 95% CI -0.06 to 0.11
  • MIS Plus Rt-PA Management vs Medical Management · Multivariate logit model · p = 0.27 · Risk difference (rd): 1.26 · 95% CI 0.82 to 1.97Adjusted for age, GCS, stability ICH volume, stability IVH volume and ICH deep location
SecondaryAll 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
Reported as:
Count of participants · Participants
All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)
ParticipantsMIS Plus Rt-PA ManagementMedical Management
All Cause Mortality Longitudinally From Ictus to 365 Days (Adjusted)4862
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Log Rank · p = 0.08
  • MIS Plus Rt-PA Management vs Medical Management · Adjusted Cox proportional Hazard · p = 0.037 · Cox proportional hazard: 0.67 · 95% CI 0.45 to 0.98Adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location, diabetes, cardiovascular disease and race.
SecondaryClot 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
Reported as:
Mean · 10mL x days
Clot Removal (Amount of Residual Blood)
10mL x daysMIS Plus Rt-PA ManagementMedical Management
mRS 0-32.69 ± 1.114.11 ± 1.35
mRS 4-63.32 ± 1.335.26 ± 1.82
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Logit model · p = <0.001 · Odds ratio (or): 0.70 · 95% CI 0.62 to 0.80
  • MIS Plus Rt-PA Management vs Medical Management · Multivariate logit model · p = <0.001 · Odds ratio (or): 0.68 · 95% CI 0.59 to 0.78Adjusted for age, GCS, stability IVH volume, and ICH deep location
SecondaryPatient 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
Reported as:
Median · Days
Patient Disposition: Home Days Over 365 Days Time From Ictus.
DaysMIS Plus Rt-PA ManagementMedical Management
Patient Disposition: Home Days Over 365 Days Time From Ictus.306 (237 to 329)300 (232 to 328)
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Wilcoxon (Mann-Whitney) · p = 0.78
SecondaryPatient 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
Reported as:
Count of participants · Participants
Patient Disposition: Patient Location at 365 Days Post Ictus (i.e., Good vs. Bad Location) (Adjusted)
ParticipantsMIS Plus Rt-PA ManagementMedical Management
Good Location163151
Bad location8798
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.34 · Risk difference (rd): 0.04 · 95% CI -0.04 to 0.11
SecondaryDichotomized, 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
Reported as:
Count of participants · Participants
Dichotomized, Adjudicated, Cross-sectional Modified Rankin Scale (mRS) Score 0-3 vs. 4-6 180 Days Post Ictus (Adjusted)
ParticipantsMIS Plus Rt-PA ManagementMedical Management
mRS 0-39993
mRS 4-6151150
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.76 · Risk difference (rd): -0.01 · 95% CI -0.10 to 0.07
  • MIS Plus Rt-PA Management · Multivariate logit model · p = 0.31 · Odds ratio (or): 1.25 · 95% CI 0.81 to 1.94Adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location
SecondaryDichotomized 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
Reported as:
Count of participants · Participants
Dichotomized Extended Glasgow Outcome Scale (eGOS) Score UGR-US vs. LS-Death at 180 Days Post Ictus (Adjusted)
ParticipantsMIS Plus Rt-PA ManagementMedical Management
eGOS UGR-US (4-8)8176
eGOS LS-Death (1-3)169167
Statistical analysis
  • MIS Plus Rt-PA Management · Chi-squared · p = 0.79 · Risk difference (rd): 0.01 · 95% CI -0.07 to 0.09
  • MIS Plus Rt-PA Management vs Medical Management · Multivariate logit model · p = 0.35 · Odds ratio (or): 1.24 · 95% CI 0.79 to 1.97Adjusted for age, GCS, Stability ICH volume, Stability IVH volume, ICH deep location
SecondaryType 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
Reported as:
Median · Days
Type and Intensity of ICU Management: ICU Days
DaysMIS Plus Rt-PA ManagementMedical Management
Type and Intensity of ICU Management: ICU Days10 (7 to 17)10 (5 to 16)
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Median test · p = 0.46
SecondaryType and Intensity of ICU Management: Hospital Days

By group comparison of total number of days in the hospital

Time frame:
Up to 365 days
Reported as:
Median · Days
Type and Intensity of ICU Management: Hospital Days
DaysMIS Plus Rt-PA ManagementMedical Management
Type and Intensity of ICU Management: Hospital Days17 (13 to 27)17 (10 to 25)
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Median test · p = 0.75
SecondaryEQ-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
Reported as:
Median · score on a scale
EQ-VAS
score on a scaleMIS Plus Rt-PA ManagementMedical Management
EQ-VAS70 (50 to 80)70 (50 to 80)
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Wilcoxon (Mann-Whitney) · p = 0.66
SecondaryEuroQol 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
Reported as:
Count of participants · Participants
EuroQol 5 Dimensional Scale (EQ-5D)
ParticipantsMIS Plus Rt-PA ManagementMedical Management
Any problem176155
No problem1615
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.87
Other pre-specifiedMortality 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
Reported as:
Count of participants · Participants
Mortality and Safety Events: First-week (Operative) Mortality
ParticipantsMIS Plus Rt-PA ManagementMedical Management
Mortality and Safety Events: First-week (Operative) Mortality210
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.02
Other pre-specifiedMortality 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
Reported as:
Count of participants · Participants
Mortality and Safety Events: All Cause Mortality
ParticipantsMIS Plus Rt-PA ManagementMedical Management
Mortality and Safety Events: All Cause Mortality2337
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.05
Other pre-specifiedMortality 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
Reported as:
Count of participants · Participants
Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose
ParticipantsMIS Plus Rt-PA ManagementMedical Management
Mortality and Safety Events: Adjudicated Symptomatic Brain Bleeding Within 72 Hours After Last Dose63
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.32
Other pre-specifiedMortality 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
Reported as:
Count of participants · Participants
Mortality and Safety Events: Adjudicated Bacterial Brain Infection
ParticipantsMIS Plus Rt-PA ManagementMedical Management
Mortality and Safety Events: Adjudicated Bacterial Brain Infection20
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.16
Other pre-specifiedMortality 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
Reported as:
Number · Number of events
Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days
Number of eventsMIS Plus Rt-PA ManagementMedical Management
Mortality and Safety Events: Total Serious Adverse Events (SAE) at 30 Days123136
Statistical analysis
  • MIS Plus Rt-PA Management vs Medical Management · Chi-squared · p = 0.01
Other pre-specifiedMortality 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
Reported as:
Number · Number of events
Mortality and Safety Events: Summary of AE and SAE by MedDRA Code and Grouped by Organ System Within the First 30 Days Post Ictus
Number of eventsMIS Plus Rt-PA ManagementMedical Management
Serious Adverse Events123136
Adverse Events477378

Adverse events

Collected over 30 days post-ictus. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
MIS Plus Rt-PA Management48/250 (19.2%)75/250 (30%)205/250 (82%)
Medical Management62/249 (24.9%)84/249 (33.7%)169/249 (67.9%)
Most frequent serious events
Showing 10 of 12
Most frequent serious events
EventMIS Plus Rt-PA ManagementMedical Management
Nervous system disordersNervous system disorders17/25033/249
General disorders and administration site conditionsGeneral disorders13/25026/249
Respiratory, thoracic and mediastinal disirdersRespiratory, thoracic and mediastinal disorders26/25014/249
Vascular disordersVascular disorders6/2500/249
Gastrointestinal disordersGastrointestinal disorders3/2504/249
Non-neurological infectionsInfections and infestations2/2504/249
Cardiac disordersCardiac disorders3/2501/249
Injury, Poisoning and procedural complicationsInjury, poisoning and procedural complications3/2500/249
Psychiatric disordersPsychiatric disorders0/2501/249
Renal and urinary disordersRenal and urinary disorders0/2501/249
Most frequent other events
Showing 10 of 18
Most frequent other events
EventMIS Plus Rt-PA ManagementMedical Management
Nervous system disordersNervous system disorders108/25047/249
Respiratory, thoracic and mediastinal disordersRespiratory, thoracic and mediastinal disorders30/25033/249
Infections, non-neurologicInfections and infestations9/25025/249
General disorders and administration site conditionsGeneral disorders17/25012/249
Vascular disordersVascular disorders14/25013/249
Gastrointestinal disordersGastrointestinal disorders5/2507/249
InvestigationsInvestigations1/2507/249
Metabolism and nutrition disordersMetabolism and nutrition disorders3/2506/249
Psychiatric disordersPsychiatric disorders6/2505/249
Cardiac disordersCardiac disorders3/2505/249

Baseline characteristics

Age, Continuous
Age, Continuous(years)MIS Plus Rt-PA ManagementMedical ManagementTotal
Median62 (52 to 70)62 (53 to 71)62 (52 to 71)
Sex: Female, Male
Sex: Female, Male(Participants)MIS Plus Rt-PA ManagementMedical ManagementTotal
Female91103194
Male159146305
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)MIS Plus Rt-PA ManagementMedical ManagementTotal
Hispanic or Latino343468
Not Hispanic or Latino216215431
Unknown or Not Reported000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)MIS Plus Rt-PA ManagementMedical ManagementTotal
American Indian or Alaska Native112
Asian121830
Native Hawaiian or Other Pacific Islander033
Black or African American464187
White190184374
More than one race022
Unknown or Not Reported101
Region of Enrollment
Region of Enrollment(participants)MIS Plus Rt-PA ManagementMedical ManagementTotal
Australia224
Canada347
China5510
Europe414485
United States199194393
Tobacco use
Tobacco use(Participants)MIS Plus Rt-PA ManagementMedical ManagementTotal
Count of participants503989
Cocaine use
Cocaine use(Participants)MIS Plus Rt-PA ManagementMedical ManagementTotal
Count of participants11920
On anticoagulants
On anticoagulants(Participants)MIS Plus Rt-PA ManagementMedical ManagementTotal
Count of participants241034

19 further baseline measures are reported on the registry.

08

Study locations

84 sites
  • University of Alabama at Birmingham
    Birmingham, Alabama 35294, United States
  • Banner Good Samaritan Hospital
    Phoenix, Arizona 85006, United States
  • Barrow Neurological Institute
    Phoenix, Arizona 85013, United States
  • Mercy San Juan Medical Center
    Carmichael, California 95608, United States
  • Scripps Health
    La Jolla, California 92037, United States
  • University of California, Los Angeles
    Los Angeles, California 90095, United States
  • University of California, San Diego
    San Diego, California 92103, United States
  • Stanford University
    Stanford, California 94305, United States
  • Hartford Hospital
    Hartford, Connecticut 06102, United States
  • Yale University
    New Haven, Connecticut 06510, United States
  • Mayo Clinic, Jacksonville
    Jacksonville, Florida 32224, United States
  • Gwinnett Medical Center
    Lawrenceville, Georgia 30046, United States
  • Northwestern University
    Chicago, Illinois 60611, United States
  • Rush University
    Chicago, Illinois 60612, United States
  • University of Illinois at Chicago
    Chicago, Illinois 60612, United States
  • University of Chicago Medical Center
    Chicago, Illinois 60637, United States
  • Northshore University Health System, Evanston
    Evanston, Illinois 60201, United States
  • Loyola University Chicago
    Maywood, Illinois 60305, United States
  • University of Kansas Medical Center
    Kansas City, Kansas 66160, United States
  • University of Louisville
    Louisville, Kentucky 40202, United States
  • Maine Medical Center
    Portland, Maine 04102, United States
  • University of Maryland
    Baltimore, Maryland 21201, United States
  • Johns Hopkins University
    Baltimore, Maryland 21287, United States
  • University of Michigan
    Ann Arbor, Michigan 48190, United States
  • Henry Ford Heath System
    Detroit, Michigan 48202, United States
  • Hennepin County Medical Center
    Minneapolis, Minnesota 55415, United States
  • St. Luke's Hospital of Kansas City
    Kansas City, Missouri 64111, United States
  • Washington University
    Saint Louis, Missouri 63110, United States
  • Rutgers - Robert Wood Johnson Medical School
    New Brunswick, New Jersey 08901, United States
  • University of New Mexico
    Albuquerque, New Mexico 87131, United States
  • Albert Einstein College of Medicine - Montefiore Medical Center
    Bronx, New York 10467, United States
  • University of Buffalo
    Buffalo, New York 14203, United States
  • North Shore Long Island Jewish Health System
    Manhasset, New York 11030, United States
  • Mount Sinai Medical Center
    New York, New York 10029, United States
  • Weill Cornell Medical College
    New York, New York 10065, United States
  • State University of New York, Upstate Medical University
    Syracuse, New York 13210, United States
  • Duke University Medical Center
    Durham, North Carolina 27710, United States
  • Wake Forest University Baptist Medical Center
    Winston-Salem, North Carolina 27157, United States
  • University of Cincinnati Medical Center
    Cincinnati, Ohio 45219, United States
  • Miami Valley Hospital
    Dayton, Ohio 45409, United States
  • Providence Brain and Spine Institute
    Portland, Oregon 97225, United States
  • Abington Memorial Hospital
    Abington, Pennsylvania 19001, United States
  • Thomas Jefferson University Hospital
    Philadelphia, Pennsylvania 19107, United States
  • Temple University School of Medicine
    Philadelphia, Pennsylvania 19140, United States
  • University of Pittsburgh Medical Center
    Pittsburgh, Pennsylvania 15213, United States
  • Medical University of South Carolina
    Charleston, South Carolina 29425, United States
  • Vanderbilt University Medical Center
    Nashville, Tennessee 37232, United States
  • University of Texas Southwestern at Dallas
    Dallas, Texas 75390, United States
  • University of Texas, Houston
    Houston, Texas 77030, United States
  • University of Texas at San Antonio
    San Antonio, Texas 78229, United States
  • Intermountain Neurosciences Institute
    Murray, Utah 84107, United States
  • University of Utah
    Salt Lake City, Utah 84132, United States
  • University of Virginia Medical Center
    Charlottesville, Virginia 22908, United States
  • Fairfax INOVA Hospital
    Falls Church, Virginia 22042, United States
  • Virginia Commonwealth University
    Richmond, Virginia 23298, United States
  • University of Wisconsin
    Madison, Wisconsin 53792, United States
  • Royal Prince Alfred Hospital
    Camperdown, New South Wales 2015, Australia
  • Royal Adelaide Hospital
    North Adelaide, South Australia 5006, Australia
  • Royal Melbourne Hospital
    Parkville, Victoria 3050, Australia
  • University of Alberta
    Edmonton, Alberta T6G 2B7, Canada
  • McMaster University
    Hamilton, Ontario L8L 2X2, Canada
  • Montreal Neurological Institute, McGill University
    Montreal, Quebec H3A 2B4, Canada
  • Guangzhou First People's Hospital
    Guangzhou, Guangdong 510180, China
  • Bayi Brain Hospital, Beijing Military General Hospital
    Beijing, 100700, China
  • Southwest Hospital, Third Military Medical University
    Chongqing, 400038, China
  • University of Bonn
    Bonn, 53127, Germany
  • University of Heidelberg
    Heidelberg, 69120, Germany
  • University of Mainz
    Mainz, D-55131, Germany
  • University of Munich
    Munich, 81925, Germany
  • University of Pecs
    Pecs, Baranya County 7623, Hungary
  • University of Debrecen
    Debrecen, 4032, Hungary
  • University of Szeged
    Szeged, 6720, Hungary
  • The Chaim Sheba Medical Center at Tel Hashomer
    Tel Hashomer, Ramat-Gan 52621, Israel
  • Rabin Medical Center
    Petach Tikva, Israel
  • Hospital Universitario Cruces
    Barakaldo, Biscay 48903, Spain
  • Vall d'Hebron University Hospital
    Barcelona, 08035, Spain
  • Hospital de la Santa Creu i Sant Pau
    Barcelona, 08041, Spain
  • Bellvitge
    Barcelona, 08907, Spain
  • Hospital Universitario Mutua de Terrassa
    Barcelona, Spain
  • Hospital Universitario Rio Hortega
    Valladolid, 47012, Spain
  • Salford Royal NHS Foundation Trust
    Salford, Manchester M6 8HD, United Kingdom
  • South Glasgow University Hospital
    Glasgow, G51 4TF, United Kingdom
  • Newcastle Royal Victoria Infirmary
    Newcastle upon Tyne, United Kingdom
  • University of Southampton Hospital
    Southampton, SO16 6YD, United Kingdom
09

References and documents

Publications

  • Magid-Bernstein JR, Li Y, Cho SM, Piran PJ, Roh DJ, Gupta A, Shoamanesh A, Merkler A, Zhang C, Avadhani R, Montano N, Iadecola C, Falcone GJ, Sheth KN, Qureshi AI, Rosand J, Goldstein J, Awad I, Hanley DF, Kamel H, Ziai WC, Murthy SB. Cerebral Microbleeds and Acute Hematoma Characteristics in the ATACH-2 and MISTIE III Trials. Neurology. 2022 Mar 8;98(10):e1013-e1020. doi: 10.1212/WNL.0000000000013247. Epub 2021 Dec 22. PubMed 34937780 ↗
  • Hanley DF, Thompson RE, Rosenblum M, Yenokyan G, Lane K, McBee N, Mayo SW, Bistran-Hall AJ, Gandhi D, Mould WA, Ullman N, Ali H, Carhuapoma JR, Kase CS, Lees KR, Dawson J, Wilson A, Betz JF, Sugar EA, Hao Y, Avadhani R, Caron JL, Harrigan MR, Carlson AP, Bulters D, LeDoux D, Huang J, Cobb C, Gupta G, Kitagawa R, Chicoine MR, Patel H, Dodd R, Camarata PJ, Wolfe S, Stadnik A, Money PL, Mitchell P, Sarabia R, Harnof S, Barzo P, Unterberg A, Teitelbaum JS, Wang W, Anderson CS, Mendelow AD, Gregson B, Janis S, Vespa P, Ziai W, Zuccarello M, Awad IA; MISTIE III Investigators. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019 Mar 9;393(10175):1021-1032. doi: 10.1016/S0140-6736(19)30195-3. Epub 2019 Feb 7. Erratum In: Lancet. 2019 Apr 20;393(10181):1596. doi: 10.1016/S0140-6736(19)30859-1. PubMed 30739747 ↗

Study documents

  • Statistical analysis plan · Jul 25, 2018
  • Study protocol · Apr 14, 2015

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Sep 27, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01827046
Lead sponsor
Johns Hopkins University
Collaborators
National Institute of Neurological Disorders and Stroke (NINDS), Genentech, Inc., Emissary International LLC
Responsible party
Sponsor
First posted
Apr 9, 2013
Start date
Dec 30, 2013
Primary completion
Sep 2018
Completion
Sep 2018
Results posted
Sep 27, 2019
Last update
Sep 27, 2019

Study contacts

Daniel F. Hanley, MD
study chair · Johns Hopkins University
Mario Zuccarello, MD
principal investigator · University of Cincinnati
Issam Awad, MD
principal investigator · University of Chicago

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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