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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01827046




Registration number
NCT01827046
Ethics application status
Date submitted
1/04/2013
Date registered
9/04/2013
Date last updated
11/12/2018

Titles & IDs
Public title
Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III
Scientific title
Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III
Secondary ID [1] 0 0
U01NS080824
Secondary ID [2] 0 0
NA_00080619
Universal Trial Number (UTN)
Trial acronym
MISTIE-III
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intracerebral Hemorrhage 0 0
Condition category
Condition code
Stroke 0 0 0 0
Haemorrhagic
Neurological 0 0 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - rt-PA

Experimental: 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.

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.


Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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). 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 (perfect health without symptoms) to 6 (death).
Timepoint [1] 0 0
Day 365
Secondary outcome [1] 0 0
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 from UGR (perfect health without symptoms) to death.
Timepoint [1] 0 0
Day 365
Secondary outcome [2] 0 0
All cause mortality longitudinally from ictus to 365 days (adjusted) - By group comparison of mortality from ictus to 365 days adjusted for baseline severity.
Timepoint [2] 0 0
Day 365
Secondary outcome [3] 0 0
Clot removal (amount of residual blood) - Relationship between clot removal as an AUC clot-assessment that estimates the time-averaged clot volume and percent clot removed 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)).
Timepoint [3] 0 0
Day 365
Secondary outcome [4] 0 0
Patient disposition: Home days over 365 days time from ictus. - By group comparison of total days at home during the 365 days post ictus.
Timepoint [4] 0 0
Day 365
Secondary outcome [5] 0 0
Patient disposition: Patient location at 365 days post ictus (i.e., good vs. bad location) (adjusted) - By group comparison of residential location at day 365 post ictus adjusted for baseline severity.
Timepoint [5] 0 0
Day 365
Secondary outcome [6] 0 0
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 (perfect health without symptoms) to 6 (death).
Timepoint [6] 0 0
Day 180
Secondary outcome [7] 0 0
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 from UGR (perfect health without symptoms) to death.
Timepoint [7] 0 0
Day 180
Secondary outcome [8] 0 0
Type and intensity of ICU management: ICU days - By group comparison of total number of days in the intensive care unit (ICU) during the acute hospitalization.
Timepoint [8] 0 0
Day 365
Secondary outcome [9] 0 0
Type and intensity of ICU management: Hospital days - By group comparison of total number of days in the hospital during the acute hospitalization.
Timepoint [9] 0 0
Day 365
Secondary outcome [10] 0 0
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).
Timepoint [10] 0 0
Day 365
Secondary outcome [11] 0 0
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.
Timepoint [11] 0 0
Day 365

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 0 0
Royal Adelaide Hospital - North Adelaide
Recruitment hospital [3] 0 0
Royal Melbourne Hospital - Parkville
Recruitment postcode(s) [1] 0 0
2015 - Camperdown
Recruitment postcode(s) [2] 0 0
5006 - North Adelaide
Recruitment postcode(s) [3] 0 0
3050 - Parkville
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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United States of America
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Arizona
Country [3] 0 0
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California
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Connecticut
Country [5] 0 0
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Florida
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Georgia
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Illinois
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Kansas
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Kentucky
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Maine
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Maryland
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Michigan
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Minnesota
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Missouri
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New Jersey
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New Mexico
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New York
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North Carolina
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Ohio
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Oregon
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Pennsylvania
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South Carolina
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Tennessee
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Texas
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Utah
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Virginia
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Wisconsin
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Canada
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Alberta
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Canada
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Ontario
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Canada
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Quebec
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China
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Guangdong
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China
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Beijing
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China
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Chongqing
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Germany
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Bonn
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Germany
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Heidelberg
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Germany
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Mainz
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Germany
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Munich
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Hungary
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Baranya County
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Hungary
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Debrecen
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Hungary
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Szeged
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Israel
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Ramat-Gan
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Israel
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Petach Tikva
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Spain
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Biscay
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Spain
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Barcelona
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Spain
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Valladolid
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United Kingdom
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Manchester
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United Kingdom
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Glasgow
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United Kingdom
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Newcastle upon Tyne
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United Kingdom
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Southampton

Funding & Sponsors
Primary sponsor type
Other
Name
Johns Hopkins University
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Institute of Neurological Disorders and Stroke (NINDS)
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Commercial sector/Industry
Name [2] 0 0
Genentech, Inc.
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Commercial sector/Industry
Name [3] 0 0
Emissary International LLC
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT01827046
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Daniel F. Hanley, MD
Address 0 0
Johns Hopkins University
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications