Intracerebral Hemorrhage
Conditions
Brief summary
The purpose of this trial is to determine the safety of using a combination of minimally invasive surgery and clot lysis with rt-PA to remove intracerebral hemorrhage (ICH). The ICES arm of the trial will determine the safety of endoscopic surgery to remove ICH. All MISTIE intention to treat subjects represent the hypothesized test group. The ICES cohort is to be analyzed separately.
Detailed description
The purpose of this trial is to determine the safety of using a combination of minimally invasive surgery and clot lysis with rt-PA to remove intracerebral hemorrhage (ICH). The procedure is to use image-based surgery (MRI or CT) to provide catheter access to ICH for the intervention, which is a one-time clot aspiration followed by instillation of rt-PA over 72 hours. The Intraoperative stereotactic CT-guided Endoscopic Surgery (ICES) arm of the trial will determine the safety, feasibility and effectiveness of endoscopic surgery to remove ICH. This tests the first step of the MISTIE surgical procedure with an endoscope, not a rigid cannula. We propose to test if these interventions facilitate more rapid and complete recovery of function and decreased mortality from this condition compared to conventional medical management without subjecting the patient to craniotomy. The specific objective of this trial is to test the safety of these interventions and assess their ability to remove blood clot from brain tissue.
Interventions
DRUGMIS+Cathflo Activase (drug)
MIS+Cathflo Activase (drug): The intervention is a comparison of the safety and preliminary effectiveness of investigational minimally invasive surgery to place a catheter into an intracerebral hemorrhage blood clot and subsequent administration in sequential tiers of 0.3 or 1.0mg of rt-PA, CathFlo® through the catheter once every eight hours for up to 72 hours, in addition to best medical care.
PROCEDUREIntraoperative stereotactic CT-Guided Endoscopic Surgery
Mechanical intracerebral hemorrhage removal via an endoscope utilizing the same operative targeting arm as MISTIE arm. No rt-PA administered, and in addition to best medical care.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Genentech, Inc.
Emissary International LLC
Daniel Hanley
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-80 * GCS \< 14 or a NIHSS \> or equal to 6 * Spontaneous supratentorial ICH \> or equal to 20cc * Symptoms less than 12 hours prior to diagnostic CT scan (an unknown time of symptom onset is exclusionary) * Intention to initiate surgery within 48 hours after diagnostic CT * First dose can be given within 54 hours after diagnostic CT (delays for post surgical stabilization of catheter bleeding or because of unanticipated surgical delay are acceptable with approved waiver from the coordinating center) (Does not apply to ICES Tier) * Six-hour clot size equal to the most previous clot size + 5 cc (as determined by an additional CT scan at least 6 hours after the initial stability scan (A\*B\*C)/2 method) * SBP \< 200 mmHg sustained for 6 hours recorded closest to time of randomization * Historical Rankin score of 0 or 1 * Negative pregnancy test
Exclusion criteria
* Infratentorial hemorrhage (any involvement of the midbrain or lower brainstem as demonstrated by radiograph or complete third nerve palsy) * Patients with platelet count \< 100,000, INR \> 1.4, or an elevated PT or APTT (reversal of coumadin is permitted but the patient must not require coumadin during the acute hospitalization). Irreversible coagulopathy either due to medical condition or prior to randomization * Clotting disorders * Any concurrent serious illness that would interfere with the safety assessments including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, and hematologic disease * Patients with a mechanical valve * Patients with unstable mass or evolving intracranial compartment syndrome * Ruptured aneurysm, AVM, vascular anomaly * Greater than 80 years (higher incidence of amyloid) * Under 18 years of ag e (high incidence of occult vascular malformation) * Pregnant (positive pregnancy test) or lactating females (likelihood of altered coagulation function associated with the high estrogen/progesterone state) * Irreversibly impaired brainstem function (bilateral fixed, dilated pupils and extensor motor posturing), GCS less than or equal to 4 * Historical Rankin score greater than or equal to 2 * Intraventricular hemorrhage requiring external ventricular drainage * Internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts (Does not apply to ICES Tier) * Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or site of recent surgical intervention (Does not apply to ICES Tier) * Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, and subacute bacterial endocarditis (Does not apply to ICES Tier) * In the investigator's opinion, the patient is unstable and would benefit from a specific intervention rather than supportive care plus or minus MIS+rtPA * Prior enrollment in the study * Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated * Participation in another simultaneous trial of ICH treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy Outcome Number 1: Dichotomized Modified Rankin Scale (mRS) at Day 180 | 180 days from randomization | Percentage of participants with dichotomized mRS score in 0-3 range. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead |
| Safety Outcome Number 1: Rate of Mortality | 30 days from randomization | Percentage of participants who died during the first 30 days after randomization. |
| Safety Outcome Number 2: Rate of Procedure-related Mortality | 7 days from randomization | Percentage of participants who died during the first 7 days after randomization. |
| Safety Outcome Number 3: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis | 30 days from randomization | Percentage of participants who had a bacterial brain infection (cerebritis, meningitis, ventriculitis) within 30 days of randomization. |
| Safety Outcome Number 4: Rate of Symptomatic Rebleeding | 72 hours post last dose | The difference in the rate of symptomatic rebleeding 72 hours post last dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ordinal Modified Rankin Scale (mRS) at Day 365 | 365 days from randomization | Ordinal distribution of the Modified Rankin Scale score at 365 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead. |
| Clot Size Reduction by End of Treatment | Time from randomization until end of treatment, up to 10 days | The percentage of blood clot resolved by the end of treatment CT scan compared to the stability CT scan. |
| Post-operative Clot Size Reduction | Time from post-operation until end of treatment, up to 10 days | The percentage of blood clot resolved by the end of treatment CT scan compared to the post-operative CT scan for surgical patients. |
| Ordinal Modified Rankin Scale (mRS) at Day 180 | 180 days from randomization | Ordinal distribution of the Modified Rankin Scale score at 180 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead. |
Countries
Canada, Germany, United Kingdom, United States
Participant flow
Recruitment details
110 patients were randomized to the trial, and 31 were recruited as pilot patients.
Pre-assignment details
Each study center was required to demonstrate proficiency in the technical aspects of enrollment, stabilization, surgery, and drug administration. This proficiency was demonstrated on at least one pilot patient prior to randomization of the first patient in the investigational cohort of 110 randomized patients.
Participants by arm
| Arm | Count |
|---|---|
| Medical Management Standard of care medical management as per American Heart Association (AHA) guidelines. | 42 |
| MISTIE Surgical Management Minimally invasive surgery (MIS) with clot lysis with recombinant tissue plasminogen activator (rt-PA).
MIS+Cathflo Activase (drug): The intervention is a comparison of the safety and preliminary effectiveness of investigational minimally invasive surgery to place a catheter into an intracerebral hemorrhage blood clot and subsequent administration in sequential tiers of 0.3 or 1.0mg of rt-PA, CathFlo®) through the catheter once every eight hours for up to 72 hours, in addition to best medical care.
This includes 54 intent-to-treat patients, and excludes 27 pilots. | 54 |
| ICES Surgical Management Intraoperative stereotactic CT-Guided Endoscopic Surgery
Mechanical intracerebral hemorrhage removal via an endoscope utilizing the same operative-targeting arm as MISTIE arm. Best medical care was provided, but no rt-PA was administered.
This includes 14 intent-to-treat patients, and excludes 4 pilots. | 14 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 4 | 2 | 0 |
Baseline characteristics
| Characteristic | Medical Management | MISTIE Surgical Management | ICES Surgical Management | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 29 Participants | 5 Participants | 58 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 25 Participants | 9 Participants | 52 Participants |
| Age, Continuous | 62 years | 60 years | 59 years | 61 years |
| Region of Enrollment United Kingdom | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 41 participants | 53 participants | 14 participants | 108 participants |
| Sex: Female, Male Female | 14 Participants | 19 Participants | 5 Participants | 38 Participants |
| Sex: Female, Male Male | 28 Participants | 35 Participants | 9 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 42 | 41 / 54 | 8 / 14 |
| serious Total, serious adverse events | 23 / 42 | 28 / 54 | 6 / 14 |
Outcome results
Primary
Efficacy Outcome Number 1: Dichotomized Modified Rankin Scale (mRS) at Day 180
Percentage of participants with dichotomized mRS score in 0-3 range. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead
Time frame: 180 days from randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medical Management | Efficacy Outcome Number 1: Dichotomized Modified Rankin Scale (mRS) at Day 180 | 23.7 percentage of participants |
| MISTIE Surgical Management | Efficacy Outcome Number 1: Dichotomized Modified Rankin Scale (mRS) at Day 180 | 34.6 percentage of participants |
| ICES Surgical Management | Efficacy Outcome Number 1: Dichotomized Modified Rankin Scale (mRS) at Day 180 | 42.9 percentage of participants |
Comparison: Null hypothesis is that the proportion with mRS score of 0-3 at 180 days is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher proportion than the medical arm.p-value: 0.189Fisher Exact
Comparison: Null hypothesis is that the proportion with mRS score of 0-3 at 180 days is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher proportion than the medical arm.p-value: 0.156Fisher Exact
Primary
Safety Outcome Number 1: Rate of Mortality
Percentage of participants who died during the first 30 days after randomization.
Time frame: 30 days from randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medical Management | Safety Outcome Number 1: Rate of Mortality | 9.5 percentage of participants |
| MISTIE Surgical Management | Safety Outcome Number 1: Rate of Mortality | 14.8 percentage of participants |
| ICES Surgical Management | Safety Outcome Number 1: Rate of Mortality | 7.1 percentage of participants |
Comparison: Null hypothesis is that rate of mortality within 30 days is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher rate of mortality than the medical arm.p-value: 0.324Fisher Exact
Comparison: Null hypothesis is that rate of mortality within 30 days is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher rate of mortality than the medical arm.p-value: 0.633Fisher Exact
Primary
Safety Outcome Number 2: Rate of Procedure-related Mortality
Percentage of participants who died during the first 7 days after randomization.
Time frame: 7 days from randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medical Management | Safety Outcome Number 2: Rate of Procedure-related Mortality | 0 percentage of participants |
| MISTIE Surgical Management | Safety Outcome Number 2: Rate of Procedure-related Mortality | 5.6 percentage of participants |
| ICES Surgical Management | Safety Outcome Number 2: Rate of Procedure-related Mortality | 0 percentage of participants |
Comparison: Null hypothesis is that rate of procedure-related mortality within 7 days is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher rate of procedure-related mortality than the medical arm.p-value: 0.174Fisher Exact
Primary
Safety Outcome Number 3: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis
Percentage of participants who had a bacterial brain infection (cerebritis, meningitis, ventriculitis) within 30 days of randomization.
Time frame: 30 days from randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medical Management | Safety Outcome Number 3: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis | 2.4 percentage of participants |
| MISTIE Surgical Management | Safety Outcome Number 3: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis | 0 percentage of participants |
| ICES Surgical Management | Safety Outcome Number 3: Rate of Cerebritis, Meningitis, Bacterial Ventriculitis | 0 percentage of participants |
Comparison: Null hypothesis is that rate of cerebritis, meningitis and ventriculitis within 30 days is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher rate of these infections than medical.p-value: 0.437Fisher Exact
Comparison: Null hypothesis is that rate of cerebritis, meningitis and ventriculitis within 30 days is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher rate of these infections than medical.p-value: 0.75Fisher Exact
Primary
Safety Outcome Number 4: Rate of Symptomatic Rebleeding
The difference in the rate of symptomatic rebleeding 72 hours post last dose.
Time frame: 72 hours post last dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Medical Management | Safety Outcome Number 4: Rate of Symptomatic Rebleeding | 2.4 percentage of participants |
| MISTIE Surgical Management | Safety Outcome Number 4: Rate of Symptomatic Rebleeding | 5.6 percentage of participants |
| ICES Surgical Management | Safety Outcome Number 4: Rate of Symptomatic Rebleeding | 0 percentage of participants |
Comparison: Null hypothesis is that rate of symptomatic rebleeding 72 hours post last dose is the same between the two groups. The alternative hypothesis tests whether MISTIE surgical management has a higher rate of symptomatic rebleeding than the medical arm.p-value: 0.409Fisher Exact
Comparison: Null hypothesis is that rate of symptomatic rebleeding 72 hours post last dose is the same between the two groups. The alternative hypothesis tests whether ICES surgical management has a higher rate of symptomatic rebleeding than the medical arm.p-value: 0.75Fisher Exact
Secondary
Clot Size Reduction by End of Treatment
The percentage of blood clot resolved by the end of treatment CT scan compared to the stability CT scan.
Time frame: Time from randomization until end of treatment, up to 10 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Management | Clot Size Reduction by End of Treatment | 3.9 percentage of blood clot resolved |
| MISTIE Surgical Management | Clot Size Reduction by End of Treatment | 64.3 percentage of blood clot resolved |
| ICES Surgical Management | Clot Size Reduction by End of Treatment | 69.5 percentage of blood clot resolved |
Comparison: Null hypothesis is that the distributions of percentage of blood clot resolved are the same between the two groups. The alternative hypothesis is that the distributions are not the same.p-value: <0.0001Wilcoxon (Mann-Whitney)
Comparison: Null hypothesis is that the distributions of percentage of blood clot resolved are the same between the two groups. The alternative hypothesis is that the distributions are not the same.p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Ordinal Modified Rankin Scale (mRS) at Day 180
Ordinal distribution of the Modified Rankin Scale score at 180 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead.
Time frame: 180 days from randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Management | Ordinal Modified Rankin Scale (mRS) at Day 180 | 4 units on a scale |
| MISTIE Surgical Management | Ordinal Modified Rankin Scale (mRS) at Day 180 | 4 units on a scale |
| ICES Surgical Management | Ordinal Modified Rankin Scale (mRS) at Day 180 | 4 units on a scale |
Comparison: Null hypothesis is that the distributions of the mRS values for both groups are the same. The alternative hypothesis is that the distributions are not the same.p-value: 0.468Wilcoxon (Mann-Whitney)
Comparison: Null hypothesis is that the distributions of the mRS values for both groups are the same. The alternative hypothesis is that the distributions are not the same.p-value: 0.294Wilcoxon (Mann-Whitney)
Secondary
Ordinal Modified Rankin Scale (mRS) at Day 365
Ordinal distribution of the Modified Rankin Scale score at 365 days. The mRS measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale ranges from 0-6: (0) no symptoms at all, (1) no significant disability despite symptoms; able to carry out all usual duties and activities, (2) slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, (3) moderate disability; requiring some help, but able to walk without assistance, (4) moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, (5) severe disability; bedridden, incontinent and requiring constant nursing care and attention, (6) dead.
Time frame: 365 days from randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Medical Management | Ordinal Modified Rankin Scale (mRS) at Day 365 | 4.5 units on a scale |
| MISTIE Surgical Management | Ordinal Modified Rankin Scale (mRS) at Day 365 | 4 units on a scale |
| ICES Surgical Management | Ordinal Modified Rankin Scale (mRS) at Day 365 | 3.5 units on a scale |
Comparison: Null hypothesis is that the distributions of the mRS values for both groups are the same. The alternative hypothesis is that the distributions are not the same.p-value: 0.395Wilcoxon (Mann-Whitney)
Comparison: Null hypothesis is that the distributions of the mRS values for both groups are the same. The alternative hypothesis is that the distributions are not the same.p-value: 0.175Wilcoxon (Mann-Whitney)
Secondary
Post-operative Clot Size Reduction
The percentage of blood clot resolved by the end of treatment CT scan compared to the post-operative CT scan for surgical patients.
Time frame: Time from post-operation until end of treatment, up to 10 days
Population: Analysis population only includes surgical patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MISTIE Surgical Management | Post-operative Clot Size Reduction | 56.7 percentage of blood clot resolved |
| ICES Surgical Management | Post-operative Clot Size Reduction | -6.4 percentage of blood clot resolved |
Comparison: Null hypothesis is that the median percent resolved is 0. The alternative hypothesis is that the median percent resolved is not equal to 0.p-value: <0.0001Sign test
Comparison: Null hypothesis is that the median percent resolved is 0. The alternative hypothesis is that the median percent resolved is not equal to 0.p-value: 0.791Sign test