Clinical trial NCT01827046
Conditions: Intracerebral Hemorrhage
Keywords: intracerebral hemorrhage ICH brain hemorrhage minimally invasive surgery rt-PA
Sponsor: Johns Hopkins University
Start date: 2013-12-30; Completion date: 2018-09-01
Enrollment: 499 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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. arm 2: 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: intervention 1: rt-PA
Intervention descriptions: intervention 1: 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.

Protocol documents:
SAP_002.pdf: 
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Johns Hopkins University  
 
PI: Daniel F. Hanley, MD 
 
 
 
MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-1 
 
STATISTICAL ANALYSIS PLAN 
Protocol: ICH02 
NCT01827046 
 
Minimally Invasive Surgery plus rt-PA for Intracerebral Hemorrhage Evacuation Phase III 
(MISTIE III) 
 
 
July 25, 2018 
 
Prepared for: 
 
BIOS Coordinating Center 
Johns Hopkins University 
 
Prepared by: 
 
MISTIE III Data Coordinating Center 
Johns Hopkins University 
Bloomberg School of Public Health 
Department of Biostatistics 
615 N. Wolfe Street 
Baltimore, MD 21205 
 
 
 
Approved by: 
Signature 
Date 
 
 
Daniel F. Hanley, MD 
Trial PI 
Daniel Hanley 
7/25/18 
 
 
Richard Thompson, PhD 
Statistical PI 
Richard Thompson 
7/25/18 
 
 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-2 
Chapter 22.0:  STATISTICAL ANALYSIS PLAN 
Table of Contents 
1.0. Statistical Analysis Plan and Statistical Reports ......................................................................................... 5 
2.0. Objectives of the Study ............................................................................................................................... 5 
2.1. Efficacy 
2.2. Efficacy Measures Summary 
2.3. Safety 
2.3.1. Safety Measures Summary 
2.3.2. Safety Monitoring and Recruitment Suspension Rules 
3.0. Study Design ............................................................................................................................................... 8 
4.0. Sample Size Determination for the Primary Efficacy Analysis.................................................................... 8 
5.0. Definition of Study Samples ........................................................................................................................ 9 
5.1. Target Population 
5.2. Intent-to-Treat (ITT) Sample 
5.3. Safety Analysis Sample 
5.4. As-Treated Sample for MIS+rt-PA 
5.4.1. As-Treated Sample for Any Form of Surgery 
5.5. Demographic and Clinically Specific Subgroups 
5.6. Definition of Treatment Failures 
6.0. Randomization .......................................................................................................................................... 10 
7.0. Blinding ..................................................................................................................................................... 10 
8.0. Multiplicity .................................................................................................................................................. 11 
9.0. Missing Data ............................................................................................................................................. 11 
10.0. Baseline Characteristics.......................................................................................................................... 11 
10.1. Demographics11 
10.2. Medical History 
11.0. Efficacy Analyses .................................................................................................................................... 11 
11.1. Primary Efficacy Analysis: Dichotomized, adjudicated mRS 0-3 vs. 4-6 at 365 days 
11.1.1. Models 
11.1.2. Additional Efficacy Analysis: Ordinal, adjudicated mRS (0-6) at 365 days 
11.1.3. Additional Efficacy Analysis: Longitudinal Analysis 
11.1.4. Additional Efficacy Analysis: Severity Subgroup Analysis 
11.1.5. Additional Efficacy Analysis: Subgroup Analysis 
11.1.6. Additional Efficacy Analysis: Random Effects (Site Differences) Analyses 
12.0. Interim Efficacy Analyses ........................................................................................................................ 16 
13.0. Secondary Efficacy Outcomes Analyses ................................................................................................ 16 
13.1. Secondary Efficacy Analysis 1: Dichotomized eGOS UGR-US vs. LS-Death at 365 days 
13.2. Secondary Efficacy Analysis 2: All Cause Mortality Longitudinally from Ictus to 365 Days 
13.2.1. Subordinate, Secondary Efficacy Analysis 2: Predictors of Mortality Analysis 
13.3. Secondary Efficacy Analysis 3: Relation Between Clot Removal as an AUC Estimating Time-Weighted 
Clot Volume from Ictus to EOT as AUC Clot Exposure and Functional Outcome (Proportion 0-3 mRS)  
13.4. Secondary Analysis 4: Patient Disposition 
13.4.a. Secondary Efficacy Analysis 4a: Home Days Over 365 Days’ Time From Ictus 
13.4.b. Secondary Efficacy Analysis 4b: Patient Location at 365 Days Post Ictus 
13.5. Secondary Analysis 5: 180-Day Efficacy 
13.5.a. Secondary Analysis 5a: Dichotomized, adjudicated, cross-sectional mRS 0-3 vs. 4-6 
 
13.5.b. Dichotomized, adjudicated eGOS UGR-US vs. LS-Death 


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Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
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13.5.1. Additional, Secondary Efficacy Analysis 5: Ordinal, Adjudicated mRS (0-6)  
13.5.2. Additional, Secondary Efficacy Analysis 5: Ordinal, eGOS UGR-US vs. LS-Death 
13.5.3. Additional, Secondary Efficacy Analysis 5: Subordinate Analyses 2-5 
13.6. Secondary Efficacy Analysis 6: Type and Intensity of ICU Management 
13.7. Secondary Efficacy Analysis 7: EQ-VAS and EQ-5D 
14.0. Safety Analyses ...................................................................................................................................... 19 
14.1. Mortality and Safety Events at 30 Days Post Randomization 
14.2. Total SAEs at 30 Days 
14.3. Summary of Adverse Events and Serious Adverse Events 
14.4. Proposed Interval Safety Monitoring 
15.0. Tertiary (Exploratory/Sensitivity) Analyses ............................................................................................. 21 
15.1. Functional Status at 180 and 365 days post ictus 
15.2. Quality of Life at 180 and 365 days post ictus 
15.3. Cost-Benefit Model 
16.0. References .............................................................................................................................................. 22 
 
 
 
 


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Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
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List of Abbreviations: 
AE 
Adverse event 
AIC 
Akaike Information Criterion 
AUC 
Area under the curve 
BCa 
Accelerated bootstrap 
BP 
Blood pressure 
CCC 
Clinical Coordinating Center 
CES-D 
Center for Epidemiological Studies - Depression 
CI 
Confidence interval 
CLEAR III 
Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase 3 
CT 
Computed tomography 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
EDA 
Exploratory data analyses 
EDC 
Electronic data capture  
eGOS 
Extended Glasgow Outcome Scale 
EOT 
End of treatment 
EQ-5D 
EuroQol five dimension 
EQ-VAS 
EuroQol Visual Analogue Scale 
EVD 
Extraventricular drainage 
GCS 
Glasgow Coma Scale 
GEE 
Generalized estimating equations 
GOS 
Glasgow Outcome Scale 
ICH 
Intracerebral hemorrhage 
ICP 
Intracranial pressure 
ICU 
Intensive care unit 
ITT 
Intent-to-treat 
IVH 
Intraventricular hemorrhage 
LGR 
Lower good recovery (eGOS) 
LM 
Lower moderate disability (eGOS) 
LS 
Lower severe disability (eGOS) 
LTF 
Loss to follow-up 
MD 
Moderate disability (eGOS) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIS 
Minimally invasive surgery 
MISTIE III 
Minimally Invasive Surgery plus rt-PA for Intracerebral Hemorrhage Evacuation Phase 3 
MMSE 
Mini-Mental State Examination 
mRS 
Modified Rankin Scale 
NIH 
National Institutes of Health 
NIHSS 
National Institutes of Health Scale 
PBSI 
Preference Based Stroke Index 
QIC 
Independence model criterion 
QOL 
Quality of life 
ROC 
Receiver Operating Characteristic 
rt-PA 
Recombinant tissue plasminogen activator 
SAE 
Serious adverse event 
SIS 
Stroke Impact Scale 
UGR 
Upper good recovery (eGOS) 
UK 
United Kingdom 
US 
Upper severe disability (eGOS) 
VS 
Vegetative state (eGOS) 
 
 


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1.0. Statistical Analysis Plan and Statistical Reports 
 
This chapter provides the details of statistical considerations, analyses, and reports planned for the 
MISTIE III Trial, including proposed regression models, sample size estimates, power considerations, 
interim analyses, and analysis of adverse events. The proposed analyses will be conducted on the whole 
patient sample and on subsets of patients defined by gender, race, and ethnicity as well as patient-
specific clinical factors/categories and treatment categories. In addition, this chapter discusses statistical 
issues relevant to these analyses (e.g., sample data to be used, missing data, adjustments for multiplicity, 
etc.). 
 
Initially, the Data Coordinating Center (DCC) will examine data quality, create secondary variables, and 
perform exploratory data analyses (EDA). All variables will be evaluated to detect gaps, patterns, and 
inconsistencies in the data. These analyses will emphasize examination of the nature and extent of 
variability for all variables. Visual techniques to explore continuous variables will include stem-and-leaf 
plots, box plots, and quantile-quantile plots. Outliers will additionally be examined for data entry errors. 
Summary statistics for continuous variables will include the number of patients, median, mean, standard 
deviation, and range, while statistics for categorical variables will include the frequency and percentage 
of patients in each category. 
 
Statistical analyses will be performed on data that have been quality-assured through DCC protocols and 
monitoring reviews, and that have been exported by the DCC directly from the MISTIE III database. The 
following analysis procedures may be applied to blinded (no treatment arm designation, for study 
investigators and staff), partially unblinded (treatment designation only as “A” and “B,” for DSMB and at 
interim analyses), and unblinded (full treatment designation, for final analyses) data, by DCC staff having 
the appropriate role permissions. 
 
The MISTIE III Executive Committee receives the open DSMB reports. 
 
2.0. Objectives of the Study 
 
2.1. Efficacy 
 
The primary aim of this multicenter, international, randomized, open-label, phase 3 trial is to determine 
the efficacy of intra-clot catheter placement and aspiration of hematoma contents, followed by gentle clot 
irrigation with low dose recombinant tissue plasminogen activator (rt-PA), referred to as Minimally 
Invasive Surgery plus rt-PA (MIS+rt-PA). The primary hypothesis of this trial is that the MIS+rt-PA 
approach to intracerebral hemorrhage (ICH) management will result in more patients having overall better 
functional outcome at 365 days, as defined by the proportion of subjects with dichotomized, adjudicated 
modified Rankin Scale (mRS) score 0-3 vs. 4-6, when compared to the mRS scores for patients managed 
with standard aggressive medical treatment. Although the mRS includes a category for death, and hence 
the primary analysis incorporates mortality outcomes, in-hospital and 30-day mortality will also be 
examined as safety outcomes for the trial. Furthermore, 365-day mortality will be evaluated separately 
as a secondary efficacy outcome. An intent-to-treat (ITT) paradigm for the analyses will be incorporated. 
The MISTIE III trial will enroll a total of 500 eligible patients, 250 randomized each treatment arm (MIS+rt-
PA or medical management). The power to detect (88%) is for an estimated effect size of 13% across all 
clot locations with this sample size (500). 
 
Additional analyses of efficacy outcomes will evaluate the therapeutic benefit of MIS+rt-PA relevant to 
medical management in improving subjects’ function and quality of life at 365 days post symptom onset 
as measured by extended Glasgow Outcome Scale (eGOS), days in various locations such as home 


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Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
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during the 365-day period, patient disposition at 180 and 365 days including proportion of days in long-
term care facilities, National Institutes of Health Stroke Scale (NIHSS), Barthel score, days in hospital, 
days in intensive care unit (ICU), Stroke Impact Scale (SIS), Preference-Based Stroke Index (PBSI), 
EuroQol-5 Dimension (EQ-5D), Mini-Mental State Examination (MMSE), Personal Health Utility 
Interview, and Center for Epidemiological Studies – Depression (CES-D). 
 
2.2. Efficacy Measures Summary: All Analyses Adjusted Similarly to the Primary Analysis 
 
• 
Primary Efficacy Analysis: Dichotomized, adjudicated, cross-sectional mRS 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).  
 
• 
Additional, Exploratory Analyses of mRS at 365 days: 
a. Dichotomized, adjudicated, cross-sectional mRS 0-3 vs. 4-6 at 365 days post ictus, 
adjusting for baseline (pre-randomization) variables used in covariate adaptive 
randomization as well as additional baseline variables determined to be associated with 
the outcome. 
b. Ordinal, adjudicated mRS (0-6) at 365 days. 
c. mRS 0-3 vs. 4-6 at 365 days based on a full longitudinal analysis of the mRS data at 90, 
180, and 270 days.  
d. Severity subgroup analyses (including, but not limited to, IVH size, location of ICH, 
presentation co-morbidities such as diabetes, CVD, and white matter disease, etc.) 
e. Cross-sectional of mRS 0-3 vs. 4-6 for demographic subgroups of patients, including for 
race and gender. (For d and e, see section 5.5.) 
f. Analysis of cross-sectional mRS 0-3 vs. 4-6 at 365 days that models random effects for 
hospital sites.  
 
• 
Secondary Analyses of other outcomes    
 
1. Dichotomized eGOS UGR-US vs. LS-Death at 365 days. 
• 
Subordinate: Ordinal eGOS UGR, LGR, MD, LM, US vs. LS, VS, Death at 365 
days.  
2. All-cause mortality longitudinally from ictus to 365 days. 
• 
Subordinate: Predictors of mortality. 
3. Relationship between clot removal as an AUC clot-assessment that estimates the time-
weighted 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 mRS). 
4. Patient disposition:  
a. Home days over 365 days’ time from ictus. 
b. Patient location at 365 days post ictus (i.e., good vs. bad location. See Tertiary 2g for 
definition.) 
5. 180-day efficacy: 
a. Dichotomized, adjudicated, cross-sectional mRS 0-3 vs. 4-6.  
• 
Subordinate (1): Ordinal, adjudicated mRS (0-6). 
b. Dichotomized, adjudicated eGOS UGR, LGR, MD, LM, US vs. LS, VS, Death. 
• 
Subordinate (2): Ordinal, eGOS UGR, LGR, MD, LM, US vs. LS, VS, Death. 
• 
Subordinate analyses 2-5 as defined under the Primary but for eGOS. 
6. Type and intensity of ICU management:  
a. ICU days 


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Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
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b. ICU management (ICP, Ventilation, BP support, osmotherapies) 
c. Hospital days  
7.  EQ-VAS and EQ-5D 
 
• 
Tertiary (exploratory/sensitivity): 
 
1. Functional status at 180 and 365 days post-stroke:  
a. GOS 
b. Barthel Index 
c. NIHSS 
d. MMSE  
2. Quality of life at 180 and 365 days post-stroke:  
a. SIS 
b. PBSI 
c. Personal Health Utility Assessment Interview 
d. CES-D 
e. EQ dimensions individually assessed 
f. Home days (180 only) 
g. Patient location including proportion of days in home, rehabilitation, acute care, long-
term care facilities. These will be evaluated by individual location type and 
dichotomized as good vs bad outcome defined as home and rehabilitation vs acute 
care, long-term care and death.  
h. Proportion of subjects in vegetative condition 
3. Cost-benefit model 
 
In addition to the primary, secondary, and tertiary (exploratory) measures, there are a number of related 
and intermediate surrogate outcomes of interest, including time to treatment, surgical task descriptors, 
clot locations, Glasgow Coma Scale (GCS), Graeb Scale, clot lysis rate and final clot size reduction. 
 
2.3. Safety 
 
The safety of MIS+rt-PA relative to medical management is assessed by comparing the proportion of 
subjects between the two groups with treatment-related SAEs within the 30-day time frame: mortality, 
rebleeding, infection, and first-week (designated as operative mortality for the surgical group) mortality. 
Additionally, the number and proportion of all SAEs across the entire time frame in the respective 
randomized groups will be evaluated starting with the follow-up time frames of 180 and 365.   
 
Interim safety analyses will be prepared for the external Data Safety and Monitoring Board (DSMB) on a 
pre-arranged schedule (such as semi-annual or after enrollment of a fixed number of subjects) to evaluate 
efficacy and safety. Safety measures include: monitoring the incidence of symptomatic and asymptomatic 
intracranial bleeding events (i.e., hemorrhage extension, new hemorrhage, catheter-tract hemorrhage) 
through daily computed tomography (CT) scans for the first four days after randomization and then 
repeated one day (approximately 24 hours) after ICH catheter removal, and monitoring the incidence of 
confirmed and suspected infection and in-hospital mortality. 
 
2.3.1. Safety Measures Summary 
 
• 
Mortality and safety events at 30 days post-randomization: 
a. First-week (operative) mortality 
b. All-cause mortality 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-8 
c. Symptomatic bleeding rate 
d. Infection rate  
e. Total SAEs at 30 days 
f. Summary of AEs and SAEs by MedDRA code and grouped by organ system 
 
2.3.2. Safety Monitoring and Recruitment Suspension Rules  
 
Safety events above pre-specified thresholds will trigger a “suspend recruitment and review” by the 
DSMB to investigate the presumed cause and impact of these events. Such events are initially reviewed 
by DCC staff to determine if an event threshold has been reached at which time the study investigators 
and the DSMB will be notified. The thresholds triggering such a review are: 30-day mortality >60%, a 
MIS+rt-PA–related symptomatic bleeding rate >25% (during active treatment or during the 72 hours after 
treatment will be monitored), first-week operative death rate >10%, and a procedure-related infection rate 
>15% (over the initial 30 days). If any of these SAEs are attributable to the intervention (catheter insertion 
or manipulation, or rt-PA injection), the study will be suspended for a complete safety review. 
 
Interim analyses for efficacy will occur after 375 subjects are enrolled and 180 days outcomes are 
available. These analyses will be based on O'Brien-Fleming stopping boundaries for efficacy and more 
aggressive (i.e., more likely to stop if there is no early signal of benefit) stopping boundaries for efficacy 
and safety analyses will be every six months or at other intervals as determined by the external DSMB. 
 
3.0. Study Design 
 
This study is a phase 3, 1:1 randomized, open-label, multicenter evaluation of MIS and ICH lysis with rt-
PA versus medical care. The study (n=500) will evaluate the efficacy and safety of MIS plus 1 mg of rt-
PA administered every eight hours for up to nine doses as compared to subjects treated with conventional 
medical management. 
 
4.0. Sample Size Determination for the Primary Efficacy Analysis 
 
The MISTIE phase 2 results, for all available data (non-randomized trial-standardized “pilot” and 
randomized participants), demonstrated an estimated absolute increase in the probability of achieving an 
mRS 0-3 of 13.0% [95% CI: (0.4% to 26.4%)] comparing MIS+rt-PA treatment versus medical 
management 180 days post-stroke.1 For the intention-to-treat (ITT) analysis, when only randomized 
patients are considered (n=96), the estimate for the unadjusted treatment effect is 10.9% [95% CI: (-8.8% 
to 29.4%)], and 16.2% [95% CI: (0.3% to 32.3%)] after adjusting for baseline clinical characteristics. This 
range of estimates provides a strong motivation for conducting MISTIE III to confirm these clinically 
beneficial findings. The analogous unadjusted and adjusted effect sizes based on non-lobar ICH patients 
are very similar to these effect sizes. The second stage of MISTIE II provided evidence of increasing 
frequency of mRS scores in the 0-2 categories between 180 and 365 days with an unadjusted proportion 
of mRS 0-3 increasing to 14%. The sample size was selected based on 180-day outcomes in MISTIE II.  
 
It was decided to change the primary outcome to be based on 365-day outcomes because of the lack 
of a plateau in good functional outcome at 180 days. 
 
 
 
 
 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-9 
5.0. Definition of Study Samples 
 
5.1. Target Population  
 
The target population to which the MISTIE intervention or conventional medical management may be 
applied are patients with site-determined ICH ≥30 mL and not requiring extraventricular drainage (EVD) 
for the management of acute obstructive hydrocephalus. 
 
5.2. Intent-to-Treat (ITT) Sample 
 
As the primary analysis, all efficacy and safety outcome measures are analyzed under the ITT. Under 
this principle, each eligible subject is analyzed according to the treatment group to which they were 
assigned at the time of randomization. A total of 500 eligible subjects will be randomized. Exposure to 
the MISTIE procedure will be considered evidence of intention to treat. 
 
5.3. Safety Analysis Sample 
 
All randomized subjects are included in the safety analysis sample. Further safety analyses may be 
determined by clinical events and subgroups of the surgical task. 
 
5.4. As-Treated Sample for MIS+rt-PA 
 
The potential for cross-overs to the MIS+rt-PA treatment in this study is minimal; none occurred in our 
prior experience. However, in the case of cross-overs, a per-protocol sample will be constructed and 
examined in which treatment-as-received is analyzed.  
 
Given that amount of clot resolution is a potentially treatment-related post-randomization variable, this 
covariate will be examined as an important potential mediator of final outcomes as part of a per-protocol 
analysis. This treatment performance variable will be explored at the protocol thresholds of 15 mL, and 
10 mL and the observed level of 5 mL. Other thresholds may be explored as determined by inspection of 
the data and clinical findings. Surgical performance will be evaluated by chosen trajectory, surgical 
experience level and compliance with Surgical Center recommendations, and by actual task performance 
versus planned performance. 
  
5.4.1. As-Treated Sample for Any Form of Surgery 
 
Given the lack of guidelines to indicate whether any form of surgery is beneficial, different combinations 
of surgical versus medical therapy will be explored, starting with all subjects receiving any surgical 
procedure versus all subjects receiving only medical therapy. Important groups that represent actual 
practices and the timing of such practices occurring will be explored. Given that clot resolution is a 
potentially treatment-related post-randomization variable, this covariate will be examined as an important 
potential mediator of final outcomes as part of the as-treated analysis.  
 
Given the absence of clinical trial demonstration of benefit of craniotomy, we will assess the benefit of 
craniotomy or not by comparing all subjects receiving craniotomy versus those receiving only MIS+rt-PA 
and those receiving only medical therapy. Craniotomies will be divided into subgroups by time performed 
(in equal size groups and by day and half day). Finally, we will consider all craniotomies as salvage and 
assign them to death, then determine the frequency at which they are “life saving.” 
 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-10 
5.5. Demographic and Clinically Specific Subgroups 
 
All the primary, secondary, and safety analyses will be performed by gender, race, and ethnicity to 
determine if the treatment effect or safety differs by these demographics. Patient-specific clinical or 
“severity” factors/categories and treatment categories will be explored. Planned explorations include 
age, GCS (or NIHSS), ICH location, time to treatment, and initial ICH size. 
 
Subgroups utilized for adaptive cut points are: age <56, age 56 through 67, and age ≥67; GCS 3–8, 9–
12 and 13–15; initial ICH size (0–<25; 25–<35; 35–<45; 45–<55; 55–<65; and ≥65). We will examine 
the following subgroups: stability ICH size <50 and ≥50; lobar vs. deep; stability IVH size; time to 
surgery at <24 hours, 24-48 hours, and >48 hours from ictus; GCS 3–8, 9–12 and 13–15; and age <65 
and ≥65.  
 
Additional analysis of groupings of these clinical factors will be dictated by group size and balance 
between groups. We will also explore time as a continuum and at other clinically meaningful cut points.  
We will treat age, ICH size, and IVH size as a continuum and collapse them to other meaningful 
subgroups, as described above. NIHSS and GCS will also be treated as a continuum of scores. Based 
on post hoc analysis of the STICH trials, we will evaluate GCS 9–12 versus all other score levels. 
 
5.6. Definition of Treatment Failures 
 
Treatment failures are defined as: rt-PA administrations discontinued due to clinically significant 
rebleeding (prolonged GCS motor deterioration >2 motor points), the Investigator’s judgment to not 
treat, and failure to achieve the target volume of 15 mL or less. 
 
6.0. Randomization 
 
Randomization will occur after completed screening for vascular malformation and central validation of 
inclusion and exclusion criteria. Subjects will be randomized to MIS+rt-PA or medical management using 
a covariate-adaptive design similar to that used for the CLEAR III trial.2 The goal of this randomization 
scheme is to obtain an improved balance across study arms in the number of subjects with certain pre-
randomization variables that are most strongly predictive of the functional outcomes (mRS) at 180 and 
365 days post-stroke. These variables include pre-randomization clot volume, age, and baseline severity 
of impairment as measured by GCS.  Under this scenario, a randomization scheme will be used which 
increases a newly enrolled subject’s probability of being assigned to the study arm that improves the 
overall balance in these important prognostic factors. Briefly, prior to randomization for each incoming 
patient, the imbalance between treatment arms will be determined using the accumulating available data 
on clot volume, age and GCS. The patient will then be randomized with high probability (e.g., “weighted 
coin toss”) to the treatment arm that lowers the imbalance. Patients at any given site will not be 
considered for covariate-adaptive randomization until the site has enrolled four or six (blinded; sites are 
randomized to four or six to maintain blinding) patients into each treatment arm by within-site block 
randomization. This randomization scheme will be implemented using software included in the MISTIE 
III EDC (electronic data capture) system similar to what has been successfully implemented in the CLEAR 
III trial. 
 
7.0. Blinding 
 
The examiner performing the 30-, 180-, and 365-day follow-up assessments will video record the mRS 
interview assessments and upload the video to the Outcome CCC at the Western Infirmary in Glasgow, 
UK, where trained reviewers will classify the interview objectively without knowledge of the examiner’s 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-11 
score, patient name, or the treatment details including therapy intensity levels. 
 
8.0. Multiplicity 
 
The primary analysis of efficacy is tested at the two-sided alpha level of 0.05. In addition, secondary 
analyses will consider the alpha=0.05 two-sided type I error. Secondary analyses will be examined in 
the order specified and will not be corrected for multiplicity of testing. 
 
Secondaries 2-7 are defined. The other analyses without specific hypotheses are considered 
exploratory. We will present descriptive statistics and CIs. 
 
For safety outcomes, we do not account for multiplicity as this study was not powered to observe 
safety. Thus, a cautionary approach is justified.  
 
9.0. Missing Data 
 
Based on previous MISTIE and CLEAR studies performed in this group of stroke patients, the CCC will 
make substantial efforts to ensure complete collection of data for all patients, and to accrue minimal 
loss to follow-up (LTF) to optimize evaluation of the primary outcome of 365-day adjudicated mRS post-
stroke. The CLEAR III trial experienced an overall LTF rate of 2%. Since we expect missingness will be 
more prevalent for the 365-day mRS (the primary efficacy end point) than at early time points, we will 
use the targeted maximum likelihood estimator (TMLE)3 to adjust for censoring, as specified in the 
description of the model for the primary efficacy model given in Section 11.1 below. The effects of 
incompleteness/noncompliance will be quantified through sensitivity analyses, the gold standard in the 
field.4 
 
10.0. Baseline Characteristics 
 
10.1. Demographics 
 
Summary statistics will be presented for age (years), gender (male or female), race and ethnicity, 
presentation center, pertinent medical history including illicit drug use, primary diagnosis (ICH vs. ICH 
with IVH), hypertension history, diabetes, anticoagulation, tobacco and cocaine use, and antiplatelet 
drug use. 
 
10.2. Medical History 
 
Summary statistics will also be presented for medical history, as well as presentation variables:  
temperature, pulse, systolic blood pressure, diastolic blood pressure, presenting NIHSS, GCS, ICP, 
ICH volume, IVH volume, extent of white matter disease (van Sweiten index), and location of bleed. 
 
11.0. Efficacy Analyses 
 
11.1.  Primary Efficacy Analysis: Dichotomized, Adjudicated mRS 0-3 vs. 4-6 at 365 Days Post 
Ictus 
 
This primary analysis will produce an estimate and 95% confidence interval for the average treatment 
effect comparing assignment to MIS+rt-PA treatment (MISTIE) versus control (standard of care, i.e., 
medical management), using the ITT principle. Specifically, we will estimate the difference between the 
probability of an adjudicated mRS score of 3 or less at 365 days post-stroke comparing assignment to 


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PI: Daniel F. Hanley, MD 
 
 
 
MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-12 
treatment versus control; this difference is called the average treatment effect. Below is a description of 
the procedure for computing estimators of the average treatment effect. We also will test the null 
hypothesis of zero treatment effect at level 0.05. 
 
To estimate the average treatment effect, we will use the targeted maximum likelihood estimator 
(TMLE) of van der Laan and Gruber.3 This estimator adjusts for baseline (i.e., pre-randomization) 
variables in order to improve precision. The baseline variables, denoted by the vector B, include the 
three variables used in the covariate-adaptive randomization as given in Section 6.0 (i.e., pre-
randomization clot volume, age, and baseline severity of impairment as measured by GCS) as well as 
the following additional variables: IVH volume and location of ICH (indicator of lobar vs. deep). All 
baseline variables are treated as categorical and included as main terms in the models below. 
 
The TMLE estimator also involves adjustment with the goal of reducing bias due to informative 
censoring, that is, participant dropout that may be correlated with the primary outcome. The TMLE 
adjusts for missing outcomes through a combination of inverse probability of censoring weights and 
outcome prediction models. Specifically, the weights and prediction models use the aforementioned 
baseline variables, study arm, and the following post-randomization variables: mRS scores measured 
at 30, 180, 365 days from ictus, denoted M30, M180, M365 respectively. The motivation is that if mRS 
score at a given visit is correlated with the mRS score at the next visit and also with dropout, then 
adjusting for observed differences in the mRS history of those who drop out versus those who stay on 
study may reduce bias (under the assumption that censoring is missing at random). As we describe 
below, this adjustment is implemented by fitting models for dropout and models for the primary outcome 
based on mRS measured at the previous visit, study arm, and baseline variables.  
 
Let A denote the study arm, where A=1 for the MISTIE treatment arm and A=0 for the standard of care 
(medical management) arm. Let C30, C180, C365 denote the indicator of being uncensored at the 30-, 
180-, 365-day visits, respectively. E.g., C180=1 means the participant attended the 180-day visit and had 
his or her mRS M180 recorded. 
 
The TMLE involves first constructing inverse probability of censoring weights W30, W180, W365, defined 
as follows: 
 
W30=1/[Pr(C30=1 | B, A) P(A | B)] 
W180= W30/Pr(C180=1 | C30=1, B, A, M30)  
W365= W180/Pr(C365=1 | C180=1, B, A, M180) 
 
where the probabilities are estimated by fitting logistic regression models. Specifically, we fit logistic 
regression models for the probability of censoring at each visit given mRS at the previous visit, study 
arm, and baseline variables, among those who attended the previous visit. Each model includes main 
terms and an intercept, e.g., the model  
 
Pr(C365=1 | C180=1, B, A, M180) = logit-1(β0+β1B+β2A+β3M180) 
 
for the probability of remaining uncensored at 365 days given 180-day mRS, study arm, and baseline 
variables, is fit among those uncensored at 180 days (C180=1). 
 
We also fit a logistic regression model for the probability of A=1 given baseline variables B, used in W30. 
When the mRS score at an interim visit (30, 180 days) is included as a covariate in a regression model, 
it is coded as a categorical variable. We also truncate each weight at 20 (i.e., for weights above 20 we 
replace them by 20). Below, there is no connection between the coefficients in different models—we 


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PI: Daniel F. Hanley, MD 
 
 
 
MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-13 
use β to denote generic coefficients in each model, for simplicity.  
 
The TMLE involves a sequence of weighted regression model fits using the inverse probability of 
censoring weights constructed above. First, the weighted logistic regression model:  
Pr(M365 ≤ 3 | C365=1, B, A, M180) = logit-1(β0+β1B+β2A+β3M180)  
 
 
 
(1) 
using weights W365 is fit using all participants who are uncensored at 365 days (C365=1). 
Next, for each participant who is uncensored at 180 days (the previous visit), this model fit is used to 
generate the predicted probability, denoted by S180, of Y=1 given their 180-day mRS M180, study arm A, 
and baseline variables B.  
 
The above two-step process (model fitting then generating predictions) is iterated by replacing 
(M365 ≤ 3) by S180 in (1) and regressing on previous visit mRS, study arm, and baseline variables. 
 
Specifically, fit E(S180 | C180=1, B, A, M30) = logit-1(β0+β1B+β2A+β3M30) with weights W180 (2) 
using all participants who are uncensored at 180 days (C180=1). 
and use the model fit to generate the predicted mean S30 of S180 for each participant with C30=1;  
next, fit E(S30 | C30=1,B, A) = logit-1(β0+β1B+β2A)  
 
 
 
 
 
(3) 
with weights W30 using all participants who are uncensored at 30 days (C30=1). 
 
Lastly, the probability of Y=1 under assignment to study arm A=1 (MISTIE treatment) is estimated by 
generating for every participant (in both arms) a prediction by substituting their vector of baseline 
variables B and setting A=1 in the model fit (3). Similarly, the probability of Y=1 under assignment to 
study arm A=0 (medical management) is estimated by generating for each participant (in both arms) a 
prediction by substituting their vector of baseline variables B and setting A=0 in the model fit (3). 
The primary analysis estimator of the average treatment effect as a risk difference is defined as the 
difference between the former and the latter.  
 
The 95% confidence interval will be computed by the non-parametric bootstrap (resampling participants 
with replacement and recomputing the above estimator), and using the bias corrected and accelerated 
(BCa) method.5 The null hypothesis of zero average treatment effect will be rejected if this confidence 
interval excludes 0. This completes the description of the primary efficacy analysis, except for how 
missing baseline variables and intermittent (non-monotone) missingness are handled, as described 
next.  
 
Missing baseline variables are imputed using the median for continuous-valued variables and mode for 
categorical variables. This and the following paragraph are done before any of the steps above. 
 
We next describe how intermittent (non-monotone) missing data are handled, such as when a 
participant misses the 30-day visit only. We consider each interim visit at v=30 and 180, in turn. First, 
for visit v=30 days, we fit a multinomial logistic regression for M30 given A, B among those with C30=1; 
for those with C30=0, we then set their M30 to be the value with highest predicted probability from the 
model fit. Next, for visit v=180 days, we fit a multinomial logistic regression for M180 given A, B, C30,  
among those with C180=1; for those with C180=0, we set their M180 to be the value with highest predicted 
probability from the model fit. We do not apply this process to the final outcome at 365 days. All models 
include intercepts and main terms for the variables listed. Next, we modify model (1) to include the 
additional main term C30C180 and its interaction with A. Similarly, in model (2) we include the additional 
main term C30 and its interaction with A. The idea is that each model (1)-(2) now contains an indicator 
of whether the mRS score on the right side was directly measured or was predicted by the above 
process based on previous mRS measurements, study arm, and baseline variables.  
 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
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We will conduct sensitivity analyses to evaluate the impact (beyond what is explained by variables used 
in the analysis above) of informative censoring on our estimators, following recommendations from the 
U.S. National Research Council Panel on Handling Missing Data in Clinical Trials.6 
 
11.2 Additional (Non-Primary) Efficacy Analyses  
 
Models as detailed in equations (1) to (3) above an analogous approach will be used to assess 365-day 
differences with other corrections described next. Estimates from these models will account for design 
aspects such as potential within-site clustering that might otherwise lead to biased estimates in the 
standard errors associated with the regression coefficients. Additionally, we will control for clinically 
important variables, including pre-randomization ICH volume, IVH volume (or presence, depending on 
the variability in IVH volumes), baseline stroke severity, age, co-morbidity (diagnosis of diabetes or 
history of cardiovascular disease), and extent of white matter disease.   
 
11.2.1. Additional Efficacy Analysis: Ordinal, Adjudicated mRS (0-6) at 365 Days 
 
When we consider analysis of the ordinal mRS, we will estimate a proportional odds model of the form: 
 
𝑙𝑙𝑙𝑙𝑙𝑙
𝛾𝛾𝑘𝑘
1−𝛾𝛾𝑘𝑘= 𝛼𝛼𝑘𝑘+ 𝛽𝛽𝛽𝛽+ 𝜃𝜃𝜃𝜃𝜃𝜃𝜃𝜃  (6) 
 
where αk = Prob(mRS < k), k=0, 1,...,5. 
 
This proportional odds model is very similar to the models described under 11.1. above, with the 
difference being that a treatment effect leads to an increase in the likelihood of a patient being in any 
subsequently lower mRS category. The probabilities, αk, are cumulative probabilities which incorporate 
all outcomes below any given level. The set of intercepts, αk k=0,1,…,5, define the initial probabilities of 
these cumulative levels, covariates are again included through β and X, and the treatment difference θ 
now describes the log-odds of moving from any cumulatively higher (worse) category, into any 
cumulatively lower (better) category. For instance, here θ describes both how the MIS+rt-PA changes 
the probability of ICH patients away from a potential mRS category of “Dead” (6) to “No Symptoms 
through Severe Disability” (0-5), as well as how the MIS+rt-PA changes patient probabilities away from 
“Severe Disability or Dead” (5,6) to “No Symptoms through Moderate Disability” (0-4) and so forth. This 
model is potentially more efficient than a simple dichotomous approach since it uses the available 
information across the scale of the measure. To examine the proportional odds assumption, we will 
additionally examine generalized ordered logit models that replace β and θ with βk and θk, allowing non-
parallel effects between successive cumulative categories. In the event that the proportional odds 
assumption is rejected, we will present results from the generalized ordered logit models. 
 
For the ordinal outcome, the average treatment effect is defined as the average of the cumulative log-
odds:  
 
𝛽𝛽=
1
𝐾𝐾−1 ∑
𝑙𝑙𝑙𝑙𝑙𝑙
𝑃𝑃(𝑌𝑌1≤𝑖𝑖)
𝑃𝑃(𝑌𝑌1>𝑖𝑖)
൘
𝑃𝑃(𝑌𝑌0≤𝑖𝑖)
𝑃𝑃(𝑌𝑌0>𝑖𝑖)
൘
𝐾𝐾−1
𝑖𝑖=1
    (7) 
 
where Yr is the mRS score at 365 days and r=1 for MIS+rt-PA and 0 for medical management.  
 
Survival models will be constructed to examine the mortality for the MIS+rt-PA and medically managed 
groups. Standard Cox proportional hazard models will initially be examined. These models are 
commonly written as: 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-15 
 
 
 
 
 
 
(8) 
 
where λ0(t) is a non-parametric baseline hazard function, γ is a vector of regression coefficients related 
to the X covariates, and φ is the parameter for the treatment effect of MIS+rt-PA on the hazard of death 
(mortality). This model may be extended by including time-dependent covariates and non-proportional 
hazards as deemed necessary through diagnostic checks. Observed mortality will also be compared 
with predicted mortality based on clinical presentation, overall, and by treatment group. Predicted 
mortality will be estimated. We will develop a severity model that predicts mortality based on the Tuhrim 
model.2,7,8  
 
11.2.2. Additional Efficacy Analysis: Longitudinal Analysis  
 
Longitudinal analysis will examine the secondary outcomes that are longitudinally collected at baseline 
and the follow-up time points (e.g., at 30, 90, 180, 270, and 365 days post-stroke). These data will have 
within-patient correlations from one time point to the next, making it necessary to use appropriate 
analytical methods that properly estimate the coefficients and their associated standard errors in the 
analysis models. Since the overall goal of the trial is to compare subjects receiving the MIS+rt-PA 
intervention with subjects receiving medical standard of care, a marginal model estimated using a 
generalized estimating equations (GEE) technique is appropriate. The GEE technique requires 
specification of the standard “mean” model, as well as specification of a working “association” model. 
One strength of GEE is that the fixed-effect parameters in the mean model (i.e., the intervention effect) 
are consistent regardless of whether the association model is specified correctly under mild regularity 
conditions. The fixed-effects will include treatment arm (coded as 1 for MIS+rt-PA and 0 for medical 
management), follow-up time represented with four indicator variables for 90, 180, 270, and 365 days 
post ictus), and their interactions. The interaction terms will test (at 0.05 level of statistical significance) 
whether the longitudinal change in the outcome is statistically different between study arms. Additional 
variables will include ICH volume, baseline GCS, age, IVH, and comorbidities, such as history of 
diabetes or cardiovascular disease. Models will be compared using quasi-likelihood under the 
independence model criterion (QIC) for GEE.  
 
11.2.3. Additional Efficacy Analysis: Severity Subgroup Analysis 
 
Regression of the treatment by subject severity. In subsequent analyses, the model in equation (1) will 
be modified to include multiple baseline severity variables, such as NIHSS, IVH, extent of white matter 
disease, co-morbidity, etc. The models will be compared using Akaike Information Criterion (AIC) to 
assess the best combination of predictors. The discriminatory ability of the models will be compared 
using the cross-validated area under the Receiver Operating Characteristic (ROC) curve. 
 
11.2.4. Additional Efficacy Analysis: Subgroup Analysis  
 
Summary statistics will be presented for the analysis sets and subgroups of gender, race, and ethnicity. 
In addition, summary statistics will be examined for the subgroups of the patients who completed the 
study and by patients who discontinued the study early from the data available for these patients. The 
reasons for early discontinuation, including bleeding, loss to follow-up, and withdrawal of care, will be 
tabulated and recorded to help improve future recruitment and retention. 
 
In addition, since data from the MISTIE phase 2 trial neither supports nor negates any significant 
difference in treatment efficacy by gender, race, or ethnicity, the analyses detailed in equations (1) to 
(4) above will be performed separately for males and females, by race (e.g., Caucasian, African 
)
exp(
)
(
)
(
0
TRT
X
t
t
hi
⋅
+
=
φ
γ
λ


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-16 
American, Asian, Native American, Pacific Islanders, etc.), and by ethnicity (e.g., Hispanic, non-
Hispanic), where adequate data are available to determine if the treatment effect varies by these 
demographic categories, which would indicate the presence of effect modification by treatment. These 
sub-analyses are required by the NIH Policy and Guidelines on The Inclusion of Women and Minorities 
as Subjects in Clinical Research, amended October 2001. Note that the trial is not powered to see 
treatment effect modifications by these demographic categories. 
 
11.2.5. Additional Efficacy Analysis: Random Effects (Site Differences) Analyses  
 
We will conduct analyses based on mixed models that assume random effects and their variance-
covariance matrix structure, including models without random intercepts, and possibly random slopes, 
for hospital sites.  
 
12.0. Interim Efficacy Analyses 
 
At the discretion of the DSMB, a formal interim efficacy analysis will occur after 375 subjects reach 180 
days of follow-up. These analyses will be based on approximate O'Brien-Fleming stopping boundaries 
for efficacy (defined below).  
 
In the MISTIE III design, subjects will be randomized to MIS+rt-PA versus medical management using 
a covariate-adaptive design described previously. The trial will initially enroll ICH patients until either a 
maximum of 500 eligible patients is accrued or the trial is stopped early for efficacy or futility using 
group sequential boundaries described below. 
 
Analyses will be conducted after 375 and 500 patients, respectively, have 180-day post-stroke 
measurements. Efficacy stopping boundaries will be based on the error-spending (also called alpha-
spending) approach using the power family with exponent rho=3, which approximates the O’Brien-
Fleming boundaries. The (one-sided) alpha allocated to the analysis (called the interim analysis) at 375 
participants is defined to be alpha1 = 0.025(375/500)3 = 0.0105. All remaining alpha, i.e., (0.025-alpha1) 
is spent at the analysis with 500 participants (called the final analysis).  
 
13.0. Secondary Efficacy Outcomes Analyses 
 
13.1. Secondary Efficacy Analysis 1: Dichotomized eGOS UGR-US vs. LS-Death at 365 days 
 
Analyses will follow the methods as described in equations 1, 2, and 3 above (11.2.1–11.2.5). 
Subordinate analyses will be adjusted for other clinically meaningful variables, in addition to the ones 
used in the covariate-adaptive randomization.  
 
13.1.1. Additional, Subordinate Efficacy Analysis 1: 365-Day Ordinal eGOS 
 
Clot removal with MIS+rt-PA produces improvements in functional outcome assessed by alternative 
outcome measures such as the extended Glasgow Outcomes Scale (eGOS). Analyses: Ordinal, linear, 
logistic, and polytomous data models to examine other levels of the eGOS as part of Secondary 
Efficacy Analysis 1 will be similar to those presented above. 
 
 
 
 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-17 
13.2. Secondary Efficacy Analysis 2: All-Cause Mortality Longitudinally from Ictus to 365 Days 
 
Mortality at 365 days post ictus for MIS+rt-PA–treated subjects will be improved as compared to that of 
medical managed subjects. Comparison of treatment groups will be examined using logistic regression 
analysis. 
 
Mortality by group will be graphically displayed with Kaplan-Meier curves, and the statistical association 
between treatment assignment and mortality will be assessed with the log-rank test. Multivariable Cox 
regression models will then be created to assess for treatment differences in the hazards of survival 
after adjusting for potential group imbalances in the covariates listed above. Finally, we will account for 
the effect of the decision to withdraw patient care on treatment differences in mortality. 
 
As a secondary assessment, time to death within the one-year follow-up period will be compared 
between the MIS+rt-PA and medically managed groups adjusting for appropriate baseline covariates. 
Provided the model assumptions are met, a proportional hazards regression model may be used for the 
analysis as described above. 
 
13.2.1. Subordinate, Secondary Efficacy Analysis 2: Predictors of Mortality Analysis 
 
Additionally, survival models will be constructed to examine the mortality, morbidity, and ICU 
distributions for the MIS+rt-PA and medical management groups. Standard Cox proportional hazard 
models will initially be examined. These models are commonly written as: 
 
 
where λ0(t) is a non-parametric baseline hazard function, γ is again a vector of regression coefficients 
related to the X covariates, and φ is the parameter for the treatment effect of EVD plus rt-PA on the 
hazard of death (mortality). This model may be extended by including time-dependent covariates and 
non-proportional hazards as deemed necessary through diagnostic checks. Observed mortality will also 
be compared with predicted mortality based on clinical presentation, overall, and by treatment group. 
Predicted mortality will be estimated. We will develop a severity model for predicting mortality based on 
the Tuhrim model.2,7,8  
 
13.3. Secondary Efficacy Analysis 3: Relationship Between Clot Removal as an AUC that 
Estimates the Time-Weighted Clot Volume from Ictus to EOT as AUC Clot Exposure and 
Functional Outcome (Proportion 0-3 mRS) 
 
EOT clot volume and/or percent EOT ICH reduction are related to mRS functional outcome regardless 
of treatment. Based on the experience of the CLEAR III trial, time-weighted average clot volumes will 
also be considered as a potential predictor of mRS outcome. The null hypothesis is that ICH clot 
reduction time course (time weighted clot volume, EOT clot volume, and/or percent EOT clot reduction) 
has no effect on functional outcome regardless of treatment. 
 
In addition, since a “plateau” or “floor” effect of clot resolution over time is likely, subsequent models to 
statistically test for these fixed effects will consider clot resolution in non-linear terms, such as linear or 
restricted cubic splines and other non-linear functions. Placement of knots for the splines will be based 
on the visual inspection of the average ICH trajectory over time. In addition, when using restricted cubic 
splines, we will consider placing the knots at equally spaced percentiles of the “follow-up time” 
variable’s marginal distribution as recommended by Harrell.9 Alternative methods that quantify the time-
weighted clot volume will also be considered in this model.7 


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PI: Daniel F. Hanley, MD 
 
 
 
MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-18 
 
From the final, most parsimonious model, the empirical Bayes estimates of the random slopes will be 
computed to be used in the next phase. The second-phase analysis will be based on multivariable 
logistic regression models that include the estimated clot resolution trajectories over time, the 
covariates listed in equation (1) above, and the dichotomized mRS at 365 days post-stroke as the 
outcome.  
 
13.4. Secondary Analysis 4: Patient Disposition  
 
13.4.a. Secondary Efficacy Analysis 4a: Home Days Over 365 Days’ Time from Ictus 
 
Multivariable linear regression models will be built on this continuous outcome of time to home. 
 
13.4.b. Secondary Efficacy Analysis 4b: Patient Location at 365 Days Post Ictus 
 
Multivariable logistic regression models will be built on the dichotomized outcome of home plus 
rehabilitation locations versus other locations for patients 365 days post-ictus. Because variations in the 
more severe levels of mRS (4,5) and eGOS (US, LS, VS) do not fully account for disposition, it will be 
assessed by adjusting for all covariates. Where discrepant conclusions about severe disability might be 
drawn from mRS, eGOS, or final location, all three descriptors will be presented for the severe levels. 
 
13.5. Secondary Analysis 5: 180-Day Efficacy 
 
13.5.a. Secondary Analysis 5a: Dichotomized, Adjudicated, Cross-Sectional mRS 0-3 vs. 4-6 
 
Analysis methods described in section 11.1 for the Primary Efficacy Analysis will be repeated using day 
180 data. 
 
13.5.b. Dichotomized, adjudicated eGOS UGR-US vs. LS-Death 
 
Analysis methods described in section 13.1 for the Secondary Efficacy Analysis 1 will be repeated 
using day 180 data. 
 
13.5.1. Additional, Secondary Efficacy Analysis 5: Ordinal, Adjudicated mRS (0-6) 
 
Analysis methods described in section 11.1.1. for the Subordinate Analysis (1) for the Primary Efficacy 
Analysis will be repeated using day 180 data. 
 
13.5.2. Additional, Secondary Efficacy Analysis 5: Ordinal, eGOS UGR-US vs. LS-Death 
 
Analysis methods described in section 13.1.1. for the Subordinate Analysis for Secondary Efficacy 
Analysis 1 will be repeated using day 180 data. 
 
13.5.3. Additional, Secondary Efficacy Analysis 5: Subordinate Analyses 2-5 as Defined under 
the Primary Efficacy Analysis 
 
Analysis methods described in sections 11.2–11.5 for the Primary Efficacy Analysis will be repeated 
using day 180 data. 
 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-19 
13.6. Secondary Efficacy Analysis 6: Type and Intensity of ICU Management 
 
MIS+rt-PA treatment of ICH leads to decreased intensity of hospital care compared to medical 
management. This includes fewer hospital days, ICU days, decreased use or duration of ventilatory 
management, decreased intensity of ICP management, decreased BP support, decreased 
osmotherapy, shorter periods of CSF drainage, lower utilization of ventriculoperitoneal shunts, and 
fewer general critical care complications. Analyses: Linear, log-linear, and logistic data models will be 
similar to those presented above. 
 
13.7. Secondary Efficacy Analysis 7: EQ-VAS and EQ-5D 
 
Clot removal with MIS+rt-PA leads to improved health-related QOL and will be assessed by subject and 
surrogate QoL domains through the EQ-VAS and EQ-5D. 
 
14.0. Safety Analyses 
 
14.1. Mortality and Safety Events at 30 Days Post Randomization 
 
The primary safety measures for this study are symptomatic intracranial bleeding, infection, and 30-day 
mortality. The safety thresholds for these measures have been set as: 30-day mortality >60%, a 
MIS+rt-PA–related symptomatic bleeding rate >25% (occurring during active treatment or during the 72 
hours after treatment will be monitored), first-week operative death rate >10%, and a procedure-related 
infection rate >15% (over the initial 30 days). Bleeding will be further characterized as during the 
exposure to dosing of alteplase and the subsequent 72 hours. Comparisons to medical subjects in the 
same time frame will be made. Total SAEs at 30 and 180 days, as well as summary of AEs and SAEs 
by MedDRA code and grouped by organ system, will be compared by treatment groups. 
 
Statistical Hypothesis: Early use of MIS+rt-PA for 3 days for the treatment of ICH is as safe as 
medically managed ICH, measured by rates of procedure-related mortality, rebleeding, and infection 
within 30 days post-randomization. The null hypothesis is: Early use of MIS+rt-PA is worse than 
medical management for a specific safety measure. 
 
Analysis: The number of SAEs will be tabulated by SAE type post-stroke for the total population as 
well as by treatment group, with particular emphasis placed on group differences at 30 days post-
randomization. Any treatment group differences in SAEs enumerated for interim analyses will remain 
blinded to investigators associated with this study. Unmasked results (e.g., group A versus B, where 
the labels “A” and “B” are randomly assigned to the surgical and medically managed groups) will be 
made available only during the closed sessions of DSMB meetings.  
 
Methods of non-inferiority will be used to statistically determine if the proportions of a particular type of 
SAE, where there are adequate data for a particular type, are not substantially different  among both 
treatment groups in order to test the hypothesis that MIS+rt-PA is as safe as standard medical 
management. Non-inferiority testing deems the rates of any SAE event in the MIS+rt-PA group to not 
be substantially greater than the SAE event rate in the standard medical management group as long as 
the group difference in this rate is statistically within some pre-specified tolerance. For this trial, the 
tolerance value will be defined as 10% for the primary adverse events of 30-day mortality, rebleeding, 
and infection, and 5% for first-week operative mortality. Thus, the rates of adverse events seen in the 
MIS group can be higher than those in the medically managed group, and yet still be considered not 
substantially different as long as the upper one-sided 95% CIs on rate differences are ≤10% or ≤5%, 
depending on the safety measure. 


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MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-20 
 
Since data from the MISTIE phase 2 trial neither supports nor negates any significant difference in SAE 
event rates by gender, race, or ethnicity, the non-inferiority analyses described above will be performed 
separately for subpopulations within each of these demographics where there are adequate data 
available.  
 
14.2. Total SAEs at 30 Days  
 
Mortality attributed to MIS+rt-PA treatment plus disease-associated adverse events are similar to the 
morbidity and mortality attributed to medical management in the first 30 days. Analyses: For initial 
evaluations, differences between the MIS+rt-PA intervention and medical management groups will be 
examined using a logistic regression model. 
 
14.3. Summary of Adverse Events and Serious Adverse Events by MedDRA Code and Grouped 
by Organ System 
 
All AEs and SAEs are summarized by type and by treatment group in terms of frequency of the event, 
number of subjects having the event, timing relative to randomization, severity (mild, moderate, 
severe), and relatedness to the study treatment (definitely, probably, possibly, definitely not). At the end 
of the study, the cumulative incidences of these events will be compared between the two treatment 
groups using Fisher’s exact test. Statistically significant differences between the treatment arms will be 
assessed after adjustments for multiplicity in the case of individual SAE/AE diagnoses and MedDRA 
codes. Additionally, generalized linear mixed models for binary data will be used to examine AE and 
SAE probabilities between treatment groups while accounting for potential confounders and site-
clustering effects. 
 
14.4. Proposed Interval Safety Monitoring 
 
The DCC will generate periodic DSMB reports. (We assume the total number of subjects enrolled per 
six months in a single treatment group will be approximately 30; thus, eight semi-annual looks at the 
data will be suggested to the DSMB. As usual, though, periods for reporting will be discussed and 
finalized at the initial DSMB meeting.) Each report will provide cumulative summary statistics on 
enrollment; subject status in the study (e.g., number completed at 3-month, 6-month, 9-month, and 12-
month assessments); baseline characteristics; protocol violations; safety data, including AEs and SAEs 
by AE code, severity, and relatedness to the study medication; outcomes data (if coinciding with an 
interim analysis—also to be discussed and finalized at the initial DSMB meeting); and data 
management/quality information (e.g., timeliness and completeness of data entry by the clinical sites 
via the MISTIE III electronic data capture (EDC) system; number of queries generated and resolved). 
Two reports will be generated: an open report with combined data from both treatment groups, and a 
closed report for the DSMB voting committee members with data provided by blinded treatment group 
(noted as A and B). The outline of these proposed DSMB reports will be included in the Manual of 
Operations and Procedures prepared by the CCC. In an interval as yet to be determined (monthly, 
quarterly, or semi-annually), the CCC will also generate a Safety Monitoring Report to be distributed to 
the DSMB. This report contains only enrollment, subject study status, safety, and data quality 
information. The trial’s Executive Committee will also receive the Safety Monitoring Reports. The DSMB 
will have discretion to recommend stopping the trial early if safety concerns become substantial. Safety 
stopping rules for each of the primary safety outcomes will be developed and used to help the DSMB 
make its safety assessments.  
 


NIH/NINDS 
 
 
Johns Hopkins University  
 
PI: Daniel F. Hanley, MD 
 
 
 
MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-21 
15.0. Tertiary (Exploratory/Sensitivity) Analyses 
 
15.1. Functional Status at 180 and 365 Days Post Ictus 
 
Clot removal with MIS+rt-PA treatment produces improvements in functional outcome will be assessed 
by alternative outcome measures such as:  
 
15.1.a. Glasgow Outcome Scale  
15.1.b. Barthel Index  
15.1.c. NIHSS  
15.1.d. MMSE 
 
Analysis methods will include linear, logistic, and polytomous data models similar to those presented 
above. 
 
15.2. Quality of Life at 180 and 365 Days Post Ictus 
 
Clot removal with MIS+rt-PA leads to improved health-related QoL and will be assessed by subject and 
surrogate QoL domains through the:  
 
15.2.a. Stroke Impact Scale 
15.2.b. PBSI 
15.2.c. Personal Health Utility Assessment Interview 
15.2.d. CES-D 
15.2.e. EQ dimensions individually assessed 
15.2.f. Home days 
15.2.g. Patient location including proportion of days in acute care, home, rehabilitation, long-term care 
facilities, and in vegetative condition.  
 
Analyses methods will include linear, logistic, and polytomous data models similar to those presented 
above. 
 
15.3 Cost-Benefit Model 
 
Cost-benefit analyses will be performed using data on median hospital stay, patient disposition 
categories (such as home, long-term ambulatory and nursing care, death), time to return home, and 
cost of procedures and hospital stay. These analyses will be performed with respect to both 180- and 
365-day periods post-stroke. For cost-benefit analyses, the cost of ICU and the rest of the hospital stay, 
including the cost of MIS+rt-PA, will be considered. Cost data will be obtained from the literature. The 
overall amount for both treatments will be assessed, and the difference in dollars will be calculated.    
 
 
 
 
 
 
 
 
 


NIH/NINDS 
 
 
Johns Hopkins University  
 
PI: Daniel F. Hanley, MD 
 
 
 
MISTIE III 
Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase 3 
 
 
 
Page 22-22 
16.0. References 
 
1. Hanley DF, Thompson RE, Muschelli J, et al. Safety and efficacy of minimally invasive surgery 
plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, 
open-label, phase 2 trial. Lancet Neurol 2016;15(12):1228-1237. 
2. Hanley DF, Lane K, McBee N, et al. Thrombolytic removal of intraventricular haemorrhage in 
treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-
controlled CLEAR III trial. The Lancet 2017;389:603-11. 
3. van der Laan MJ, Gruber S. Targeted minimum loss based estimation of causal effects of 
multiple time point interventions. Int J Biostat 2012;8(1):1370. 
4. Permutt T. Sensitivity analysis for missing data in regulatory submissions. Statistics in medicine 
2016;35:2876-9. 
5. Diciccio TJ, Efron B, Hall P, et al. Bootstrap confidence intervals. Statistical Science 
1996;11(3):189-228. 
6. National Research Council Panel on Handling Missing Data in Clinical Trials. The prevention 
and treatment of missing data in clinical trials. Washington, DC: National Academies Press 
(US); 2010. 
7. Tuhrim S. Intracerebral hemorrhage—improving outcome by reducing volume? N Engl J Med 
2008;358(20):2174–6. 
8. Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important 
determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med 1999;27:617-
621. 
9. Harrell F. Regression modeling strategies: with applications to linear models, logistic regression, 
and survival analysis. New York: Springer; 2001. 
 

Prot_003.pdf: 
MISTIE III 
A phase III, randomized, open-label, 500-subject clinical trial of minimally 
invasive surgery plus rt-PA in the treatment of intracerebral hemorrhage. 
MTI-M3 
Mechanisms of Tissue Injury in MISTIE III  
Rebleeding and inflammation: predicting risk of excessive bleeding in minimally invasive 
surgery and inflammatory marker evaluation 
Study Chair: 
Daniel F. Hanley, MD, Professor of Neurology, Johns Hopkins University 
Issam Awad, MD, Professor of Neurosurgery and Neurology, University of Chicago 
Mario Zuccarello, MD, Professor of Neurosurgery, University of Cincinnati 
Supported by: 
The National Institute of Neurological 
Disorders and Stroke (NINDS) 
(Grant # 1U01NS080824-01A1) 
National Institute of Health Research (NIHR, UK) 
Study Intervention Provided by: 
Genentech, Inc. (US and Canada only) 
Sponsor of IND 8523: 
Daniel F. Hanley, MD 
Protocol Number: 
ICH02 
Version/Version Date: 
Version 4.0/14 April 2015 
NCT01827046


 
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AGREEMENT ON THE PROTOCOL 
 
 
Trial ID:  
MISTIE III 
 
   A phase III, randomized, open-label, 500-subject clinical trial of minimally  
invasive surgery plus rt-PA in the treatment of intracerebral hemorrhage. 
NIH/NINDS  
IND #:  8523  
 
The Principal Investigator (hereafter referred to as Investigator) and The Johns Hopkins Medical 
Institutions (hereafter referred to as JHMI) agree to conduct the trial as outlined in this protocol 
with reference to national/local/international regulations and in accordance with current Good 
Clinical Practice (GCP) and International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
 
Any modification to the protocol must be agreed upon by both the Investigator and JHMI and 
documented in writing.  By written agreement to this protocol, the Investigator agrees to allow 
direct access to all documentation, including source data, to authorized individuals representing 
JHMI (including monitoring staff and auditors), to Institutional Review Boards (IRB) and/or to 
regulatory authorities. 
 
 
 
 
Signature:  ______________________________  
Date:  ______________________ 
 
 
 
Name Printed:  ___________________________ 


 
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TABLE OF CONTENTS 
Page 
 
SYNOPSIS ………..……………………………………………………………………… 
5 
 
1. 
STUDY OBJECTIVES ………………………………………………………… 
6 
 
1.1 
Primary Objective (Efficacy)……………………………………………….… 
6 
1.2 
Primary Objective (Safety) …………………………………………………….… 6 
1.3  
Secondary Objectives ..……………………………………………………….. 
6 
 
2.         BACKGROUND ………………………………………………………………… 
6 
 
 
2.1 
Rationale ………...…………………………………………………………… 
6 
2.2 
Supporting Data …… ………………………………….…………………….. 
9 
 
 
3. 
STUDY DESIGN ……………………………………………………………......  
20 
 
4.         SELECTION AND ENROLLMENT OF SUBJECTS ……………………..... 
21 
 
 
4.1 
Inclusion Criteria …………………………………………………………….. 
21 
 
4.2 
Exclusion Criteria ……………………………………………………………. 
21 
 
4.3 
Study Enrollment Procedures ………………………………………………… 
23 
 
5.         STUDY INTERVENTIONS ………………………………………………….… 
26 
 
 
5.1 
Interventions, Administration, and Duration ...………………………………... 
26 
 
5.2 
Handling of Study Interventions ……………………………………………… 
35 
 
5.3 
Concomitant Interventions ……………………………………………………. 
36  
 
5.4 
Adherence Assessment ……………………………………………………….. 
37  
 
6.         CLINICAL AND LABORATORY EVALUATIONS ………………………… 
38 
 
 
6.1 
Schedule of Evaluations …………………………………………………….… 
38 
 
6.2 
Timing of Evaluations ………………………………………………………… 
39 
 
6.3 
Special Instructions and Definitions of Evaluations ………………………….. 
41 
 
 
7.          MANAGEMENT OF ADVERSE EXPERIENCES ……...………………….. 
46 
 
8.          CRITERIA FOR INTERVENTION DISCONTINUATION ……………….. 
47 
 
9.          STATISTICAL CONSIDERATIONS ………………………………………… 
48 
 
 
9.1 
Statistical Analysis Plan ………………………………………………………… 48 
 
9.2 
Data Monitoring ………………………………………………………………… 61 


 
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10.          DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE    
               REPORTING ……………………………………………………………………. 62 
 
 
10.1 
Records to be Kept ……………………………………………………………… 62 
 
10.2 
Role of Data Management ………………………………………………………. 64 
 
10.3 
Quality Assurance ……………………………………………………………….. 64 
 
10.4 
Adverse Experience Reporting ………………………………………………….. 76 
 
11.          HUMAN SUBJECTS …………………………………………………………….. 86 
 
 
11.1 
IRB Review and Informed Consent ………………...…………………………… 86 
 
11.2 
Subject Confidentiality ………………………………………………………….. 87 
 
11.3 
Study Modification/Discontinuation ………………………………………….… 87 
 
12.          PUBLICATION OF RESEARCH FINDINGS ………………………………... 87 
 
13.          REFERENCES ………………………………………………………………...… 88 
 
 
 
APPENDICES 
 
1. 
Sample trial consent form  
2. 
Sample HIPAA authorization form for international research 
3. 
Medical management guidelines 
4. 
Sample consent form for videotaping a proxy during the modified Rankin Scale 
interview 
5. 
Expected Adverse Events 
6. 
Genentech Drug Safety: Safety Reporting FAX Cover Sheet 
7. 
Abbreviation list 
8. 
MTI-M3 ancillary study protocol 
 
 


 
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SYNOPSIS 
 
Study Title 
 
MISTIE III. 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. 
 
Objectives 
 
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 180 days. 
  
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.  
 
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. 
 
Design and Outcomes  
 
This study is a phase III, randomized, open-label, multicenter evaluation of MIS and ICH 
lysis with rt-PA versus medical care. The study (n=500) will evaluate the efficacy and 
safety of MIS plus 1 mg of rt-PA administered every eight hours for up to nine doses as 
compared to subjects treated with conventional medical management. Endpoint 
assessment will be performed by blinded investigators at the University of Glasgow. 
 
Subjects enrolling in this study may also consent to participate in an ancillary study titled 
Mechanisms of Tissue Injury in MISTIE III. This ancillary study offers a tremendous 
opportunity to leverage clinical trial data to bring novel insights from ICH 
pathophysiology into the clinical realm, using neuroimaging, genetic and inflammatory 
markers of disease to provide clinicians with powerful new tools to guide surgical 
therapy and develop new therapeutic targets. See Appendix 8 for the ancillary study 
protocol. 
  
Interventions and Duration 
 
The study is proposed to require five years. All subjects will be followed daily for six 
days post randomization. Subjects randomized to receive the surgical intervention will 


 
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undergo aspiration of clot followed by up to nine drug administrations. All subjects will 
be required to attend follow-up clinic visits at 30, 180, and 365 days after onset of ICH. A 
telephone follow-up will occur at 90 and 270 days. 
 
Sample Size and Population 
 
The study population will include 500 subjects, adaptively randomized 1:1 across 
approximately 90 to 100 study centers, with supratentorial ICH without suspected 
underlying structural etiology (tumor, vascular malformation or aneurysm). Subjects will 
be identified and recruited through the Emergency Department, clinical stroke service, 
and direct admissions to the Neurocritical Care Unit at each study center. See section 
9.1.1. Randomization below for a more detailed description of the randomization 
procedure. 
 
1 
STUDY OBJECTIVES 
 
1.1 
Primary Objective (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 at 180 
days. 
  
1.2 
Primary Objective (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. 
 
1.3 
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. 
 
2 
BACKGROUND 
 
2.1 
Rationale 
 
Scope of Problem:  Brain hemorrhage is a worldwide problem without strategies for 
treatment or prevention.1 Its incidence is persistent and its prevalence keeps increasing 
with an aging population.2-4 The high burden of disease is well-established with a 30-day 
mortality of approximately 40%.2 Substantial health disparities exist, with an increased 
incidence for Asians, African-Americans, Hispanics, those without access to blood 
pressure (BP) management, and the aged.5   


 
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ICH affects a young and productive population with morbidities that produce disastrous 
economic and social consequences,3,6,7 and functional impairment produces an intolerable 
degree of dependency.8 When hemorrhages of all sizes are considered, only 10%-25% 
return to functional independence, and functional performance is likely to be much worse 
(≤10%) when initial hematoma volumes are greater than 20-30 mL.3,9,10  
 
 
We deliver care in a default position, where we provide complex brain monitoring and 
ICU support without evidence of benefit or emphasis on mitigation. The state of care for 
ICH is similar to care for ischemic stroke three decades ago—care is frequently not 
rendered. When rendered, it is palliative and supportive of cardiorespiratory function 
rather than reversing the brain injury. The absence of an evidence-validated treatment is 
associated with high cost, variability in care, uncertainty in decision-making, 
unacceptable mortality rates, and long-term functional dependency requiring skilled 
nursing.11-13 The ICU stay for a patient with a moderately sized ICH (>30 mL) averages a 
month, requiring prolonged ventilation, nutrition support, and acute cardiovascular and 
infection treatments.14 Health professionals make widely variable treatment, level-of-
care, and prognostic decisions without trial evidence15,16 or consideration of long-term 
survivor benefit/burden.15-18  
 
Similarly, routine surgical decision-making (patient selection, procedure selection, & 
timing) is done without an evidence-based model;11 yet surgery is often offered as a last 
life-saving resort.11,19-21 A small number of clinical trials have produced results that 
greatly inform patient selection but showed no benefit for early craniotomy, ultra-early 
craniotomy, ultra-early treatment of bleeding, or early neuroprotection.22 A practical 
approach—craniotomy to remove clots in all patients, from all locations, regardless of 
stability—is neither unequivocally accepted18 nor fully evidence-based.11 Craniotomy 
being only slightly better than medical management leaves strong community equipoise 
around a good body of evidence regarding volume-reduction therapy20,23,24 and, more 
specifically, the MISTIE image-guided approach.  
 
 
ICH is unlike stroke, in that the mechanism of injury, the requirements of care, and the 
likely pathway to a primary treatment are different.22 The current default position falls 
short of mitigating the primary injury pathway.22 An effective treatment is urgently 
needed that reduces impairment and increases functional independence in the home.8,13,25 
The two most pressing ICH investigational goals are: 1) early BP control and 2) 
hematoma volume reduction. Answering these questions would support decision-making, 
level-of-care choices, and the global research strategy of developing biologically 
informed treatments in general.22  
 
Defining The Strategic Path: Consensus has developed slowly but firmly in favor of 
investigating the role of clot size reduction using less invasive methods and, perhaps, the 
use of disease-modifying biologics.22,24,26 It is now recognized that “the mechanisms 
believed to play a part in brain injury induced by ICH differ in type, magnitude and 
timing from those of ischemic stroke.”22 In this environment, the MISTIE investigators 


 
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have produced some of the first encouraging data. The phase II findings utilized the path 
of biologically plausible animal models, validation via adaptive human studies, and 
advanced surgical consensus/data sharing, leading to an innovative image-based 
anatomically-targeted delivery of a biologic that modifies the clot and the interstitial 
space. The ICH SPRG recommendations prioritized a MIS trial. This goal, coupled with 
newly available MISTIE II trial evidence demonstrating proof-of-concept and surgical 
standardization in humans now offers substantial promise for mitigating a clinically 
beneficial portion of the primary injury in ICH. MISTIE III provides a major opportunity 
to gain critically needed knowledge about volume reduction and extravascular t-PA and 
produce an evidence-guided treatment for ICH.8,22 
 
Remedying the Current State of Treatment: Prospective trial results will close the gap 
in treatment knowledge, define the benefit (or not) of MIS removal, and eventually assist 
with better decision-making. Until now, a Phase III trial, whose safety and feasibility are 
supported by animal data has not been undertaken.27-29 The proposed trial, carefully 
developed over seven years of NIH funding to test the reliability of removal and the 
viability of the inclusion criteria, including the 72 hour time frame, can provide needed 
clinical and disease strategy answers. Outcome evidence can inform level-of-care 
decision-making for the choice of intervention and or the intensity of treatment. From the 
technical standpoint, results could demonstrate how to perform an explicitly defined, 
readily available, surgical technique that utilizes widely-available technology (CT, triage 
systems, & image guidance). This knowledge would be sufficient for broad national 
dissemination. From a biologic perspective, if the MIS+t-PA treatment translates current 
animal findings from clot size reduction to tissue preservation as a fully-tested human 
therapy, then this knowledge will build the foundation for a pipeline of biologically 
plausible injury-mitigating intervention(s).22,30-33 And, rigorous data would greatly inform 
family decision-making based on individual preference in terms of both treatment options 
and long-term functional goals. Unique and reliable data from tools such as the Stroke 
Impact Scale34-37 will help families as they make decisions based on personal health 
priorities (i.e., ability to live at home with independence) and individual patient 
wishes.15,38   
 
Patient Population: Functionally independent (historical mRS of ≤ 1), male and female 
patients, who are age 18 to 80, with spontaneous, non-traumatic ICH with or without 
intraventricular hemorrhage (IVH), will be screened for enrollment. Radiographic 
imaging will be done to rule out underlying sources of bleeding other than hypertension. 
This specific group of patients will allow the investigators to determine if MIS+rt-PA can 
successfully reverse the brain-damaging effects of brain bleeding and return patients to 
functional baseline. 
 
Method of Dosing: Subjects randomized to surgical management will receive 1.0 mg of 
rt-PA through the intraclot catheter every eight hours for up to nine doses. MISTIE II 
demonstrated that this dosage and route of administration is safe and balances clot 
dissolution against the complications of infection and symptomatic bleeding. Because the 
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to or less than those in our previous IVH treatment safety study, which has an 8.3% rate 
of ventriculitis. MISTIE II further substantiated our choice of dosing every eight hours 
with a cerebral bacterial infection rate of 1%. 
 
Choice of Control:  The treatment group will be compared to the subjects receiving only 
conventional medical treatment. Subjects receiving MIS+rt-PA will be compared to an 
equal number of subjects randomized to receive conventional medical treatment.  No 
vehicle controlled, placebo treated patients are planned in this study. This decision was 
made not to expose medically treated patients to the additional risk of surgical insertion 
of catheter. The medically treated patients do allow for the comparison of the 
intervention-induced complications that is the overall goal of this study, thus medically 
treated patients are the best overall control.   
 
2.2 
Supporting Data 
 
Craniotomy for Superficial or Lobar Hematoma. STICH I was a negative trial where 
craniotomy was as safe as medical treatment and a small trend (2%-4%) mRS benefit 
favored surgery.39 Because superficial (≤1 cm below the cortical surface) lobar hematoma 
locations possibly benefited from craniotomy,20 STICH II tested the hypothesis that non-
stabilized superficial lobar hematomas can undergo craniotomy safely and that surgery 
will produce a 12% benefit of improved functional outcome. Other post-hoc analyses of 
STICH I subgroups demonstrated that the deep location had a bad prognosis in both 
medically and surgically treated subjects; deep location subjects experienced the worst 
overall prognosis.19,20 Additionally, there was no beneficial effect of early (<8 hr.; <24 
hr.) craniotomy observed.20 In fact, STICH demonstrated a trend that favored initiation of 
surgery after 24 hours compared to before 24 hours.23   
 
MISTIE III Design and STICH II Results. Based on the published results of STICH 
II101, the MISTIE III approach remains valid for lobar and deep hematomas. MISTIE III 
will continue to include the deep ICH location which opportunely is more common and 
has a stronger trend toward benefit. MISTIE III will test its innovative technique on 
hematomas at both locations where MISTIE II data has demonstrated benefit. STICH II, 
and MISTIE III when completed, will provide the missing human data to accept or reject 
clot removal in the overall strategy of tissue preservation and the care for the ICH 
subject.  
 
Minimally Invasive Surgery (MIS) Volume Reduction and Outcome. A meta-analysis 
of world-wide clinical trials of craniotomy demonstrates a benefit for surgery over 
supportive care.40 Importantly, a similar meta-analysis of MIS from China suggests an 
even stronger effect of the minimally invasive approach over a 72 hour time window.24 A 
deficiency of scientific data exists from these studies on adequacy of or variation in 
surgical task performance.30 The absence of data related to the surgical task, specifically 
extent of clot removed, limits the evaluation of a relation between outcome and volume 
removed.41 MISTIE II did measure volume removed and correlated good outcomes with 


 
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greater removal of clot, making a removal strategy practical, safe, and reasonably 
promising.  
 
Timing of Surgery (Other Trial Results and other Meta-Analysis Results). In the 
small number of trials with measures of volume reduction and functional outcomes, there 
is a remarkable consistency with the hypothesis that volume reduction is beneficial but 
not always technically optimal41-46 and that a broad 72 hour time window exists.24 Careful 
investigation suggests the stabilized subject in a non-emergent setting is the best 
candidate for removal. Neither ultra-early surgery (6hr)47 nor the combination of factor 
VIIa and ultra-early surgery (<8hr) seem promising. In primary reports, the trends are for 
harm in the initial 6-8 hours.23,47,48 Steiner’s analysis of time to surgery shows a trend of 
benefit for the 24-72 hour time frame in contrast to outcomes when surgery was 
performed in the initial 24 hours as these early craniotomies were associated with 
additional hematoma growth and poorer outcomes.48 Thus, safety analysis of the FAST 
data,48 the experience of Morganstern and Grotta47 point towards  the 24-72 hour time 
frame. STICH showed a similar trend with harm if craniotomy was performed in the 
initial 8 hours, no benefit for craniotomy performed in the initial 24 hours, and a trend 
towards benefit for craniotomy if performed in the 24 to 72 hour time frame.23 This is the 
time frame used in the proof-of-concept trials (3 MIS/1 Craniotomy) that have 
demonstrated benefit.24,49,50,52 The MISTIE II positive outcome data utilized this timing 
which indicates that surgery performed on average after 6 hours of stabilizing hematoma 
growth, at a median time of 35 hrs, is associated with decreased tissue injury and 
improved functional outcome. The randomized medical subjects have the same ICU stay 
but a different acute and chronic course, experiencing 20 mL more edema by day 4, and 
37 days greater care prior to return home, as well as fewer good mRS outcomes. The 
timing for surgery was tested in MISTIE II and represents the optimal window to both 
avoid hematoma growth and perform uncomplicated surgical removal.48 
 
Medical Therapy Trial Results (Medical Therapy to Stabilize the ICH). 
Epidemiologic and trial-based data confirm that 15%-30% of subjects experience 
hematoma growth in the first 3-6 hours and represent a group at higher risk for poor 
functional outcome and mortality. This is consistent with the idea that bigger hematomas 
produce unwanted outcomes.52 Unfortunately, neither ultra-early hemostasis (Factor 
VIIa)53 nor ultra-early neuro-protection54 led to improved outcome—in both cases the 
treated groups demonstrated small reductions in hematoma size compared to the 
untreated but these 1- to 4-mL differences were not associated with functional benefit. 
The FAST trial screening data suggest that 9% of all ICH subjects were in the ultra-early 
time frame and were candidates for “early stabilization.” These data nicely show that the 
influence of hematoma expansion is limited to a small segment of the ICH population and 
also demonstrates that hematoma expansion of 2-8 mL (11%-26% of baseline volume) 
does not improve functional or mortality outcomes when tested in trials of 600 subjects.53 
These findings are in harmony with the hypothesis that cessation of bleeding (i.e. 
stabilization) provides no meaningful clinical benefit when pursued as the sole 
management goal. Meta-analysis of a similar, larger population from the VISTA database 
suggests that the threshold of ICH volume change required to produce functional 


 
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alteration is larger than the change produced in these “ICH growth” trials (a basement of 
about 6 to 12 mL of clot size change).41,55 MISTIE III will produce a large volume 
change above this threshold. 
 
Other Medical Trials (Testing for Benefit from Early BP Reduction).  ATACH II and 
INTERACT are exploring the possible benefits of early stabilization and volume 
reduction via ultra-early control of blood pressure. Their post hoc analysis also finds a 
threshold of 6 mL of hematoma size change is needed to possibly alter mRS at 180 
days.41,56 MISTIE II produced early BP control (ED, 187/105; randomization, 145/72) in 
a manner similar to that of ATACH and INTERACT. If the ICH Guidelines are revised to 
include aggressive BP reduction based on the findings from INTERACT II, then its 
protocol will be incorporated into MISTIE III, to incorporate best practice. Stabilizing BP 
(and hematoma size) prior to enrollment will open treatment to a much larger set of ICH 
subjects, as more than 85% of subjects present after the ultra-early (<6 hr) time frame.53,57 
The MISTIE III protocol will skip the “ultra-early” time when MIS could interrupt the 
primary clotting process—plausibly based on the time needed for fibrin clot cross-linking 
providing fibrin chains stability and the formation of covalent links between fibrin and 
extracellular matrix proteins.58  
 


 
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Review of MISTIE II Data: The MISTIE II trial was a Phase II, two-stage trial of 96 
randomized subjects with the overall goal of assessing the practical feasibility of image-
guided, catheter placement and removal of clot from subjects with hypertensive ICH, as 
defined by absent vascular malformation and the presence of hypertension. Its goal was 
to provide proof that the same benefits that occurred in animals with rt-PA clot irrigation 
could be translated into humans. Results of MISTIE II hypotheses testing suggest 
successful translation of the technical aspects of removal and the putative benefit to 
humans. Specific information about the removal of clot from humans utilizing the 
MIS+rt-PA technique is summarized in Figure 1 as “Post Hoc Observations.”  
 
 
MISTIE II Trial Design: Stage 1 escalated the rt-PA dose (0.3 mg Q8hr, Tier 1 
increased to 1.0 mg Q8hr, Tier 2) to test for dose response and safety. When compared to 
controls, both doses increased clot removal with no difference in bleeding rate (7% vs. 
9%), leading to a decision to use the 1.0 mg dose. Tier 3 used the same precise image 
localization but a wider cannula and higher negative pressures (up to 300 mmHg) and is 
identified as the “ICES” Tier.63 We report on 123 subjects (117 MISTIE & medical; 6 
ICES, medical only).  
Figure 1.  MISTIE II trial goals and post hoc observations. In Stage 1, 40 subjects were randomized 1:3 over two tiers. In Stage 2, 50 subjects were enrolled 
1:1. Clot removal utilizing the MIS+rt-PA technique accomplished greater clot size reduction with improved outcome at 180 days as compared to the medical 
group. Recurrent bleeding, infection, and early mortality were low and similar in both groups.  
Hypothesis 1
Clot removal occurs with rt-PA and 
is dose dependent 
• Clot removal: 27 mL (surgical) 
vs. 7 mL (medical) 
• 0.3 mg & 1.0 mg Q8hr not 
different for clot removal 
Hypothesis 2
MIS+rt-PA is safe 
• Rebleeding is low and similar in 
both groups 
• Infection is similar in both 
groups 
• Early mortality is rare in both 
groups 
Hypothesis 3
MIS+rt-PA improves clot removal 
and functional outcomes 
compared to medical group 
• Clot removal: 30 mL (surgical) 
vs. 7 mL (medical) 
• mRS 0-3: 35% (surgical) vs. 
24% (medical) @180 days) 
• causal analysis - OR  3.03 for 
MIS+rt-PA associated good 
outcome, if <15ml residual clot 
and >60% clot reduction  
STAGE 1 
40 subjects 1:3 med:surg  
(2 tiers: 0.3 mg and 1.0 mg rt-PA in surgical group) 
STAGE 2 
50 subjects 1:1 med:surg  
(1.0 mg rt-PA in surgical group) 
• Mechanical removal is sufficient 
in approximately 15% of MIS 
patients (not requiring rt-PA 
dosing to achieve target clot 
reduction) 
POST HOC OBSERVATIONS 
• Accuracy of catheter placement 
relates to volume clot removed 
• 87% of surgeons mastered  
operative task in one pilot Not 
all surgeons can perform the 
procedure (4% failed) 
•  Medical + MIS subjects may 
require emergent craniotomy 
• 2% Post procedure mortality  
• Stage 2 surgical performance 
improved  
•
62% of clot removed on 
average 
•
Over 3 days, clot 
reduction from 47ml to 
18 mL (29ml removal) 
 
MISTIE II TRIAL SYNOPSIS
GOAL: > 80% ICH reduction or ICH reduction to 15 mL
RESULTS 


 
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Figure 2. Kaplan Meier plot of mortality for randomized MISTIE II subjects. No 
differences were noted for mortality at any time point. Withdrawal of care was 
proportionally similar in both groups, and occurred at similar time frames in each group
(Fischer’s Exact Chi Square; non-significant).  
 
MISTIE II Trial Safety: The MIS+rt-PA procedure was evaluated for safety by dose, 
trial stage and comparison to medically treated subjects as defined by the MISTIE 
protocol utilizing AHA ICH guidelines.64 All emergent and ICU care was rendered 
according to guideline for each subject independent of randomization status. Of note, the 
influence of the withdrawal of care occurred equally among randomized subjects 
(surgical, 13%; medical, 10%).15,65 
 
 
Mortality: Data on intention-to-treat (54 surgical, 42 medical, n= 96) and all subjects (27 
pilot, 96 randomized, n= 123) are 
provided. Including pilots, 81 
subjects underwent MIS+rt-PA. 
There were no intra-operative 
deaths. Seven-day mortality was 
chosen as the immediate post-
operative period; mortality was 
2% in the MISTIE II cohort, 
comparing favorably to the 7-day 
mortality in FAST (12%-14%). 
The two deaths were related to 
the severity of the primary 
bleeding event, with cause of 
death preoperative respiratory 
failure (case1) and pre-existing 
coronary artery disease leading to 
postoperative myocardial 
infarction (case2). Thirty-day mortality was 10% and 15% for the medical and surgical 
groups respectively. No differences were noted for mortality at any time point, for the 
intention-to-treat, or the total group (Fig. 2). Withdrawal of care was equal in each group 
(36% vs. 53%) as well as the withdrawal of care temporal profile.  
 
Specified Safety Measures: Post-operative bleeding and infection occurred at low 
frequencies and below the literature-defined thresholds.44,66 Two brain infections were 
observed: culture-negative ventriculitis, surgical subject and culture-negative meningitis, 
medical subject. Both resolved without consequence. Recurrent bleeding rate was 5% 
overall: surgical, 2.65% (CI 0.07, 13.5), medical, 6.2% (CI2.0, 13.8); pilot, 11%; 
randomized surgical, 3.7%; and randomized medical, 2.6%. It is difficult to attribute 
bleeding to the procedure or the drug; however, bleeding sites were frequently associated 
with the hematoma or catheter, preserving the need for caution of MIS+rt-PA as a trigger 
for increased likelihood of bleeding. MISTIE III will provide a better estimate of these 
rates. The overall rate of rebleeding (3.7%) compares well to the 10%-17% rate in other 
surgical and MIS trials.49,50,66 
 
 
Edema:  Edema is an early indicator of tissue injury26,30,31,67 and is measured more easily 
in humans than cell death and ischemia.68 In MISTIE II, the protocol prospectively tested 


 
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the idea that clot reduction would lead to edema reduction as is observed in animals30,69,70 
and preliminary data.68 Analysis of perihematomal  regions of MISTIE II surgical 
subjects, utilizing a validated method,71 shows a reduction of 22 ml of edema when 
compared to medical subjects in the same time frame ( % reduction of 22+35 % surgical 
vs. increase of 47+46% medical). This finding is consistent with the reduction of toxic 
metabolic injury seen in animal models30,72 and inconsistent with a small number of prior 
“convenience samples” and clinical reports demonstrating an increase in edema after 
exposure to rt-PA.73 The Phase III will confirm the consistency of benefit across a broad 
population, the degree to which hematoma and edema reduction relates to improved 
functional performance, and the possible cellular basis of a beneficial effect.  
 
 
Functional Outcome Benefit: ICH recovery requires more time than recovery from 
ischemic stroke, with stable clinical 
and functional performance occurring 
at 180 to 365 days.6,45,74 Surgical 
subjects achieved good functional 
outcomes more frequently than 
medical subjects, despite having a 
slightly worse initial ICH volume 
severity (34 mL vs. 43 mL), GCS 
score (12 vs. 11), and IVH size (2 mL 
vs. 4 mL). At 180 days, 35% of 
surgical subjects had reached mRS 0-
3 compared to 24% in the medical 
group. When analyses were adjusted 
for initial severity imbalance, the 
effect increases. MISTIE II was 
amended to following the mRS 4, 5 
subjects through 365 days. The differential benefit for the mRS 0-3 state increases to 
14% and a significant proportion of mRS 0,1 and 2 states are observed in the surgical 
group where the difference between surgery and medical is also 14% (Fig. 3). Thus, an 
improvement across all levels of mRS appears to be associated with the MIS+rt-PA 
group and is consistent over time, with an important proportion reaching high degrees of 
independence. MISTIE III will confirm the reproducibility, size and generalizability of 
the benefit previously observed in the MISTIE II proof-of-concept trial. Subgroup 
analysis suggests no effect of location (deep vs. lobar), size, time to surgery or age (Fig. 
4).  
 


 
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Figure 4. Multivariable analysis of severity factors. Analysis of factors other than catheter location 
within the clot in Stage 1 did not identify any other significant factors that could account for 
variation. This resulted in the simplification of instructions for the surgical task in Stage 2 regarding 
optimal catheter placement. 
Figure 5. Correlation of Clot MIS+rt-PA catheter placement accuracy. Accuracy was 
the only factor related to extent of clot removal. 
i
f
S
180
36
f
&
Surgical Performance and 
Functional Benefit: A 
range of clot size 
reductions occurred in the 
surgical group. Several 
reasons exist for this 
finding. Despite having set 
the goal of >80% clot 
reduction from the animal 
studies to the MISTIE II 
subjects, this goal was not 
well achieved at the 
MISTIE II sites in Stage 1. 
Initial evaluation of factors 
associated with clot size 
reduction suggests that the 
precision of the catheter 
location within the clot accounts for at least half of the variation (Fig. 5). Multivariate 
analysis of other factors, such as clot location, coagulation state, and age of the clot, did 
not identify a second critical factor; thus the instructions were simplified for the surgical 
task in Stage 2 and each site-
surgeon was encouraged to replace 
catheters, if the initial placement 
was not optimal. Stage 2 results 
confirm the idea that a catheter 
more completely in contact with 
the clot will remove more blood 
(see Fig. 5 & Table 3). Prior to 
MISTIE II, no data existed 
describing the optimal amount of 
blood to remove or when to stop 
removing it. In 2004 the “a priori” 
goals of 80% clot size reduction 
and /or decrease clot size to < 15ml 
to rectify the deficiency in surgical 
goals were selected. For this reason the MISTIE subjects are now evaluated with respect 
to the percent and absolute amount of blood clot removed (see Fig. 6). The odds ratio for 
a good result is enhanced (OR 3.04; CI 1.22, 8.03) if the MIS+rt-PA procedure removes 
more than 60% of the clot and produces end-of-treatment clot volume of 15 mL or less. 
Importantly, a causal analysis does not link the good outcomes in this “higher 
performance” surgical group to unequal (i.e., overly favorable) distribution of factors 
such as medical co-morbidities, age initial severity factors or clot properties.  
 
 
 


 
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Figure 6. Relationship between percent clot size reduction with MIS+rt-PA vs. end of treatment clot 
volume demonstrates how change in clot size increases the likelihood of good outcomes. Medical 
subjects show minimal clot size reduction. A range of larger and smaller reductions is demonstrated for 
MIS+rt-PA subjects. Large percentage of clot reduction > 60% and end of treatment clot size < 15 mL (|)
was associated with increased likelihood of mRS 0-3 (OR: 3.04). 
 
 
 
 
 
 
 
Multivariate Model of Outcome: When well-established severity factors (ICH size, IVH 
size, presenting GCS, NIHSS) are considered, a multivariate model of outcome (mRS. 0-
3 vs. 4-6), removal of clot is the third important factor in association with good outcome. 
Removal of clot has an OR of 0.27; (CI 0.066 to 1.07, p< 0.062), consistent with animal 
models as well as the 
primary hypothesis that 
removal of clot is 
beneficial. The factors 
that produce variability 
have now been 
adequately identified and 
this phase III trial is 
appropriately powered to 
definitively test for the 
benefits of MIS+t-PA and 
for the surgical 
importance of the clot 
volume reduction 
hypothesis. 
 
Patient Utility: Besides 
mRS, the Barthel Index 
and Stroke Impact Scale 
(SIS) provide additional 
insights to post-stroke recovery. These include physical recovery, such as strength, hand 
function, ADL, mobility, emotion, communication, memory, thinking and social 
participation (all on a scale of 0 to 100 with a higher score indicating better recovery). 
MIS+rt-PA appears to improve physical ability compared to the standard treatment at 180 
days. This is supported by SIS strength (mean difference = 11.8, SD = 7.6, p-value = 
0.122) and mobility (mean difference = 10.3, SD = 8.8, p-value = 0.244) scales as well as 
by higher proportion of patients with independence in toilet use, sphincter control and 
mobility on Barthel scale in MIS+rt-PA group. Importantly, the observed mean 
differences are within the range of change regarded as clinically important.75 Further, the 
memory score is also markedly higher in the MIS+rt-PA arm by 180 days post stroke 
Table 1. Factors effecting functional outcome (n=90). 
 
Univariate Analysis 
Multivariate Analysis 
 
Odds Ratio (p-value) 
ICH Severity Parameters 
 
Model 1 
Model 2 
Age 
0.96 (0.029) 
0.92 (0.004) 
0.91 (0.002) 
Stability ICH per 10 mL 
0.65 (0.008) 
0.85 (0.342) 
0.95 (0.755) 
Enrollment Total GCS Score 
1.57 (< 0.001) 
1.73 (< 0.001) 
1.77 (< 0.001) 
Surgical vs. Medically managed 
1.71 (0.266) 
2.73 (0.121) 
NA 
<15 mL remaining after treatment 
2.65 (0.068) 
NA 
3.82 (0.056) 
n= 
90 
90 
90 


 
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(mean difference = 8.8, SD = 8.3, p-value = 0.291). Although statistical significance was 
not achieved in these data, due to (suspected) small sample size in the standard treatment 
arm, the results suggest that MIS+rt-PA leads not just to better physical status, but also 
potentially to better quality of life (QOL) based on these measures. The MISTIE II data 
show that although the recovery of physical function and activities of daily living at 30 
days is slow, other functions, such as emotion, memory and communication, respond to 
treatment earlier in the cohort. The average difference in SIS emotion and SIS-16 total 
score is 40.3, SD = 27.8, and the average emotion score at 30 days is 62.3, SD = 22.4. 
Social participation is most affected by altered physical function and has the lowest 
average score at 30 days. As expected, it increases in parallel to improvement in physical 
function at 180 days post stroke. 
 
MISTIE III Innovation (Surgical Task and Trial Execution): Surgical centers with 
written feedback about each surgeon’s task performance has produced uniform results in 
oncologic trials.76-78 The outcomes of clinical trials testing surgical and skill-dependent 
therapies may be confounded by technical variations in the procedure and the skills and 
experience of the practitioner.79 This could have happened in MISTE II, but did not. Both 
potential standardization problems were successfully addressed using innovative surgical 
center adjudication processes in MISTIE II. Until this NINDS trial, catheter location 
within the ICH had not been clearly demonstrated to play a critical role in the outcome of 
minimally invasive evacuations of ICH, nor had it been emphasized in previous 
publications on the safety and purported effectiveness of these techniques.43 Not only did 
MISTIE II optimize the dose of thrombolytic, it defined, standardized and replicated the 
best surgical technique and catheter location strategies for optimal execution of the 
“MIS” surgical task. The process of standard surgical task description led rationally to the 
description of three specific trajectories with respective skull entry points for clots in 
three main brain locations. The sequential refinement of the surgical protocol resulted in 
enhanced clot evacuation and improved surgical outcome (See Table 1). Thirty-one 
surgeons used this technique without performance difference related to experience or 
frequency of performance. The surgery was standardized and applied in a coordinated 
manner following a brief, targeted training and achieved a uniform post-operative result. 
This is unique in its efficiency and innovative in its use of virtual teams. This program 
will again be utilized with well-defined MIS technical standardizations for the expanded 
group of sites needed for the trial. These tested and proven tools (87% proficiency 
following one pilot) will be deployed by the virtual Surgical Center to instruct new sites 
to maintain the same quality across the study period. If successful for 500 subjects and 90 
sites, the investigators will have the road map for disseminating the protocol through 
leading clinical and research bodies, such as the AANS joint section on vascular 
neurosurgery and NINDS.80  
 
What is the MISTIE Task & Can It Be Translated to Routine Practice? The MIS 
technique and its related image-guided catheter placement are universally practiced in 
treatment of tumors, functional disorders, aneurysms and hydrocephalus; techniques for 
each of these applications are performed in neurosurgical programs daily. The access to 
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Figure 7. Individual surgeon performance (n=57 subjects). These box plots define the median            
25th, 75th percentiles of pre-surgical and end-of-treatment clot volume. All surgeons were able to 
accomplish reduction from > 40 mL to < 20 mL. 
and catheter-based clot removal is a simple procedure and simpler than other MIS 
procedures using laparoscopic devices, robots, electrode sensors and/or remote-controlled 
manipulation of instruments. The investigators now have a 10-year clinical trial history of 
placing catheters for the delivery of rt-PA in a standardized manner. The obvious benefits 
of less operative trauma for the patient, less expense, shortened healing time, less pain 
and scarring, and less time in the operating room (OR) are universally attractive to 
patients, physicians and hospitals. Kojita has compared craniotomy (175 min) to MIS (45 
min) and confirmed the simplicity of this procedure. In MISTIE II, the surgery total time 
was 56 minutes (± 31 min) with a median time of 48 min; the 1st and 2nd stage medians 
were 51 and 44 minutes respectively. To be broadly adopted, “directive evidence” needs 
to exist, thus the safety and effectiveness of the procedure must be demonstrated with a 
randomized controlled trials (RCT). The simplicity of MIS creates the opportunity for 
such a trial and subsequent broad adoption. 
 
Surgical Center: The trial’s Surgical Center is the critically important trial management 
innovation our team perfected in the MISTIE II and CLEAR III trials. Innovations critical 
to standardization, not 
previously utilized in 
surgical trials such as 
STICH, include: 1. 
training modules for 
credentialing surgical 
investigators; 2. 
quarterly “Surgical 
Matters that Matter” 
updates based on 
emerging experience 
from ongoing cases; 3. 
collegial surgical 
review, telementoring, 
and telemonitoring of 
cases at screening and 
enrollment, as needed, 
including  operative 
planning with 
dialogues on burr hole 
location and catheter placement trajectory; 4. uniform external review of surgical 
performance for each enrolled subject and feed-back about protocol deviations; and 5. 
ongoing reviews of  adverse events vs. surgical morbidity, and protocol optimization. 
Written reporting and review have led to uniform surgical results in oncologic surgical 
trials.76-78 The novel structure of real-time, web-based quality assurance has not, to the 
knowledge of the investigators, been used in any neurologic/neurosurgical trial prior to 
CLEAR III and MISTIE II; it has been very effective in establishing the innovative and 
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of-treatment volumes. The use of a virtual surgical center has been highly productive and 
successful. 
 
Volume Reduction & Catheter Trajectory Efficacy: A wide range of clot size reductions 
occurred in the Stage 1 surgical group despite the goal of >80% clot reduction. Initial 
evaluation suggested that precision of catheter location within the clot accounts for at 
least half of the variation. Utilizing univariate and multivariable regression no other 
significant critical factors such as clot location, coagulation state, and age of the clot 
could be identified; thus, the instructions for targeting the clot were simplified and 
surgeons were encouraged to replace catheters if the initial anatomic placement was not 
optimal. Stage 2 results confirm that catheters more completely in contact with clots will 
remove more blood (see Fig. 5). In addition to accurately engaging the clot, trajectory 
analysis by the principal surgical investigator and the central image center determined 
that all Stage 1 catheters could have been advanced by one of three approaches. The 
DSMB approved the trajectory design change and three specific trajectories were added 
to the surgical task description and used in Stage 2 with improved results. Data 
demonstrates improved removal; with an average of 29 +15 mL absolute volume of blood 
removed representing 63% reduction in clot size (Table 3). The proportion of subjects 
experiencing reduction to 15 mL or less also increased from 39 to 48%. This explicit task 
description, which is now validated against the surgical goal, has led to a standardized 
surgical intervention. All elements of surgical technical performance improved in Stage 
2, including: operative duration, operative efficiency of catheter trajectory, clot targeting, 
percentage of subjects achieving >60% removal, and percentage of patients achieving 
clot reduction to 15 mL or less.  
 
Table 3: Surgical Performance Results for Stage I and II MISTIE Subjects. Simplifying the definition of the 
surgical task after Stage I improved the percent of subjects achieving 60% removal and end of treatment 
volume < 15 mL. 
 
 
Baseline Vol 
Vol 
Removed 
Removed
% 
EOT Vol 
pts EOT
< 15 (%) 
pts with
> 60% 
Removal 
(%) 
Medical 
n= 42 
Stage 1  
43 ± 16  
4 ± 3  
9
39 ± 15  
0  
0  
Stage 2  
43 ± 15  
2 ± 9  
3
41 ± 17  
1(3%)  
1(3%)  
Surgical 
n= 53 
Stage 1  
49 ± 23  
26 ± 19  
51
22 ± 12  
11(39%)  
10(36%)  
Stage 2  
47± 16  
29 ± 15  
63
18 ± 14  
12(48%)  
18(72%)  
*All volumes mean ± SD(mL), Pts=Patients, Vol=Volume, EOT=End of Treatment 
 
Reproducibility of Surgical Results: Improved catheter localization after completion of 
Stage 1 was a function of explicit trajectory planning. Specifically, sequence and number 
of procedures conferred no clot removal performance advantage. Analysis of sequential 
performance showed neither ongoing improvement nor a threshold of multiple subjects 
operated on before adequate clot removal. The MISTIE II data support the assumption 
that, via this proof-of-concept trial the investigators have: 1) adequately defined the 
surgical task; 2) identified routine variations in standard surgical practice (across sites 
and operations) that might limit the effectiveness of surgery; 3) trained the trial surgeons 
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identified stopping rules for the surgical goal associated with the primary hypothesis of 
safe clot size reduction. No adverse events associated with these surgical goals have been 
observed. MISTIE III will provide robust data to test supporting or rejecting these 
surgical procedures, their associated goals, and the adequacy of simple surgical training.  
 
3 
STUDY DESIGN 
 
This study is a phase III, randomized, open-label, multicenter evaluation of MIS and ICH 
lysis with rt-PA versus medical care. The study (n=500) will evaluate the efficacy and 
safety of MIS plus 1 mg of rt-PA administered every eight hours for up to nine doses as 
compared to subjects treated with conventional medical management. Outcome 
assessment will be performed by local certified investigators and adjudicated by central 
blinded investigators.  
 
 
Subjects enrolling in this study may also consent to participate in an ancillary study titled 
Mechanisms of Tissue Injury in MISTIE III. This ancillary study offers a tremendous 
opportunity to leverage clinical trial data to bring novel insights from ICH 
pathophysiology into the clinical realm, using neuroimaging, genetic and inflammatory 
markers of disease to provide clinicians with powerful new tools to guide surgical 
therapy and develop new therapeutic targets. See Appendix 8 for the ancillary study 
protocol. 
 
 
ICH 
BP control 
MRI/MRA or CTA to rule 
out underlying pathology 
CT to Demonstrate ICH 
Stability & acquire images 
for Surgical Planning and 
Image Guidance
Consent & Randomize 
Surgical Management: 
Initiate surgery and give 
1.0 mg rt-PA Q8hr for up to 
9 doses
6+ hrs 
MISTIE III 
Dosing 
Day:   1 
2 
3 
4 
5 
6 
7 
30 
90 
180 270 
365 
= CT scan 
= MRI 
= Dose 
Diag 
Stability 
Randomization 
MIS 
Surgery 
Post-Surgery 
24hr post-
removal
Follow-up 
*green indicates surgical patients only 


 
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4 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Spontaneous supratentorial ICH ≥ 30 mL measured by the site utilizing ABC/2 
method using radiographic imaging (CT, CTA, etc.), with a GCS ≤ 14 or a NIHSS 
≥ 6. 
4.1.2 Stability CT scan done at least 6 hours after diagnostic CT showing clot stability 
(growth < 5 mL as measured by ABC/2 method).  
If the clot volume measured on this stability CT scan increases by 5 mL or 
more, a second stability determination is allowed by repeat CT scan at least 12 
hours later. Additional scans are permitted as needed every 12 hours to continue 
to monitor for stability up until the eligibility time window closes. Subsequent 
clot retraction remains inclusionary as long as the ICH clot size remains ≥ 25 mL. 
 
4.1.3 Symptoms less than 24 hours prior to diagnostic CT (dCT) scan. An unknown 
time of onset is exclusionary. Use the time the patient was last known to be well 
for patients that awaken from sleep with symptoms. 
 
4.1.4 Ability to randomize between 12 and 72 hours after dCT.  
 
4.1.5 SBP < 180 mmHg sustained for six hours recorded closest to the time of 
randomization.  
 
4.1.6 Historical Rankin score of 0 or 1. 
 
4.1.7 Age ≥ 18 and older. 
 
4.2 
Exclusion Criteria 
 
4.2.1 Infratentorial hemorrhage.  
 
4.2.2 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. 
 
4.2.3 Patients with unstable mass or evolving intracranial compartment syndrome. 
 
4.2.4 Irreversible impaired brain stem function (bilateral fixed, dilated pupils and 
extensor motor posturing), GCS ≤ 4. 
 


 
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4.2.5 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.  
 
4.2.6 Intraventricular hemorrhage requiring treatment for IVH-related (casting) mass 
effect or shift due to trapped ventricle. EVD to treat ICP is allowed. 
 
4.2.7 Platelet count < 100,000; INR > 1.4.  
 
4.2.8 Any irreversible coagulopathy or known clotting disorder.  
 
4.2.9 Inability to sustain INR ≤ 1.4 using short- and long-acting procoagulants (such as 
but not limited to NovoSeven, FFP, and/or vitamin K).  
   
4.2.10 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.  
 
4.2.11 Use of Dabigatran, Apixaban, and/or Rivaroxaban (or a similar medication from 
the similar medication class) prior to symptom onset. 
 
4.2.12 Internal bleeding involving retroperitoneal, gastrointestinal, or genitourinary site 
or respiratory tract bleeding.  
 
4.2.13 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. 
 
4.2.14 Positive urine or serum pregnancy test in pre-menopausal female subjects without 
a documented history of surgical sterilization. 
 
4.2.15 Allergy/sensitivity to rt-PA.  
 
4.2.16 Prior enrollment in the study. 
 
4.2.17 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. 
 
4.2.18 Not expected to survive to the day 365 visit due to co-morbidities, or are 
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4.2.19 Any concurrent serious illness that would interfere with the outcome assessments 
including hepatic, renal, gastroenterologic, respiratory, cardiovascular, 
endocrinologic, immunologic, and hematologic disease. 
 
4.2.20 Patients with a mechanical heart valve. Presence of bio-prosthetic valve(s) is 
permitted. 
 
4.2.21 Known risk for embolization, including history of left heart thrombus, mitral 
stenosis with atrial fibrillation, acute pericarditis, or subacute bacterial 
endocarditis. Atrial fibrillation without mitral stenosis is permitted. 
 
4.2.22 Any other condition that the investigator believes would pose a significant hazard 
to the subject if the investigational therapy were initiated. 
   
4.2.23 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.24 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. 
 
4.2.25 Inability or unwillingness of subject or legal guardian/representative to give 
written informed consent. 
 
4.3 
Study Enrollment Procedures 
 
4.3.1 Screening Procedures 
 
1. Diagnostic CT (dCT) scan. This scan is defined as the first CT scan performed 
that is used to diagnose the ICH. At each study center ICH volume will be 
determined in the following manner: On the CT slice with the largest area of ICH, 
the largest diameter (A) of the hematoma will be measured in centimeters. The 
dimension of the hemorrhage perpendicular to the largest diameter will represent 
the second diameter (B) in centimeters. The height of the hematoma will be 
calculated by multiplying the number of slices involved by the slice thickness, 
providing the third diameter (C). The three diameters will be multiplied and then 
divided by two (AxBxC/2) to obtain the volume of ICH in cubic centimeters. 
 
2. Stability CT scan. This scan will be done at least six hours after the dCT scan 
to determine clot stability. The clot volume measured using the technique 
described above must not increase from the volume measured on the dCT scan by 
5 mL or more. Fiduciary markers should be placed at the time of this scan if the 
patient appears to be eligible (or suitable anatomic landmarks noted). Fiducials 
should remain in place until after the post catheter insertion CT scan for those 
subjects randomized to surgical management.  


 
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If the clot volume measured on the first stability CT scan (at least 6 hours 
after initial/diagnostic scan) increases by 5 mL or more, a second stability 
determination is allowed by repeat CT scan at least 12 hours after the previous 
stability scan. Additional CT scans are permitted as needed at least every 12 hours 
to continue to monitor for stability up until the eligibility time window closes. 
 
3. Imaging to rule out underlying pathology. A CTA will be done prior to 
randomization, preferably at the time of the stability CT scan, to rule out 
underlying cerebro-vascular or brain pathology. If a CTA is contraindicated due 
to renal impairment, an MRA will be done at this time instead. In addition, an 
MRI will be done at baseline and repeated on day 7-10 (± 1 day) to assess edema 
and cerebral ischemia and contain the following sequences: T1, MPRAGE, DWI, 
AXIAL FLAIR, AXIAL SWI, PWI, Axial T1 POST, and DTI. In cases where 
SWI of sufficient quality cannot be adequately obtained, T2W GRE may be 
substituted. B0 and ADC Maps should be uploaded along with the DWI B-100 
images. Obtaining the baseline MRI prior to first dose of rt-PA is preferred, or 
obtain any time on days 1-3 per scanner availability. The requirement to obtain 
either MRI is waived for study centers located in Spain. 
 
CT angiogram or routine angiogram with evaluation for “spot sign” is encouraged 
and considered standard of care to complete the evaluation for aneurysm, AVM, 
or other malformations if the CTA or MRA are inconclusive. 
 
4. Blood pressure. Blood pressure stability is defined as SBP < 180 mmHg 
sustained over six hours prior to randomization.  
 
5. NIHSS. A NIHSS score must be obtained and must be > 6 (or a GCS of ≤ 14) 
for the patient to be eligible (using distal motor function). The NIHSS must be 
done by a certified examiner. The NIHSS must be done at the time of enrollment 
to confirm eligibility. 
 
4.3.2 Tracking Procedure.  All study center investigators and study coordinators must 
have an established relationship with their emergency department personnel and 
must be routinely notified of hemorrhagic and ischemic strokes. Each center will 
design a system for patient tracking that best suits its needs according to time, 
personnel, and the patient population. The study coordinator will be responsible 
for tracking subjects and scheduling appointments. The study coordinator will 
inform subjects of the follow-up expectations when informed consent is obtained, 
and will maintain contact through telephone calls and letters. The Clinical 
Coordinating Center (CCC) database will drive a monthly report and centers will 
receive emails listing subjects due for assessment and overdue for assessments. 
The study coordinator will be required to document in the VISION EDC system 
whenever subjects are lost to follow-up or assessments are overdue. A subject is 
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Attempts to find and establish contact with a subject must be made at every 
follow-up time-point, even if unsuccessful at an earlier time-point. A subject lost 
to follow-up will not be tolerated; in such case the site investigator will be placed 
on a remediation plan to improve subject tracking. 
 
4.3.3  Facilities. To be eligible as a site, a center must demonstrate uniform referral, 
triage, and medical management practices. Each center must have emergency 
stroke transport services, stroke triage screening, a full time neurovascular 
neurosurgeon, and a full-time stroke research coordinator dedicated to this trial. 
To assure standardization of technical capabilities, the study chairman and 
appropriate CCC administrators will review each site’s triage capabilities, 
emergency department facilities, pharmacies, imaging resources, and neurological 
ICUs. The Executive Committee (EC) along with approval from NINDS is 
ultimately responsible for the selection of the sites and investigators. In addition 
to these site criteria evaluated by the CCC, each site must designate a Surgical co-
PI or Lead Surgeon, with an additional surgeon designated as a back-up, who will 
oversee all MISTIE cases, act as a liaison with the trial leadership on surgical 
matters, and who will help coordinator the credentialing of site surgeons who will 
perform the MIS procedure. MISTIE qualified surgeons at each site must be 
identified and individually credentialed by the trial’s Surgical Center. This 
includes the demonstration of previous experience with the MIS procedure, 
current active surgical privileges in stereotactic neurosurgery, and the successful 
completion of a mandatory Surgical Center initiation conference on surgical 
protocol and procedure. 
 
4.3.4 Documentation for ineligibility. Monthly reports of subject accrual (enrolled and 
screened but not enrolled) and other protocol compliance data will be provided by 
the CCC. All patients with ICH, whether eligible or not, who have been screened 
by study personnel at participating hospitals will be documented in the VISION 
EDC system. All reasons for exclusion for each patient not entered into the trial 
will be recorded. Each participating hospital will enter screening data into the 
VISION EDC system daily for review of screening and eligibility performance. 
Once all fields are completed, or an inclusion/exclusion criterion is failed, the 
system will either document the subject as a screen failure or prompt the 
coordinator to randomize the eligible subject.   
 
Study centers failing to enroll over 5-7 months will undergo remediation 
with possible termination. Study centers in this situation may appeal to the CCC. 
If the study center can present a strong case for extenuating circumstances, then 
the site will remain in the trial for up to 9 months. At 9 months, study centers will 
be placed on probation with a final opportunity to enroll or be closed at 12 
months. 
 
4.3.5 Informed consent. The informed consent document will be used to explain the 
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before the patient is entered into the study.  The informed consent document must 
contain a statement that the consent is freely given, that the patient/authorized 
representative is aware of the risks and benefits of entering the study and the 
patient is free to withdraw from the study at any time.  A sample informed 
consent form for all sites is included in Appendix 1 with an additional HIPAA 
template for international enrolling centers in Appendix 2. 
 
The Investigator or designee is responsible for obtaining informed consent 
from each patient or their authorized representative and for obtaining the 
appropriate signatures and dates on the informed consent document prior to the 
performance of any protocol procedures and prior to the administration of study 
drug.  Informed consent by an authorized representative of the patient should be 
obtained according to the clinical judgment of the investigator. 
 
4.3.6 Randomization. Patients who meet all of the inclusion and exclusion criteria 
using the above screening procedures and who provide consent will be 
randomized to conventional medical management or surgery (MIS+rt-PA).   
 
For those subjects randomized to surgery (MIS+rt-PA), the operative procedure 
should occur as close as possible to the time of randomization. If the surgical 
procedure is postponed to accommodate scheduling (i.e., it is preferable to wait 
until 6 am instead of midnight), obtain a CT scan to re-confirm stability of the 
ICH and re-confirm blood pressure stability prior to beginning the surgical 
procedure. If either or both are unstable, refer to page 23, Stability CT scan for 
clot stability and page 27, Cardiovascular management for BP stability.  
 
The first dose of study drug is administered six or more hours after the surgical 
procedure and only after surgical center review. 
 
5 
STUDY INTERVENTIONS 
 
5.1 
Interventions, Administration, and Duration 
 
All subjects will be followed daily for six days post randomization. All subjects will have 
an MRI (unless contraindicated) performed once at day 7-10 (± 1 day) or hospital 
discharge, whichever occurs first, to compare with the baseline MRI (if done) to measure 
edema. The requirement to obtain MRI is waived for study centers located in Spain. See 
section 4.3.1 Screening procedures, item 3 above for specific sequences. 
 
All subjects will be required to return for a follow-up clinic visit at days 30 (± 7 days), 
180 (± 14 days), and 365 (± 14 days). A telephone follow-up will be done at days 90 (± 7 
days) and 270 (± 14 days).  
 
5.1.1 Medical Management: All Subjects. Subjects in both groups, medical 
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ICU protocols (Appendix 3). This includes but is not limited to the following 
guidelines: 
 
1. Intracranial pressure (ICP) management. Placement of an ICP monitor is 
recommended for subjects demonstrating obtundation, which we define as GCS ≤ 
8 on a minimum of two observations over eight hours. ICP monitoring device 
selection is the discretion of the treating surgeon; however, the Camino 
parenchymal catheter has been pre-specified as the device of choice for the trial. 
The non-emergent ICP monitor would ideally be placed prior to rt-PA 
administrations or at least six hours after dosing. A new CT scan must be obtained 
after ICP monitor placement to assess stability of the current hemorrhage and to 
monitor for any new bleeding. If ICP is monitored, nursing assessments and ICP 
monitoring will be performed on a Q4hr basis, as will routine zeroing and 
recalibration of the system. The goals of ICP management are to sustain 
intracranial pressure below 20 mmHg and to improve the patient’s level of 
consciousness. 
 
2. Neurological status will be assessed Q4hr using GCS scoring. A neurological 
deterioration (neuroworsening) will be defined as any GCS decrease of greater 
than two points on the motor scale sustained for eight hours without sedation and 
is required to be reported as an AE/SAE. Daily attempts to discontinue sedation 
will be made. A daily neurologic exam is recommended to be coordinated with 
this attempted sedation withdrawal.  
 
3. Cardiovascular management. The patient’s blood pressure must be stable to be 
eligible for randomization. Blood pressure stability is defined as SBP < 180 
mmHg for a period of six hours. This six-hour period must be maintained and 
documented as close to but prior to randomization as possible. Blood pressure 
management should conform to current AHA guidelines to maintain SBP < 180 
mmHg throughout the first 6 days of the ICU stay to reduce the risk of bleeding 
events. The systolic and diastolic pressures over the six-hour monitoring period 
should be documented in the medical record as source documentation. 
 
Current AHA Guidelines (Morgenstern 2010): 
1. If SBP is >200 mm Hg or MAP is >150 mmHg, then consider aggressive 
reduction of BP with continuous intravenous infusion, with frequent BP 
monitoring every 5 min. 
2. If SBP is >180 mm Hg or MAP is >130 mmHg and there is the possibility of 
elevated ICP, then consider monitoring ICP and reducing BP using intermittent 
or continuous intravenous medications while maintaining a cerebral perfusion 
pressure ≥60 mmHg. 
3. If SBP is >180 mmHg or MAP is >130 mmHg and there is no evidence of 
elevated ICP, then consider a modest reduction of BP (eg, MAP of 110 mmHg 
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medications to control BP and clinically reexamine the patient every 15 min. 
 
4. Respiratory care will be directed at promoting adequate oxygenation without 
airway compromise, with full pulmonary inflation, and with oxygenation > 90% 
on room air or supplemental O2 by face mask of 28% or less.  
 
5. Nutritional support will consist of optimal calories, defined as > 30 kcal/kg and 
1.5 gm protein/kg. Feeding will be achieved by the least invasive means 
necessary, but with the goal of reaching full nutritional support by no later than 
day 7 of illness.  
 
6. Deep venous thrombophlebitis and pulmonary embolus prophylaxis will be 
undertaken on the day of admission with the use of sequential compression 
devices (SCDs). For patients at high risk of thromboembolism, study center 
standard of care policies may govern the use of low molecular weight, 
fractionated and unfractionated heparins for DVT prophylaxis during the acute 
treatment and follow-up periods (criteria established by the American Orthopedic 
Association).  
 
7. Withdrawal of care discussions of prognosis and decisions to continue or limit, 
or to withdraw, life-sustaining interventions will be conducted according to each 
institution’s policies for end-of-life decision-making, as well as their institutional 
codes of medical ethics. The study assumes any such discussion will reflect the 
patient’s wishes and the known facts regarding prognosis. Where the PI is not the 
managing physician it is assumed that those individuals will confer prior to 
presentation of the consensus prognosis and planned course of treatment. In some 
situations, the investigator may choose to select a colleague to serve in the 
clinician role or request a review by the hospital’s ethics committee or other 
knowledgeable expert.  
 
5.1.2  Experimental Intervention: MISTIE-Surgery. A neurosurgeon credentialed by 
the Surgical Center will perform the procedure. Credentialing shall include 
successful participation in MISTIE II or the review of at least one case of a 
MISTIE-type intervention by the surgeon outside of the trial, verification of 
hospital privileges in stereotactic and image-guided procedures, and 
documentation of viewing a surgical standardization presentation of the MIS 
procedure to insert the catheter is mandatory before credentialing a center’s 
neurosurgery personnel. A PowerPoint presentation has been produced describing 
the catheter placement procedure and apparatus, sterile field techniques and the 
exact process for aspirating the clot. The presentation is available on the trial 
website (www.braininjuryoutcomes.com). It will be used continuously to train 
and retrain personnel performing the surgery to assure the standardization of 
surgical procedure.  This presentation will be edited as new safety data are 
developed. Each site will maintain a log of eligible surgeon(s) along with the date 
and time of viewing. Each credentialed surgeon must also complete a mandatory 


 
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Surgical Center teleconference to review the surgical protocol and technical 
aspects of the procedure. 
 
Optimal trajectory determination: The neurosurgeon will review a 3D 
reconstruction of the ICH on the CT scan to determine the burr hole location, 
catheter trajectory, and hematoma target to be used during the operative 
procedure. The neurosurgeon will select the representative slices reviewed for 
trajectory determination and the coordinator will submit the full set of DICOM 
(digital imaging and communications in medicine) images for review. The images 
will be uploaded to the EDC system, the surgical review form will be completed 
by the neurosurgeon or coordinator in the EDC system and both will be reviewed 
by the Surgical Center. Burr hole location, trajectory determination, and target 
will be coded as A, B, or C.  
 
Option A is used for a deep-seated ICH occupying the anterior third of the 
basal ganglia with a typical “oval” shape (American football shape). A type A 
ICH should have an entry point in the low anterior frontal area frequently close to 
the midline near the eyebrow, and the trajectory of the catheter must be along the 
longitudinal axis of the clot.  
 
Option B is used for a deep-seated ICH occupying the posterior third of 
the basal ganglia with a more roundish to elliptical shape. A type B ICH should 
have an entry point in the posterior parietal-occipital area, almost always several 
centimeters lateral from the midline to avoid the occipital ventricular horn, and 
the trajectory of the catheter has to be along the longitudinal axis of the clot.  
 
Option C is used for superficial (lobar) ICH with variable shape, but is 
often more spherical. A type C ICH should have an entry point at the superficial 
area closest to the clot. This is a skull entry point sitting on the widest “equatorial 
point” of a spherical-shaped clot. The trajectory of the catheter has to be along the 
widest, or “equatorial”, axis of the clot. 
 
Surgical Center review of optimal surgical plan: The Surgical Center personnel 
will perform real-time (within six hours of data submission) review of 3D images 
to instruct the site that the proposed burr hole location and trajectory are 
appropriate or that a different location/trajectory is recommended. Feedback of 
the results of their review is documented in the EDC. The site neurosurgeon will 
proceed with the proposed surgical plan or the Surgical Center recommended 
plan. If there is disagreement between the two surgical plans, the site 
neurosurgeon has to demonstrate the rationale of his/her plan before using a 
surgical plan different from that proposed by the Surgical Center. See the Manual 
of Operations and Procedures (MOP) for a detailed description of personnel 
involved, responsibilities, and contact information. 
 


 
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Catheter placement: Antibiotic therapy should be administered pre-operatively 
(hospital protocol or 1-2G Ancef IV; dose is subject-weight dependent) then 
repeated every eight hours until the catheter is removed (hospital protocol or 
Ancef IV 1 G Q8hrs). If the subject has a known or suspected penicillin drug 
allergy, then antibiotic coverage will be administered pre-operatively and 
continued with each institution’s non-penicillin drug of choice until the catheter is 
removed. 
 
The procedure will be performed in the operating room, procedural CT or 
MRI scanner, or the ICU. After administration of the appropriate anesthetic, a 
Mayfield headrest is secured to the subject’s head. A reference device is clamped 
to the Mayfield headrest. The image guidance system unit must be in direct line to 
the table with no line-of-sight obstruction. Registration is completed by 
correlating six points on the subject’s head to six points on the previously loaded 
CT scan. Verification of accuracy is accomplished by testing various known 
landmarks on the subject’s face to the image on the computer monitor. Re-
registration during the case is accomplished as needed by repeating the correlation 
of the six landmarks on the subject’s head to the CT scan. The procedure is 
completed in the usual sterile manner for burr hole and catheter placement. Other 
forms of image guidance which are acceptable include stereotactic robotic arms, 
electromagnetic tracking without skull fixation (only under general anesthesia and 
pharmacologic paralysis), or direct “real-time” image guidance in procedural CT 
or MRI. 
 
The site of the entry burr hole is determined using radio-opaque dot 
localization if a standard frontal burr hole is insufficient. Standard frontal burr 
holes will be placed 3 cm lateral to the midline, anterior to the coronal suture for 
ipsilateral frontal, capsular and thalamic hematomas. If the subject has a deep 
brain hemorrhage (Options A and B), a large frontal burr hole will be used. If a 
lobar hemorrhage (Option C), the burr hole will be placed over the affected lobe. 
The position of the burr hole should be made posterior to the thickest portion of 
the hematoma.  Surgical considerations regarding eloquent tissue and hematoma 
shape and location may require other burr-hole locations to optimize 
trochar/catheter trajectory to the target. A one-inch incision will be made in the 
scalp. The burr hole is drilled and the dura is opened with a small incision.   
 
After the proper process of registration and localization with the image 
guidance system an introducer cannula will be placed stereotactically into the 
center of the hematoma. Up to two rigid cannula passes will be allowed to 
minimize morbidity from the catheter implantation. The introducer portion is then 
removed and careful hematoma aspiration is performed free hand using a 10 cc 
syringe until there is no longer any fluid component of the clot noted in the 
aspirate and/or until first resistance. Multiple aspirations may be used to meet 
these criteria. Volume aspirated will be documented.  Following completion of 
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rigid cannula and then the rigid cannula is removed leaving the soft catheter with 
all its perforations in the center of the residual hematoma. Tunnel the catheter 
subcutaneously away from the incision. The catheter is then connected to a three-
way stopcock and then to a closed drainage system.  
 
A CT scan should be done at this time to confirm correct placement, using 
windowing to view the side ports of the catheter, and measure clot size reduction 
as compared to the volume measured on the stability CT scan. The catheter should 
be placed 2/3 of the way along the longest axis of the clot and in the middle of the 
width of the clot (i.e., within the middle 2/3 of the diameter). The Surgical 
Center will review this CT scan to confirm adequate catheter position prior to rt-
PA administration. This review is repeated after any catheter adjustment or 
placement. 
 
After placement of the catheter and a CT scan to confirm correct 
placement, a six-hour post-surgical stabilization period is required prior to first 
injection of rt-PA. Keep the drainage system to drainage for six hours post 
catheter placement prior to first dose of rt-PA. This time is mandated to reduce 
the possibility of secondary hemorrhage. If new bleeding or bleeding expansion is 
seen on the post-op CT scan, wait 12 hours and repeat the CT scan. When the 
bleeding is stable, dosing can be initiated. 
 
 
If post-operative clot volume is 10 to 15 mL, rt-PA should not be given. 
The catheter should remain in place and open to drainage for 24-36 hours prior to 
removal.  
 
Catheter adjustment/replacement: Correct catheter placement will be CT-
confirmed locally and post-operative measurements will be repeated centrally by 
the Surgical Center. Catheter adjustments will be made at this time, if necessary.  
If the hematoma appears larger or the shape is altered on CT scan after the 
catheter is placed, the catheter may require repositioning and a post-repositioning 
CT scan to confirm correct placement within the clot as well as stability of clot 
size. Repositioning is defined as the partial removal or “pull back” of the non-
optimally placed catheter. Replacement is defined as removal of the catheter and 
replacement with a better targeted catheter using the introducer method described 
above with either the same or a different trajectory of insertion. There is a one-
time allowance for a new  rigid cannula placement.  Soft catheter placements or 
replacements, usually done through an existing burr hole and always done using a 
stylet with image guidance, do not count against this limited number of rigid 
cannula passes. There is no limit to the number of soft catheter placements or 
replacements as long as stability requirements are met. Occasionally it may be 
necessary to create a new burr hole/trajectory to access the clot. This will be done 
only after consultation with the Surgical Center. Repeat CT scan and upload 
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Center review and approval of catheter location in residual hematoma prior to 
dosing.  
 
The catheter is then tunneled subcutaneously, connected using sterile 
technique to a three-way stopcock and then to a closed drainage system. Level the 
drainage bag to zero.  
 
If the catheter must be repositioned or replaced after dosing has begun, the 
procedure must be done equal to or greater than 24 hours after the most recent 
dose and all stability protocols must be repeated as if this were the original 
catheter placement. 
 
Complete replacement of the catheter is allowed if the catheter to clot 
relation has been disturbed by inadvertent catheter movement or partial clot 
reduction. Complete replacement should be performed only once (i.e., in any 
subject only two, new rigid cannulas  may ever be placed).  
 
If repositioning or replacement does not correct the catheter-clot relation 
and the rigid cannula  has already been replaced once during the trial, rt-PA 
administration must be stopped or not initiated and the catheter removed 24 hours 
later. This requirement will control the delivery of rt-PA only into space 
containing clot that can be lysed. The catheter may be left in place greater than 24 
hours later if the catheter supports ventricular drainage as clinically required. 
 
In addition, an unscheduled CT scan must be performed should the subject 
clinically deteriorate or significantly improve his or her GCS score. These 
additional safety provisions will keep under surveillance the most ideal time for 
stopping drug after clot is fully lysed.   
 
Catheter removal. After keeping the catheter closed for the one hour following 
the last dose of rt-PA, the catheter should be opened and then left open to drain 
for 24-36 hours prior to catheter removal. The catheter must be closed at the time 
of removal and not open to air to avoid pneumocephalus. The catheter may be left 
in place greater than 24 hours later if the catheter supports ventricular drainage as 
clinically required. 
 
To limit infection risk, remove the catheter at the bedside 24 to 36 hours 
after the last rt-PA administration, unless the catheter supports ventricular 
drainage as clinically required. Send the catheter tip for culture. A CT scan must 
be done 24 hours post catheter removal and examined for stability, new bleeding, 
or hemorrhage extension. 
 
 
 


 
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5.1.3 Experimental Drug Treatment: Drug Therapy 
 
Prerequisite training for dosing. A neurosurgeon, neurocritical care physician, 
or their trained designee will perform hematoma catheter injections under 
standard sterile technique in the intensive care unit.  Viewing a demonstration of 
the catheter injection protocol is mandatory before credentialing a center’s 
physicians and coordinators. A training video has been produced describing the 
injection procedure and apparatus, sterile field techniques and the exact process 
for delivering the drug. The training video is available on the trial website 
(www.braininjuryoutcomes.com). It will be used continuously to train and retrain 
personnel administering the injections. A full step-by-step description of drug 
administration is also available in the MOP. Great care and time has been and will 
be expended to assure the standardization of safe drug administration. This 
presentation will be edited as new safety data are developed. 
 
After placement or repositioning of any pre-dosing catheter a six-hour 
stabilization period is required prior to first dose to assess patient clinical status 
and minimize rebleeding. During this time, the neurological status of the subject 
will be assessed to document clinical worsening or improvement. Surgical 
Center confirmation of catheter placement, replacement, or manipulation is also 
required prior to initiation of dosing. Following surgery, a CT scan is to be 
obtained and catheter placement approved by the surgical center. This CT scan 
can be obtained any time prior to administering first dose. Furthermore, a period 
of at least 6 hours is to be observed prior to first dose to ensure subject is 
clinically stable.  
 
The pharmacist will prepare the rt-PA and flush as detailed in the 
Pharmacy Manual, which is part of the MOP. The two prepared syringes 
containing the rt-PA and flush will be provided by the pharmacy to the 
appropriate study personnel for administration to the patient. The labels on the 
syringes must be compared with the patient’s records to confirm identity, and to 
confirm correct dosage, labeling, and correct timing in the series of 
administration.  
 
Dosage. The drug will be administered as a sterile solution and in a sterile 
manner every 8 (+ 2) hours for up to 9 doses. The total volume of injectate will 
equal 1.0 mg rt-PA @ 1 mg/mL plus at least 3 mL of flush or as much flush is 
needed for the rt-PA to clear the catheter tubing.  
 
Dosing schedule allowances. There is a two (2) hour window on either 
side of the eight (8) hour dosing schedule to allow for scheduling problems, 
stability determination, INR correction, or any other concern the PI may have 
regarding giving the dose on schedule. This schedule adjustment should be used 
as infrequently as possible to maintain a Q8hr schedule for dosing consistency. 
 


 
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Holding a dose. If a dose must be held or delayed more than 10 hours to 
correct an INR value above 1.4 (or other coagulopathy), hold the next scheduled 
dose, institute corrective therapy and re-assess the INR. Once INR is corrected, 
dosing may be resumed keeping to the original dose count. If the INR remains > 
1.4, continue corrective therapy as required and the investigator may discontinue 
dosing.  
 
In the event of severe or life-threatening anaphylaxis or hypersensitivity 
reaction, the treatment phase would be discontinued. The patient would not be 
retreated with rt-PA.  A description of the reaction would be added to the patient’s 
medical record as a serious adverse event for future reference. 
 
Dosing decision-making by CT. Before initial dosing and subsequently 
after every three (3) doses (daily), the investigator is required to view the most 
recent CT scan to measure clot size and compare to the prior day’s scan in order 
to decide continuation or discontinuation of dosing. As clot size decreases and 
approaches the target reduction, the next CT may be obtained earlier than after 
three doses. This process allows the PI and team to confirm that: 1) remaining clot 
is greater than 10 mL, 2) the blood clot is in direct contact with the catheter, and 
3) that the catheter is placed in the clot to be dissolved. Bone windows must be 
done when obtaining any CT scan in order to confirm that the catheter side ports 
have contact with the clot. If none of the side ports are in contact with the clot, 
drug should not be given. Partial contact with the clot should be reviewed by the 
PI on a daily basis, prior to further dosing.  
 
Catheter repositioning during dosing. If these criteria are not met, the catheter 
must be repositioned. Repositioning to allow for the correct catheter to clot 
relationship may be performed once under direction of the investigator as needed 
during the dosing time of the protocol. Open the catheter to drain for 24 hours 
after the most recent rt-PA administration before repositioning or replacing the 
catheter. After repositioning obtain a repeat CT scan to confirm catheter 
placement and clot stability. After both are confirmed and after Surgical Center 
review, wait six (6) or more hours from the time of catheter repositioning and 
then resume dosing.  
 
Stability determination during dosing. Stability must be demonstrated in the 
following ways on all CT scans: 1) no expansion of ICH greater than 5 mL as 
compared to the most previous CT scan, 2) no catheter tract bleed greater than 
5mm, and 3) no new IVH or new expansion of IVH. If the clot is stable, dosing 
may resume.  
 
Repeat CT scans will be performed earlier than every 12 to 24 hours if or 
when the treating physician determines that there is a sustained improvement or 
worsening of neurological condition (GCS motor scale score increase or decrease 
by more than two points for eight hours or more). Therapy will be stopped at this 


 
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time if there is any increase in hematoma volume on CT or emergence of systemic 
bleeding disorders. These additional safety provisions will keep under 
surveillance the most ideal time to stop rt-PA administration. 
 
 
Intracranial pressure (if monitored), cerebral perfusion pressure, and blood 
pressure will be monitored before, during, and after each injection.  After 
injection, the catheter will be closed for 1 hour to prevent drainage of the rt-PA 
away from the clot and to allow adequate time for drug-clot interaction. After one 
hour of closure, the catheter will be opened with an appropriate drainage gradient.  
ICP will be measured every four hours, or more frequently, as clinically indicated.  
A neurosurgical consult should be obtained for sustained intracranial 
hypertension. Sustained intracranial hypertension is defined as ICP greater than 
20 mmHg for two or more consecutive hours despite maximal medical ICP 
management. 
 
Documentation of dosing. In addition to documenting each dose in the EDC 
system, each dose administration should be documented in the Medical 
Administration Record of the medical record as source documentation. A progress 
note should also be written in the medical record as source documentation to 
record the date and time of each dose, the amount of rt-PA administered, the 
amount of flush administered, the catheter in which the drug was administered 
(when more than one catheter is in place), the time the catheter was closed and 
reopened, the ICP (if monitored), systolic blood pressure (SBP), and diastolic 
blood pressure (DBP) prior to the dose and prior to reopening the catheter, and the 
name and title of the person who administered the dose. 
 
5.2 
Handling of Study Interventions 
 
Alteplase (recombinant human tissue-type plasminogen activator) is a sterile powder for 
reconstitution with Sterile Water for injection. The reconstituted preparation results in a 
colorless to pale yellow transparent solution containing Alteplase 1mg per ml at 
approximately pH 7.3. The Alteplase will be prepared in a sterile syringe labeled for 
investigational use.  See the Alteplase Package Insert for additional product information. 
See MOP Chapter 19 (Pharmacy Manual) for additional instructions regarding Alteplase 
and flush preparation and labelling. 
 
 
The following measures will be taken for storage and accountability of the investigational 
product:  
 
1. The investigational product is Alteplase, which is stored refrigerated at 2-8° (36-
46°F). The refrigerator temperature must be monitored and the documentation logs 
must be maintained for the time period that investigational product is stored at the 
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2. Accountability for each box of Alteplase will be emphasized during the training 
sessions.  
 
3. Investigational product should be stored in a secure area according to local 
regulations. It is the responsibility of the investigator to ensure that investigational 
product is only dispensed to study subjects. The investigational product must be 
dispensed only from the official study sites by authorized personnel according to local 
regulations. 
 
4. The investigational product shall be dispensed in accordance with the authorized 
prescriber’s prescription. 
 
5. A drug accountability form will be provided to the site. This form will be used to 
document all investigational product transactions (i.e., receipt of drug, dispensings, 
wasted doses, etc.). This documentation will be maintained at the site however, copies 
will be requested periodically and at the end of the study. 
 
6. Drug accountability will be checked remotely and/or during on-site monitoring visits 
by review of drug accountability logs and other study documentation. 
 
7. All unused investigational product may be discarded on site according to each site-
specific policy for disposal of pharmaceutical waste. Prior to disposal of the drug, the 
Coordinating Center Study Pharmacist must receive a copy of the center’s policy for 
study drug disposal (pharmaceutical waste) and documentation of the drug to be 
discarded. 
 
8. The total of amount of Alteplase administered will be recorded on the source 
documents and case report forms. 
 
5.3 
Concomitant Interventions 
 
5.3.1. Required Interventions. Intraclot administration of 1mg of rt-PA followed by 3 
ml of flush every eight hours for up to nine doses. 
 
5.3.2. Permitted Interventions. Study center standard of care policies may govern the 
use of low molecular weight, fractionated and unfractionated heparins for DVT 
prophylaxis during the acute treatment and follow-up periods. Heparin flushes of 
systemic lines are also permitted. Use of enoxaparin for DVT prophylaxis in the 
ICU at the usual doses of 30 mg sc Q12 h or 40 mg sc QD is permitted as long as 
the patient has good renal function (creatinine clearance of > 30 ml/min) or does 
not have an unusually low body weight (< 45 kg). 
 
 
Including but not limited to NovoSeven, fresh frozen plasma, plasma concentrate 
and vitamin K, are permitted singly or in combination (but not required) for 
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5.3.3. Prohibited Interventions. During the study period (randomization through the 12 
month visit), avoid enoxaparin at therapeutic doses >1.0 mg/kg sc Q12 h.   
 
After the day 30 follow up visit other antithrombotic and antiplatelet agents such 
as Coumadin (warfarin) and Dabigatran, glycoprotein IIb/IIIa inhibitors 
(eptifibatide/Integrilin, abciximab/Reopro, tirofiban/Aggrastat), ASA, 
clopidogrel/Plavix may be administered.  
 
The use of Urokinase, Retevase, Desmoteplase, Tenecteplase or any other 
thrombolytic agent (other than the study agent) administered via any brain 
catheter is prohibited. Clogged catheters should be treated with normal saline 
flushes. 
 
5.3.4. Precautionary Interventions. If any brain catheter (ICH or IVH, if present) 
needs to be replaced or repositioned during dosing, wait 24 h after the most recent 
dose to perform the procedure. A stability CT scan must then be done > 6 h after 
all placements/repositioning to confirm correct placement, clot stability, and 
absence of significant blood along the catheter tract. Once these are confirmed by 
the site and Neurosurgical Center, dosing may restart. 
 
If a subject experiences asymptomatic bleeding (ICH expansion < 5 cc, IVH 
expansion as assessed by < 2mm increase in 2 out of 3 ventricular regions, or 
catheter tract hemorrhage that is < 5 mm in the largest diameter), continue the 
dosing and CT schedule. If the bleeding is larger than these thresholds, with or 
without mass effect, the next scheduled dose is held and a repeat CT scan is done 
> 24 h after the previous dose. If the ICH, IVH, and catheter tract hemorrhage are 
stable (i.e., has not further grown by > 5 mm), then dosing may restart.  
 
Particular caution needs to be observed with renal dialysis patients receiving rt-
PA. Because this group of patients can experience wide variations in blood 
pressure with dialysis attendant cardiac volume changes, attention to long-term 
and intra-procedure blood pressure control is important. Similarly, attention to 
regional anti-coagulation management is important. 
 
Consider administering platelets to eligible patients who are on antiplatelet 
therapy (Plavix, aspirin, etc.) at the time of symptom onset. Platelet counts should 
be closely monitored in this population. 
 
5.4 
Adherence Assessment 
Protocol adherence will be determined by review of data recorded on the case report 
forms that has been verified through comparison with the medical record and other 
source documentation. Compliance and treatment fidelity will be reported overall and by 
center to the DSMB at each scheduled review session. Study centers demonstrating poor 
protocol compliance will be retrained and, if necessary, replaced. 
 


 
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6 
CLINICAL AND LABORATORY EVALUATIONS 
6.1 
Schedule of Evaluations 
*Assessments should be performed daily through Day 6 regardless of treatment assignment. 
†An MRI is an acceptable substitute for this CT scan with Coordinating Center approval. 
§ Subjects enrolled to medical management: The Day 1 CT scan does not need to be repeated if enrollment occurs on the same calendar day as the 
stability CT scan (done 6h post the diagnostic CT scan).  
 
Screening
/ Baseline 
Day 1 
(day 
of 
rando
mizati
on) 
Day 
2 
Day 
3 
Days* 
4 - 6 
Day 7 
Day 
30 
± 7 
days 
Day 
90 
± 7 
days 
Day 
180 
± 14 
days 
Day 
270 
± 14 
days 
Day 
365 
± 14 
days 
Diagnostic CT 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Stability CT (6 hours after diagnostic CT) 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Review of Systems 
X 
 
 
 
 
 
 
 
 
 
 
CTA (MRA)/MRI 
X 
 
 
 
 
Day 
7-10 
± 1 
day 
X 
(MRI) 
 
 
 
 
 
Image-Guided Catheter Placement  + 
Aspiration (Surgical Group Only)  
 
X 
 
 
 
 
 
 
 
 
 
Post catheter placement CT scan  
 
X 
 
 
 
 
 
 
 
 
 
rt-PA admin. (Surgical Group Only; Q8h 
up to 9 doses) 
 
X 
X 
X 
 
 
 
 
 
 
 
MTI-M3 specimen collection 
 
X 
X 
X 
X 
 
 
 
 
 
 
Daily CT Scan 
 
X§ 
X 
X 
X 
(Day 4) 
 
X† 
 
X† 
 
 
obtain a CT 24 h post catheter 
removal on any of these days 
Vital Signs 
 
X 
X 
X 
X 
 
 
 
 
 
 
Neurocheck 
 
X 
X 
X 
X 
 
 
 
 
 
 
Lab Assessments* 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Concomitant treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NIHSS 
X 
 
 
 
 
X 
X 
 
X 
 
X 
Barthel Index 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Modified Rankin Scale 
Historic 
 
 
 
 
 
X 
X 
X 
X 
X 
Stroke Impact Scale 
 
 
 
 
 
 
X 
 
X 
 
X 
GOS-E Scale 
 
 
 
 
 
 
X 
 
X 
 
X 
Mini-Mental Exam 
 
 
 
 
 
 
X 
 
X 
 
X 
Euro-Quol-5D Scale 
 
 
 
 
 
 
X 
X 
X 
X 
X 
PBSI 
 
 
 
 
 
 
X 
 
X 
 
X 
Personal Health Utility Assessment 
Interview 
 
 
 
 
 
 
 
 
X 
 
 
CES-D 
 
 
 
 
 
 
 
 
X 
 
 


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening/Baseline.  
 
Screening/Baseline is the start of the screening process and begins when the study 
team is notified of a potentially eligible subject. If any of the assessments required 
to determine eligibility (stability CT scan, pregnancy test, serum lab assessments) 
are not part of routine patient management, then these assessments will be listed 
in the consent form as trial-related procedures and informed consent will be 
obtained prior to determining eligibility for the trial. The prospective subject will 
be informed as part of the consent discussion that the screening procedures will 
determine eligibility for the trial and that signing the consent form does not 
constitute enrollment into the trial. 
 
6.2.2 Day 1 through Day 6 
 
The acute phase of the protocol is defined as day one (day of randomization) 
through day six post randomization. All subjects randomized to the surgical 
intervention plus rt-PA will receive up to nine doses of intracatheter injections of 
rt-PA. Dosing will be discontinued prior to nine doses if an endpoint is satisfied.  
 
Randomization should occur as close as possible to the time that all eligibility 
criteria are met. If randomization is postponed to accommodate scheduling (i.e., it 
is preferable to wait until 6 am to randomize instead of midnight), obtain a CT 
scan to re-confirm stability of the ICH and re-confirm blood pressure stability 
prior to randomization. For those subjects randomized to surgery (MIS+rt-PA) the 
surgical procedure should be initiated as close as possible to the time of 
randomization. 
 
6.2.3 Day 7 through Day 365 
 
The follow-up phase of the protocol begins on day 7 and continues through the 
12-month follow-up visit. 
 
6.2.4 Intervention Discontinuation Evaluations 
 
Subjects withdrawn early from treatment or who withdraw consent or are lost to 
follow-up will not be replaced. If a subject is withdrawn early from treatment due 
to a clinical safety endpoint, we expect standard clinical judgment to be applied to 
continue to monitor the subject until resolution of the event including but not 
limited to repeat CT scans and repeat laboratory assessments. 
 
Discontinuation of drug administration and catheter removal. rt-PA injections 
will continue as defined by the protocol until an endpoint of clot lysis is reached 
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comes first) or an adverse treatment endpoint occurs, such as symptomatic 
hemorrhage. ICH clot resolution of 10-15 mL will be estimated by comparing the 
daily dosing CT scans and performing the ABC/2 measurement on sequential 
scans. A CT scan must be done one day after the catheter is removed to monitor 
for new bleeding or bleeding extension. After last dose the catheter will be closed 
for one hour and then reopened to drain for 24 hours to allow for complete 
removal of rt-PA. The catheter must be closed at the time of removal to avoid 
pneumocephalus.  
 
A subject will have rt-PA administrations discontinued for any of the following 
reasons: 
 
1) The ICH volume is reduced to less than or equal to 10 mL (surgical endpoint). 
 
 
2) The subject receives nine doses of rt-PA (surgical endpoint). 
 
 
3) Clinically significant rebleeding (treatment failure). 
 
 
4) Uncontrolled coagulopathy defined as INR > 1.4 (treatment termination). 
5) In the investigator’s judgment, withdrawal from the trial would be in the 
patient’s best interest (treatment failure). 
6) The patient withdraws consent. 
 
6.2.5 On Study/Off-Intervention Evaluations 
 
The follow-up phase of the protocol begins on day seven and continues through 
the 12-month follow-up visit. All subjects will be required to return for a follow-
up clinic visit at months one, six, and 12, with a CT scan to be done at the one and 
6 month visit. A telephone follow-up visit will occur at months three and nine. 
Daily monitoring of all adverse events will continue until day six. This includes 
monitoring of additional medications used, additional procedures and ICU care 
required. Serious adverse events will be monitored throughout the initial 
hospitalization. Serious adverse events, neurological adverse events, and total 
time at home (i.e., excluding hospital re-admissions and admission to 
rehabilitation facilities) will be recorded at all subsequent follow-up visits.   
 
Subjects withdrawn early from the treatment protocol are asked to return to clinic 
for all scheduled follow-up assessments including the one, three (telephone 
contact), six, nine (telephone contact) and 12 month visits. 
 
6.2.6 Final On-Study Evaluations 
 
At the subject’s final visit to occur at approximately 12 months post ictus, the 
following will be done: NIHSS, Barthel Index, videotaped modified Rankin 
Scale, extended GOS, Stroke Impact Scale, Mini-Mental State Exam, EQ-5D, and 
PBSI. Also at this time the subject will be asked about any new neurological 
adverse events or any serious adverse events that may have occurred since the 
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any neurosurgical procedures. All serious and non-serious adverse events that 
occurred prior to the 12 month visit but remain documented as “ongoing” will be 
confirmed as “ongoing” or documented as “resolved” and a resolution date 
recorded. The examiner will document if the subject was prescribed and is 
compliant with any blood pressure medications prior to the 12 month visit and 
document if any of the following have occurred since the nine-month telephone 
contact: death, new brain bleeding, brain bleeding extension, and/or cerebral 
infection. The subject will be instructed that this is the final visit. 
 
6.2.7 Pregnancy 
 
Pregnant women are ineligible to participate in the trial. Women who become 
pregnant during the follow-up period will be followed through the 12 month visit 
to document clinical and functional outcome but no CT scans will be done. 
 
6.3 
Special Instructions and Definitions of Evaluations 
 
6.3.1 Diagnostic CT:  This CT scan is the initial CT used to diagnose the ICH and is 
done per standard medical care upon presentation to the Emergency Department. 
If this scan is done at an outside hospital prior to transfer to the enrolling center, 
the outside hospital scan must be obtained and uploaded to the EDC. CT 
angiogram or routine angiogram with evaluation for “spot sign” is encouraged to 
complete the evaluation for aneurysm, AVM, or other malformations. If this 
imaging is not done, the rationale must be documented in the EDC system. The 
dCT scan will be used to calculate the ICH and as the start time for the 72 hour 
surgery initiation window. ICH size less than 30 mL on this scan does not exclude 
the patient from participation. The patient should be followed until the enrollment 
window closes to monitor for ICH expansion. The dCT scan will be compared 
with the first stability CT scan to determine if the hemorrhage continues to 
expand or if stability has been achieved (ICH size does not increase by ≥ 5 mL). 
A copy of the dCT DICOMs will be uploaded to the EDC prior to randomization. 
The Reading Center will centrally review this scan if requested to confirm 
eligibility and to measure ICH (and IVH if present) clot volume for efficacy 
analysis.   
 
At each study center ICH volume will be determined in a standardized manner. 
Instructions for calculating ICH volume are included in the MOP.  
 
The size of the ICH and the IVH along with the date and time of the dCT scan 
should be documented in the medical record as source documentation. 
 
6.3.2 Informed consent: Consent forms must be reviewed by the CCC for 
completeness and accuracy prior to submission to local study center IRB/Ethics 
Committees. This review must occur after each time the document is modified. 
 


 
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The informed consent process can begin at any time during the screening process 
but must be obtained prior to randomization. A signature on the consent form 
does not translate into enrollment in the study. Only after all inclusion/exclusion 
criteria have been met and informed consent has been signed can a patient be 
randomized into the study. 
 
Informed consent must be obtained from the patient, or if the patient is aphasic, 
confused, or obtunded, the legal representative of that patient. Patients will not be 
treated if consent cannot be obtained from a competent patient or from their legal 
representative.  
 
The study center will document the informed consent process and the signing of 
the consent form in a written progress note, place a signed copy of the consent 
form in the hospital medical chart, and keep the signed original consent form in 
the study subject file. A signed copy must be given to the subject as well. The 
study monitor will review and confirm the signed consent form while reviewing 
subject data collection forms and/or during on-site monitoring visits. 
 
6.3.3 Stability CT (six or more hours after dCT): See page 23, 2. Stability CT scan. If 
this CT is not done per standard medical care at a participating study center, 
informed consent must be obtained prior to ordering the CT. All CT scans done 
after the dCT and prior to randomization are considered stability CT scans. All 
stability CT scans must be reviewed by a radiologist or an investigator and 
compared to the Diagnostic or most previous CT to confirm that the ICH (and 
IVH if present) clot is stable. A DICOM formatted copy of the final stability CT 
scan used for randomization will be uploaded to the EDC prior to randomization. 
All other stability CT scans done after the dCT and prior to randomization will be 
uploaded to the EDC prior to day 7. The Surgical Center will review the images 
as outlined on page 29. The Reading Center will centrally review this scan/these 
scans to measure stability of ICH, IVH, and catheter tract clot volume.  
 
The size of the ICH (IVH, if present) along with the date and time of all stability 
CT scans should be documented in the medical record as source documentation. 
 
6.3.4 Pregnancy test: Female patients of childbearing ability (i.e., of childbearing age 
and not surgically sterilized) must have a negative urine or serum pregnancy test 
to be eligible. If this test is not done per standard medical care at a participating 
study center, informed consent must be obtained prior to ordering the test. 
 
The date and time of the pregnancy test and the result should be documented in 
the medical record as source documentation. 
 
6.3.5 Medical history/Review of systems: The medical/treatment history must be 
documented as part of the screening process to rule out exclusion criteria (i.e., 
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Medical history obtained for data collection purposes may be recorded in the 
medical record as source documentation and then transcribed to the VISION EDC 
system or can be recorded directly on the eCRF to document discussions with the 
patient, family, and/or health care team not otherwise collected in the medical 
record.  
 
6.3.6 CTA (or MRA) and MRI: See section 4.3.1: Screening Procedures, 3. Imaging 
to rule out underlying pathology on page 24 above. Repeat imaging (MRI) will be 
done on day 7-10 (± 1 day), unless contraindicated, to assess cerebral edema, 
cerebral infarction, and other clinical sequelae.  
 
6.3.6 Image-Guided Catheter Placement + Aspiration (Surgical Group Only). See 
section 5.1.2: Experimental Intervention: MISTIE-Surgery, above. 
 
6.3.7 Post catheter placement CT scan: A CT scan will be done after the MIS 
procedure as described in section 5.1.2: Experimental Intervention: MISTIE-
Surgery, above. 
 
6.3.8 rt-PA administration: See section 5.1.3: Experimental Drug Treatment: Drug 
Therapy, above.  
 
6.3.9 Daily CT scan: A CT scan is required daily on days one through four for both 
surgical and medical subjects. For surgical subjects, a CT scan is repeated one day 
(approximately 24 hrs) post catheter removal. During dosing, all patients must 
receive a minimum of one scan per day, preferably in the morning, but at least 
after every three doses are administered. This CT scan will monitor for clot lysis 
and asymptomatic bleeding and will be evaluated by the investigator prior to the 
next administration of rt-PA. This does not represent an increase in the total 
number of scans requested; rather, it reflects two data collection goals: 1) to 
match drug administration times with independent assessment of safety and 
efficacy data points and to provide additional safety precautions during dosing; 
and 2) to collect the primary surrogate outcome measure on a fixed daily schedule 
for optimal measurement of the rate of clot resolution. 
 
The catheter tract must be reviewed on the daily CT scan to determine if there is a 
new onset or expansion of catheter tract hemorrhage.     
 
The date and time of all daily and unscheduled CT scans should be recorded in 
the medical record as source documentation. We will also record and analyze all 
CT scans ordered during the acute hospitalization. 
 
6.3.10 Vital Signs: Monitoring of vital signs includes documentation of blood pressure 
and ICP (if monitored).. Vital signs are to be collected once every six hours 
beginning at randomization through day six.  
 


 
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6.3.11 Therapy Intensity Levels (TILs): In addition, therapy intensity levels will be 
documented at Baseline and day seven. The TILs will be used to document the 
management intensity of reversal of anticoagulation, Glasgow coma score, blood 
pressure, temperature, blood glucose, ICP, and cerebral herniation. 
 
All vital signs and TIL data must be recorded in the medical record, or as ICU 
monitor print outs as source documentation. 
 
6.3.12 Neurocheck: GCS may be assessed clinically as frequently as every hour. For the 
purposes of neuromonitoring, GCS will be recorded once every six hours to 
assess for neuroworsening or clinical improvement. An unscheduled CT scan 
should be done if the subject improves or worsens by more than two points on the 
GCS motor scale that is sustained for at least eight hours, or sooner if clinically 
indicated.  
 
6.3.13 Lab Assessments: The results of daily white blood cell count, serum glucose, 
platelet count, aPTT, and INR will be reviewed and recorded in the EDC. These 
lab assessments will be monitored through day six. The following lab assessments 
must be done and reviewed to screen the patient for eligibility: platelet count, 
INR, and, if applicable, urine or serum pregnancy test. The INR must remain < 
1.4 during dosing.  
 
All lab results and sampling dates and times must be recorded in the medical 
record as source documentation. 
 
6.3.14 Concomitant treatments: All concomitant medications administered that are 
inclusive of the drug classes of interest and procedures performed (randomization 
through day 6) will be recorded on the eCRF. Drug classes of interest include but 
are not limited to: anti-hypertensives, sedatives, hypnotics, hematologic 
modifiers, antiplatelet and anticoagulant medications, antibiotics and any other 
medication used to treat a neurological adverse event or any serious adverse 
event. Medications used to treat a neurological adverse event or any serious 
adverse event will be recorded on the eCRF through day 365.  
 
6.3.15 NIHSS. The NIHSS should be done by a certified examiner as close to the time of 
randomization as possible, at day seven, and again at months one, six, and 12. 
 
The NIHSS results may be recorded directly on the electronic case report form. 
 
6.3.16 Barthel Index. A historical Barthel Index score should be obtained to assess the 
patient’s level of functioning, prior to symptom onset and will be used in a 
comparison with scores obtained at one, three, six, nine, and 12 months. 
 
The Barthel Index items and total score may be recorded directly on the electronic 
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6.3.17 Modified Rankin Scale. A historical modified Rankin Scale score should be 
obtained as part of the screening procedures. The patient must have a mRS score 
of 0 or 1 to be eligible for the study. This historical score is based on the patient’s 
level of functioning prior to the onset of symptoms and will be used in a 
comparison with scores obtained at one, three, six, nine, and 12 months. The one, 
six, and 12 month evaluations will be done by a certified examiner and videotaped 
with digital images sent to the Outcome CCC at the Western Infirmary in 
Glasgow, UK. A sample consent form for videotaping an interview with a proxy 
caregiver can be found in Appendix 4. 
 
The historical modified Rankin score may be recorded directly on the electronic 
case report forms. The Outcome Coordinating Center will adjudicate all follow-up 
mRS scores. 
 
6.3.18 Stroke Impact Scale (SIS). A SIS score should be obtained as part of the follow-
up procedures at one, six, and 12 months. If the subject has a Mini-Mental exam 
score of 18-30, you should attempt to interview the subject. If the subject is 
unable to complete the interview or has a Mini-Mental score < 18, then an 
appropriate caregiver should be interviewed to complete the SIS.  
 
The SIS must be recorded on the bedside worksheets and then entered into the 
EDC. The bedside worksheets are required source documentation. 
 
6.3.19 Extended Glasgow Outcome Scale (GOSE). A GOSE score should be obtained 
as part of the follow-up procedures at one, six, and 12 months. If the subject has a 
Mini-Mental exam score of 18-30, you should attempt to interview the subject. If 
the subject is unable to complete the interview or has a Mini-Mental score < 18, 
then an appropriate caregiver should be interviewed to complete the GOSE. A 
GOS score will be computed by the Statistical Center from the GOSE scale. 
 
The GOSE must be recorded on the bedside worksheets and then entered into the 
EDC. The bedside worksheets are required source documentation. 
 
6.3.20 Mini-Mental Exam. A Mini-Mental exam will be done as part of the follow-up 
procedures to determine the subject’s ability to complete the GOSE and SIS 
interviews. If a subject has a Mini-Mental score of 18-30, subject interview will 
be attempted. If the subject is unable to complete the interview or has a Mini-
Mental score < 18, then an appropriate caregiver should be interviewed to 
complete the GOSE and the SIS at one, six, and 12 months. 
 
The Mini-Mental Exam may be recorded directly on the electronic case report 
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6.3.21 Euro-Quol-5D. An EQ-5D score should be obtained as part of the follow-up 
procedures at one, three, six, nine, and 12 months.   
 
The EQ-5D must be recorded on the bedside worksheets and then entered into the 
EDC. The bedside worksheets are required source documentation.    
 
6.3.22 Preference-Based Stroke Index. A PBSI score should be obtained as part of the 
follow-up procedures at one, six, and 12 months. If the subject has a Mini-Mental 
exam score of 18-30, you should attempt to interview the subject. If the subject is 
unable to complete the interview or has a Mini-Mental score < 18, then an 
appropriate caregiver should be interviewed to complete the PBSI. 
 
The PBSI must be recorded on the bedside worksheets and then entered into the 
EDC. The bedside worksheets are required source documentation.    
 
6.3.23 Personal Health Utility Assessment Interview.  A Personal Health Utility 
Assessment Interview will be done as part of the follow-up procedures at six 
months. 
 
The Interview must be recorded on the bedside worksheets and then entered into 
the EDC. The bedside worksheets are required source documentation. 
 
6.3.24 Center for Epidemiological Studies – Depression screen (CES-D). A CES-D 
screen will be done as part of the follow-up procedures at six months. 
 
The CES-D must be recorded on the bedside worksheets and then entered into the 
EDC. The bedside worksheets are required source documentation. 
 
 
7 
MANAGEMENT OF ADVERSE EXPERIENCES 
 
In the event of an adverse event, the first concern will be for the safety of the subject. 
Investigators are required to report to the CCC any serious adverse event and any adverse 
event which is assessed by the investigator to be possibly, probably, or definitely related 
to the surgical procedure or rt-PA. All events meeting these criteria will be reported for 
the time period beginning with randomization through the protocol-defined follow-up. 
Serious criteria, definitions, and guidance for reporting follow in section 10.4: Adverse 
Experience Reporting. 
 
Management of recurrent bleeding.  Best care criteria defined by the American Heart 
Association (AHA) guidelines for management of ICH will be the standards of care for 
all general medical care in this protocol. Specifically, the guidelines are (1) Stroke 
Council special writing group guidelines for the management of ICH,11 (2) European 
Stroke Initiative (EUSI) Guidelines for the management of intracranial hemorrhage,81 and 
(3) the AANS guidelines for management of elevated intracranial pressure.82 Adverse 


 
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events will be managed similarly by employing these guidelines. Specific management 
for new intracranial bleeding does not exist. Each instance is managed by the care team 
as required to preserve life and function. Management may include blood pressure 
reduction, use of platelets and clotting factors, use of prothrombotic agents, and use of a 
surgical procedure. The management of each adverse event will be recorded and may be 
reviewed by the Safety Event Committee.   
 
Management of brain infection.  Routine antibiotic management of symptomatic brain 
infection (bacterial or non-bacterial) will be performed according to accepted principles 
of infection care. The selection of an antibiotic on the basis of culture and sensitivity data 
will be the primary means of management. Removal of any infected hardware and the 
subsequent adjustment of antibiotic on the basis of response to therapy will be applied to 
all patients.  
 
The occurrence and management of all brain infections, with and without positive 
CSF cultures, will be recorded and reviewed reported by the Safety Event Committee so 
that an independent assessment of clinical significance may be made as necessary.  
 
We consider both bacterial ventriculitis and bacterial meningitis compulsory 
SAEs and treat both the same. This is the most conservative safety profile. We provide 
separate SAE codes for a clinical determination between ventriculitis and meningitis and 
bacterial and non-bacterial, to accommodate investigator diagnostic classifications. 
 
Procedures for modification. Injections of rt-PA will be discontinued for all 
symptomatic hemorrhage occurrences. No other modification of “best care” is anticipated 
for symptomatic hemorrhage. All care associated with this event will be recorded on the 
SAE eCRF.  Injection of rt-PA will not be discontinued for infection. The same adverse 
event reporting will be employed.   
 
8 
CRITERIA FOR INTERVENTION DISCONTINUATION 
 
rt-PA administration will be discontinued for any of the following reasons: 
 
1. Dosing will be discontinued when the ICH clot volume is reduced to less than 
or equal to 10 mL, or the subject receives 9 doses of rt-PA (treatment 
endpoint), whichever occurs first.  
2. Dosing will not be started if the ICH clot volume is reduced to less than or 
equal to 10 mL by clot aspiration alone during catheter placement (surgical 
endpoint). 
3. The subject experiences a clinically significant bleeding event (local or 
systemic) (treatment failure). 
4. In the investigator’s judgment, withdrawal from the trial would be in the 
subject’s best interest (treatment failure). 
5. The subject or legal representative withdraws consent.  
 


 
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All subjects will be followed by the site team through day 365 (reasons 1 to 5) as part of 
the outcome assessment for the intervention. The use of the phone and mail will be the 
main means of maintaining contact after discharge. The subject or legal representative 
has the right to withdraw consent. At the time of consent withdrawal, the site personnel 
will discuss with the subject or legal representative the level of their consent withdrawal 
to determine if they are willing to discontinue study treatment but agree to in-person and 
by phone follow up visits, disagree to follow up visits but agree to phone contact to 
determine vital status, or no further contact at all.    
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1.  
Statistical Analysis Plan 
 
Primary Efficacy. The primary objective of this multicenter, randomized, controlled, 
Phase III clinical trial is to determine the efficacy of intra-clot catheter placement and 
aspiration of hematoma contents, followed by gentle clot irrigation with low dose 
recombinant tissue plasminogen activator (rt-PA), referred to as Minimally-Invasive 
Surgery plus rt-PA (MIS+rt-PA). The primary hypothesis of this trial is that the MIS+rt-
PA approach to intracerebral hemorrhage (ICH) management will result in more patients 
having overall better functional outcome at 180 days, as defined by the modified Rankin 
Scale (mRS)1 in the range 0-3, when compared to patients managed with standard 
aggressive medical treatment. Although the mRS includes a category for death, and hence 
the primary analysis incorporates mortality outcomes, mortality as a separate outcome 
will also be examined. An intent-to-treat (ITT) paradigm for the analyses will be 
incorporated. The proposed trial would enroll a total of 500 patients, 250 randomized to 
each treatment arm (MIS+rt-PA and medical management). The power to detect the 
effect size of 13% across all clot locations with this sample size is 88%. The power to 
detect the conservatively estimated effect size of 11% in this patient population is 81%. 
 
Efficacy Measures Summary.  
 
• Primary measure: 
Dichotomized adjudicated mRS 0-3 vs. 4-6 at 180 days post-stroke 
 
• Secondary measures: 
1. Dichotomized adjudicated mRS at 365 days post-stroke 0-3 vs. 4-6 and 0-2 vs. 3-6 
2. Ordinal adjudicated mRS (0 – 6) at 180 days post-stroke 
3. Mortality and Safety Events at 30 days post-randomization, including procedure-
related mortality, symptomatic bleeding rate, and infection rate 
4. Mortality at 180 days post stroke 
5. Functional Status: NIHSS, Barthel Index, GOS, extended GOS, MMSE at 180 days 
post-stroke 
6. Type and intensity of ICU management: ICU days, hospital days, patient disposition 
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7. Quality of life: SIS, EQ-5D, PBSI, Personal Health Utility Assessment Interview, 
days to return to home; patient disposition at 180 and 365 days post-stroke including 
proportion of days in long-term care facilities 
8. Cost: amount of billed and reimbursed 
 
In addition to the primary and secondary measures, there are a number of related and 
intermediate surrogate outcomes of interest, including Glasgow Coma Score (GCS), 
Graeb Scale, clot lysis rate and final clot size reduction. 
 
Safety Measures. Interim safety analyses will be prepared for the external Data Safety 
and Monitoring Board (DSMB) on a pre-arranged schedule (such as semi-annual or after 
enrollment of a fixed number of subjects) to evaluate efficacy and safety. Safety 
measures include: monitoring the incidence of symptomatic and asymptomatic 
intracranial bleeding events (i.e., hemorrhage extension, new hemorrhage, catheter-tract 
hemorrhage) through daily computerized tomography (CT) scans for the first four days 
after randomization and then repeated one day (approximately 24 hours) after ICH 
catheter removal, and monitoring the incidence of confirmed and suspected infection and 
in-hospital mortality. 
 
Safety Monitoring and Recruitment Suspension Rules. Safety events above pre-
specified thresholds will trigger “a suspend recruitment and review “by the DSMB to 
investigate the presumed cause and impact of these events. Such events are initially 
reviewed by a Data Coordinating Center (DCC) staff member to determine if an event 
threshold has been reached at which time the study investigators and the DSMB will be 
notified. The thresholds triggering such a review are: 30-day mortality > 60%, a MIS+rt-
PA related symptomatic bleeding rate > 25% (events identified within the first 30 days 
and assessed as occurring during active treatment or during the 72 hours after treatment 
will be monitored), first week operative death rate > 10%, and a procedure-related 
infection rate > 15% (over the initial 30 days). If any of these SAEs are attributable to the 
intervention (catheter insertion or manipulation, or rt-PA injection), the study will be 
suspended for a complete safety and efficacy review.  
 
Efficacy Monitoring and Recruitment Suspension Rules. Interim analyses for safety 
will occur after 125, 250, 375 and 500 subjects are enrolled. One interim look at efficacy 
and futility will occur after 375 subjects are enrolled. These analyses will be based on 
'Brien-Fleming’ stopping boundaries for efficacy and more aggressive (i.e., more likely 
to stop if there is no early signal of benefit) stopping boundaries for futility.(Jennison C, 
Group sequential methods with applications to clinical trials. Boca Raton, FL. Chapman 
& Hall/CRC Press, 2000.) 
 
9.1.1. Randomization. Subjects will be randomized to MIS+rt-PA surgery: medical 
management using a covariate-adaptive design similar to that used for the 
CLEAR III trial. The goal of this randomization scheme is to obtain an improved 
balance across study arms in the number of subjects with certain pre-
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(mRS) at 180 days post-stroke. These variables include pre-randomization clot 
volume, and baseline severity of impairment as measured by GCS. The design of 
Pocock and Simon83 will be used, which increases a newly enrolled subject’s 
probability of being assigned to the study arm that improves the overall balance in 
these important prognostic factors.84 Briefly, prior to randomization for each 
incoming patient, the imbalance between treatment arms will be determined using 
the accumulating available data on clot volume and GCS. The patient will then be 
randomized with high probability (e.g. ‘weighted coin toss’) to the treatment arm 
that lowers the imbalance. Patients at any given site will not be considered for 
adaptive randomization until the site has enrolled two patients into each treatment 
arm by within-site block randomization. This randomization scheme will be 
implemented using software included in the MISTIE III data base similar to what 
has been successfully implemented in the CLEAR III trial. 
  
9.1.2. Blinding. The examiner performing the 30, 180, and 365 day follow-up 
assessments will video tape the mRS interview assessments and upload the video 
to Glasgow where trained reviewers will classify the interview objectively 
without knowledge of the examiner’s score, patient name, or of the treatment 
details including treatment intensity. 
 
9.1.3. Target Population and Study Samples 
 
i. Target Population. The proposed trial design calls for the enrollment patients 
with ICH ≥ 30 mL and not requiring extraventricular drainage (EVD) for the 
management of obstructive hydrocephalus. The proposed plan includes patients 
with ICH clots in all locations of the brain. 
 
ii. Intent-to-Treat Sample. As the primary analysis, all efficacy and safety 
outcome measures are analyzed under the ITT. Under this principle, the evaluable 
sample includes all subjects who are randomized and receive at least one dose of 
Alteplase and each subject is analyzed according to the treatment group to which 
they were assigned at the time of randomization. 
 
iii. Safety Analysis Sample. All randomized subjects are included in the safety 
analysis sample.   
 
iv. Per-Protocol Sample. The potential for cross-overs in this study is minimal; 
none occurred in the phase II trial.  However, in the case of cross-overs, a per-
protocol sample will be constructed and examined in which treatment-as-received 
is analyzed. Given that clot resolution is a potentially treatment-related post-
randomization variable, this covariate will be examined as an important potential 
mediator of final outcomes as part of a per-protocol analysis. 
 
9.1.4. Overall Methodology Description. Statistical analyses will be performed on data 
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protocols and monitoring reviews and have been exported by the DCC directly 
from the MISTIE III data base (Section D.3.e - DCC grant). The following 
analysis procedures may be applied to blinded (no treatment arm designation, for 
study investigators and staff), partially unblinded (treatment designation only as A 
and B, for DSMB and at interim analyses), and unblinded (full treatment 
designation, for final analyses) data, by DCC staff having the appropriate role 
permissions. 
 
9.1.5. Patient Disposition. Summary statistics will be presented for the analysis sets 
and subgroups, the patients who completed the study, the patients who 
discontinued early from the study, and the reasons for early discontinuation 
including bleeding, loss to follow up, patient withdrawal or refusal, other 
complicating disease, error, or other reasons. 
 
9.1.6. Baseline Characteristics.  
 
i. Demographics. Summary statistics will be presented for age (years), gender, 
ethnicity, presentation center, hypertension history, diabetes, coumadin use, 
antiplatelet drug use. 
 
ii.Medical History. Summary statistics will be presented for medical history, as 
well as presentation temperature, pulse, systolic blood pressure, and diastolic 
blood pressure. Presenting NIHSS, intracranial pressure (ICP), ICH volume, IVH 
volume, location of bleed and IVH score will be provided. 
 
9.1.7. Efficacy Analyses 
 
9.1.7.a. Analysis by MISTIE III Specific  Aims 
 
Primary Aims 
 
Hypothesis 1a: Minimally invasive surgery (MIS) plus recombinant tissue plasminogen 
activator (rt-PA) for 3 days for the treatment of ICH improves functional outcome at 180 
days as measured by the adjudicated mRS 0-3 by an estimated 13% increase as compared 
to the medically-managed patients. The null hypothesis will be a test of no improvement 
of MIS+rt-PA over medical management. Below is a description of the procedure for 
computing estimators of the treatment difference in probability of mRS 0-3 at 180 days 
post-stroke, for the study’s population. 
 
Analysis 1a: To evaluate this null hypothesis in the context of the covariate-adaptive 
randomization scheme, the model in equation (1) will be used, where Trt is 1 for MIS=rt-
PA patients and 0 for medically-managed patients, ICH is pre-randomization ICH clot 
volume, GCS, Age, Diabetes and CVD (cardiovascular disease) are at randomization. 
logit	 ≤3
 =  +  +  + 	 +  +  +    (1) 
 


 
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The standardized estimator of the marginal treatment effect, in the form of RD, will then 
be computed. The advantage of this estimator, compared to the estimator based on a 
simple test of proportions using a z-test without covariates, is that it can lead to greater 
power for hypothesis testing.85 
 
The estimator in this approach is standardized to the overall distribution of covariates in 
equation (1) across the two treatment arms. Under this framework, the probability of a 
good outcome is defined under two scenarios for each patient: if assigned to MIS+rt-PA 
treatment vs. if assigned to the standard medical treatment arm (i.e. the counter-factual 
probabilities). The counter-factual probabilities based on model 1 are presented below as 
equations (2) and (3):  
 = ( +  + 	
 + 
 +  +  + 	
)     (2) 
 
 = ( + 	
 + 
 +  +  + 	
)             (3) 
                 
In equation (2), all patients are ‘forced’ into the MIS+rt-PA group (i.e., Trt=1) and  
estimates the treatment effect, while in equation (3), all patients are ‘forced’ into medical 
management (i.e., Trt=0) and  drops out. The standardized estimator of the average treatment 
effect, using (2) and (3) above, is obtained by first computing the average of the patient-specific 
counter-factual probabilities of a good outcome under assignment to each treatment arm, across 
all patients. Next the difference is taken between this average under assignment to the MIS+rt-PA 
arm, and this average under assignment to the medical management arm. 
 
To derive the average treatment effect, the patient-specific probabilities are averaged across 
patients. The average treatment effect on the log odds ratio scale can be formulated according to 
equation (4). 
 
 
 
It has been shown that this estimator is consistent even if the model in equation (1) is 
mis-specified.86 To test the null hypothesis, a Wald statistic will be computed that is 
equal to the above estimator of the ITT average treatment effect between assignment to 
MIS+rt-PA versus assignment to medical management (on the risk difference scale) 
divided by its estimated standard error. Rejection of this null hypothesis will be based on 
group sequential thresholds (Table 1 below). 
 
In subsequent analyses the model in equation (1) will be modified to include another 
baseline severity measure, such as NIHSS. In addition, a model with IVH volume will be 
explored. The models will be compared using Akaike Information Criterion (AIC) to 
assess the best combinations of predictors. The discriminatory ability of the models will 
be compared using cross-validated area under the Receiver Operating Characteristic 
(ROC) curve. 
 


 
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Hypothesis 1b: Early use of MIS plus rt-PA for 3 days for the treatment of ICH is as safe 
as medically-managed ICH, as measured by rates of procedure-related mortality, 
rebleeding, and infection within 30 days post-randomization. The null hypothesis is: 
Early use of MIS+rt-PA is worse than medical management for a specific safety measure. 
 
Analyses 1b: The number of severe adverse events (SAEs) will be tabulated by SAE type 
at each follow-up time point for the total population as well as by treatment group, with 
particular emphasis placed on group differences at 30 days post-randomization. Any 
treatment group differences in SAEs enumerated for interim analyses will remain blinded 
to investigators associated with this study. Partially un-blinded results (e.g. group ‘A’ 
versus ‘B’ where the labels ‘A’ and ‘B’ are randomly assigned to the surgical and 
medically-managed groups) will be made available only during the closed sessions of 
DSMB meetings.  
 
Methods of equivalence87 will be used to statistically determine if the proportions of a 
particular type of SAE are equal among both treatment groups in order to test the 
hypothesis that MIS plus rt-PA is safe. Equivalence testing deems the rates of any event 
to be equivalent between populations as long as the group difference in this rate is 
statistically within some pre-specified tolerance. For this trial, the tolerance value will be 
defined as 10% for the primary adverse events of 30-day mortality, rebleeding, and 
infection, and 5% for first-week operative mortality. Thus, the rates of adverse events 
seen in the MIS+rt-PA group can be higher than those in the medically-managed group, 
and yet still be considered equivalent as long as the upper one-sided 95% confidence 
intervals on rate differences are ≤ 10%, or < 5%, depending on the safety measure. 
 
Specific Aim 2.  
 
Hypothesis 2a:  EOT clot volume and/or percent EOT ICH reduction are related to mRS 
functional outcome regardless of treatment. The null hypothesis is: EOT clot volume 
and/or percent EOT ICH reduction trajectories has/have no effect on functional outcome 
regardless of treatment. 
 
Analysis 2a: This hypothesis investigates the relationship between the magnitude of clot 
resolution and functional outcome as measured by dichotomized mRS scores (i.e., mRS 
0-3 vs. 4-6) at 180 days post-stroke. This is an important component of analysis that has 
been missing from other surgical trials and will provide for a very stringent test of 
volume-reduction hypothesis. The goal of this analysis is to test the importance, or lack 
thereof, for volume-reduction goals in all study patients. This will be best implemented 
by considering the relationship between clot resolution and functional outcome, as 
measured by mRS, irrespective of treatment assignment. 
 
The analysis for this aim will proceed in two phases. In the first phase a model for clot 
resolution over time will be developed. In the second phase, predicted trajectories from 
phase one will be used to assess the relationship between the magnitude of clot resolution 
and “good” outcome at 180 days. Generalized Linear Mixed Models (GLMMs) will be 


 
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used88,89 to estimate patient-specific clot resolution over time. These models will include 
a random intercept for each patient to represent unobserved factors that are common to 
ICH volumes for a given patient and a random slope to represent the heterogeneity of 
clot-resolution trajectories over time across patients as shown in equation 5. 
 
 
Several extensions to the “base model” described above will be considered by changing 
the assumptions about the random effects and their variance-covariance matrix structure, 
including models a) without random intercept, b). without random slope, c) with 
heteroscedastic within person residual errors, d) with grouped covariance structure by 
study arm, where the variance-covariance matrix of random effects becomes a block-
diagonal matrix, where one block represents the variances and covariances of random 
effects for MIS+rt-PA arm, and the other block – for the medical management arm and e) 
heteroscedastic residual errors that are different by study arm.90 The models will be 
compared using likelihood ratio tests and Akaike Information Criterion (AIC). In 
addition, since a ‘plateau’ or ‘floor’ effect of clot resolution over time is likely, 
subsequent models to statistically test for these fixed effects will consider clot resolution 
in non-linear terms, such as linear/cubic splines and other non-linear functions. From the 
final model, the empirical Bayes estimates of the random slopes will be computed to be 
used in the next phase. The second-phase analysis will be based on multivariable logistic 
regression models that include the estimated clot resolution trajectories over time, the 
covariates listed in equation (1) above, and the dichotomized mRS at 180 days post-
stroke as the outcome.  
 
Hypothesis 2b: There is a percent EOT clot reduction and/or EOT clot volume that 
maximize(s) the probability of a “good” outcome. The null hypothesis is: There is no 
relationship between percent EOT clot reduction and/or EOT clot volume (as 
dichotomized categories) and “good” functional outcome. 
 
Analysis 2b: In this analysis, the clot resolution will be represented as either percent clot 
resolved at EOT or the EOT clot size. The following cut-points will be investigated as 
best predictors of “good” outcome at 180 days: 60, 70 and 80% (EOT percent clot 
resolved), and 10, 15 and 20 mL (EOT clot volume). For each cut point, a dummy 
variable will be included in the multivariable logistic regression model for “good” 
outcome adjusted for covariates in equation (1). The models will also assess whether the 
best cut-points are treatment dependent by including an interaction term between 
category or percent EOT clot resolution (or the EOT clot volume) and the treatment 
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The models in aims 2a and 2b will be expanded to consider any mediating or modifying 
factors for the effect of surgical intervention on functional outcome scores. The statistical 
investigation of mediators that may have an effect on surgery is motivated by the desire 
to understand whether there is a causal chain whereby surgery affects clot resolution, 
which in turn affects functional outcome. Although there is no direct test for the existence 
of such a causal chain, the data can be examined to explore whether they are consistent 
with such a hypothesis. The methods proposed by Baron and Kenny91 will be used in 
these analyses, where a series of three regression models will be created to test for 
bivariable associations between surgery on functional outcome, surgery on clot 
resolution, and clot resolution on functional outcome, respectively. 
 
Analysis of Secondary Outcomes. Analysis of the secondary outcomes as described 
above will proceed in three phases: 1) exploratory, 2) cross-sectional evaluations (30 day 
mortality and safety events, 180 and 365 day post-stroke outcomes, etc.), 3) full 
longitudinal evaluations (30 to 365 days), and 4) cost-benefit and cost-effectiveness 
analyses. 
 
Exploratory Phase. The initial phase of the statistical analysis will consist primarily of 
exploratory methods that include the examination of these data for indications of unusual 
observations, inconsistencies, or gaps in any pertinent outcomes and related measures; 
use of visual techniques (e.g., histograms, box-plots, etc.) to determine the distribution 
and spread of these data; the calculation of summary statistics (e.g. means, medians, 
variances, etc.) to determine the central tendencies and variability for continuous 
variables; and the use of contingency tables to assess frequency distributions for 
categorical variables. Any unusual observations or outliers will be reviewed with the 
DCC for possible data entry errors, and verified prior to any analyses performed on the 
data. Exploratory data analyses will be used to summarize these data for the overall 
patient population and separately by treatment arm (with appropriate blinding restrictions 
as required), and will primarily occur in conjunction with DSMB evaluations, that is, 
before the end of the trial and before unblinding of the leadership team. 
 
Cross-Sectional Phase. The second phase begins after the unblinding, and will compare 
cross-sectional outcomes between the treatment arms using univariate confirmatory 
analyses (e.g., t-tests, analysis of variance models, logistic regression models, etc.). These 
group comparisons will be guided by our initial exploratory analyses. Logistic regression 
will be used to assess 365-day differences in mRS (0-3 vs. 4-6 and 0-2 vs. 3-6). The 
logistic models will account for design aspects such as potential within-site clustering 
that might otherwise lead to biased estimates in the standard errors associated with the 
regression coefficients. Additionally, these models will control for potentially 
confounding variables, including pre-randomization ICH volume, IVH volume (or 
presence, depending on the variability in IHV volumes), baseline stroke severity, age, and 
co-morbidity (diagnosis of Diabetes or history of cardiovascular disease). 
 
When we consider the secondary analysis of the ordinal mRS, we will estimate a 
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The proportional odds model is very similar to the logistic regression model described 
above, with the difference being that a treatment effect leads to an increase in the 
likelihood of a patient being in any subsequently lower mRS category. The probabilities, 
ak, are now cumulative probabilities which incorporates all outcomes below any given 
level. The set of intercepts, ak k=0, 1, …, 5, define the initial probabilities of these 
cumulative levels, covariates are again included through β and X, and the treatment 
difference θ now describes the log-odds of moving from any cumulatively higher (worse) 
category, into any cumulatively lower (better) category. For instance, here θ describes 
both how the MIS+rt-PA changes the probability of ICH patients away from a potential 
mRS category of ‘Dead’ (6) to ‘No Symptoms through Severe Disability’ (0-5), as well 
as how the MIS+rt-PA changes patient probabilities away from ‘Severe Disability or 
Dead’ (5,6) to ‘No Symptoms through Moderate Disability’ (0-4) and so forth. This 
model is more efficient than the simple dichotomous approach since it uses the available 
information across the scale of the measure. To examine the proportional odds 
assumption, we will additionally examine generalized logistic models that replace β and θ 
with βx and θx, allowing non-parallel effects between successive cumulative categories. 
In the event that the proportional odds assumption is rejected, we will present results 
from the generalized logistic models. 
 
Survival models will be constructed to examine the mortality, for the MIS+rt-PA and 
medically-managed groups. Standard Cox proportional hazard models will initially be 
examined. These models are commonly written as: 
 
 
where λ0(t) is a non-parametric baseline hazard function, γ is a vector of regression 
coefficients related to the X covariates and ϕ is the parameter for the treatment effect of 
MIS+rt-PA on the hazard of death (mortality). This model may be extended by including 
time-dependent covariates and non-proportional hazards as deemed necessary through 
diagnostic checks. Observed mortality will also be compared with predicted mortality 
based on clinical presentation, overall and by treatment group. Predicated mortality will 
be estimated using the most recent Tuhrim model which takes IVH volume and presence 
of hydrocephalus into account.92 
 
Longitudinal Phase. Finally, the third analysis phase will examine the secondary 
outcomes that are longitudinally collected at baseline and the follow-up time points (e.g. 
at 30, 90, 180, 270, and 365 days post-stroke). These data will have within-patient 
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analytical methods that properly estimate the coefficients and their associated standard 
errors in the analysis models. Since the overall goal of the trial is to compare subjects 
receiving the MIS+rt-PA intervention with subjects receiving medical standard of care, a 
marginal model estimated using a generalized estimating equations (GEE) technique93 is 
appropriate. The GEE technique requires specification of the standard ‘mean’ model, as 
well as specification of a working ‘association’ model. One strength of GEE is that the 
parameters of main interest in the mean model (i.e. the intervention effect) are consistent 
regardless of whether the association model is specified correctly. Generalized Linear 
Mixed Models (GLMMs) may also be used to estimate subject, surgeon, and site-specific 
effects.88,89 
 
Cost-effectiveness Analysis. Cost-benefit and incremental cost-effectiveness analyses 
will be performed using data on length of hospital stay, patient disposition (home, long-
term ambulatory and nursing care, death), time to return home, and cost of procedures 
and hospital stay. These analyses will be performed with respect to both 180 and 365-day 
periods post-stroke. For cost-benefit analyses, the cost of ICU and the rest of the hospital 
stay, including the cost of MIS+rt-PA will be considered. Cost data will be obtained from 
the trial (secondary outcomes) and from the literature.94,95 For the incremental cost-
effectiveness analysis, the distribution of hazard rates of changes in mRS and in-hospital 
stay will be applied between the treatment arms, considering both short-term (acute care) 
and long-term care post-stroke. The model will include a one-year time horizon and a 
secondary analysis of life-time horizon. The analysis will be generated from the health 
care system perspective for costs combined with the quality-of-life measures for 
effectiveness (i.e. SIS, EQ-5D, and Personal Health Utility Interview). Various measures 
of effectiveness will be employed and the robustness of the findings to changes in the 
source of patient utility/quality of life measures will be reviewed. This will be 
supplemented by looking at ranges for patient utilities reported in the literature.96 Finally, 
probabilistic sensitivity analyses will be conducted using a bootstrap approach, producing 
a scatter plot of incremental costs and effects to assess the impact of statistical 
uncertainty on the robustness of the conclusions.96  
 
9.1.8. Safety Analyses. The primary safety measures for this study are symptomatic 
intracranial bleeding, infection, and 30-day mortality.  The safety thresholds for 
these measures have been set as: 30-day mortality > 60%, first week operative 
death rate > 10%, a MIS and rt-PA related symptomatic brain bleeding  rate > 
25% (events identified within the first 30 days and assessed as occurring during 
active treatment or during the 72 hours after treatment will be monitored), and a 
procedure-related brain infection rate > 15% (over the initial 30 days). 
 
9.1.8.1. Adverse Events (AE) and Serious Adverse Events (SAE). All AEs and 
SAEs are summarized by type and by treatment group in terms of frequency of 
the event, number of subjects having the event, timing relative to randomization, 
severity (mild, moderate, severe), and relatedness to the study treatment 
(definitely, probably, possibly, definitely not). At the end of the study, the 
cumulative incidences of these events will be compared between the two 


 
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treatment groups using Fisher’s exact test. Additionally, generalized linear mixed 
models for binary data will be used to examine AE and SAE probabilities 
between treatment groups while accounting for potential confounders and sites 
center clustering effects. 
 
9.1.8.2. Time to Death and Time to Re-Bleed. As a secondary assessment, time 
to death or re-bleed within the one-year follow up period are compared between 
the MIS+rt-PA and medically-managed groups adjusting for appropriate baseline 
covariates. Provided the model assumptions are met, a proportional hazards 
regression model may be used for the analysis as described above. 
 
9.1.8.3. Safety Monitoring. The DCC will generate periodic DSMB reports (We 
assume that the total number of subjects enrolled per six months in a single 
treatment group will be approximately 30; thus, eight semi-annual looks at the 
data will be suggested to the DSMB. As usual though, periods for reporting will 
be discussed and finalized at the initial DSMB meeting). Each report will provide 
cumulative summary statistics on enrollment; subject status in the study (e.g., 
number completed at 3-month, 6-month, 9-month, and 12-month assessments); 
baseline characteristics; protocol violations; safety data, including AEs and SAEs 
by AE code, severity, and relatedness to the study medication; outcomes data (if 
coinciding with an interim analysis – also to be discussed and finalized at the 
initial DSMB meeting); and data management/quality information (e.g., 
timeliness and completeness of data entry by the clinical sites centers via the 
MISTIE III Trial Website; number of queries generated and resolved). Closed 
reports will be generated for the DSMB voting committee members with data 
provided by blinded treatment group (noted as A and B). Only the unblinded 
statistician has access to the efficacy endpoint data. These data will not be 
included in the reports for the safety reviews. The outline of these proposed 
DSMB reports will be included in the Manual of Operations and Procedures 
prepared by the Clinical Coordinating Center (CCC). In an interval as yet to be 
determined (monthly or quarterly), the CCC will also generate a Safety 
Monitoring Report to be distributed to the DSMB. This report contains only the 
enrollment, subject study status, safety, and data quality information. The 
Executive Committee also receives the Safety Monitoring Reports. The DSMB 
will have discretion to recommend stopping the trial early if safety concerns 
become substantial.  Safety stopping rules for each of the primary safety 
outcomes will be developed and used to help the DSMB make its safety 
assessments. The DSMB makes recommendations to NINDS who has authority to 
stop the investigation for safety or any other reason after discussion with the trial 
PI. 
 
9.1.9. Statistical Power for the Primary Efficacy Aim. The MISTIE Phase II results, 
for all available data (trial-standardized “pilot” and randomized), demonstrated a 
best estimate for the increase in the probability of achieving an mRS 0-3 of of 
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management 180 days post-stroke. When only randomized patients are considered 
(N=90), the best estimate for the unadjusted effect size is approximately 11.0% 
[95% CI: (-7.9%, 29.7%)], and approximately 12.0% [95% CI: (-2.7%, 26.9%)] 
after adjusting for baseline clinical characteristics. These estimated effect sizes 
are statistically equivalent given the similarity in the CIs. Nevertheless, their 
range provides a strong motivation for conducting the proposed Phase III trial to 
confirm these clinically beneficial findings. The analogous unadjusted and 
adjusted effect sizes based on non-lobar ICH patients are very similar and 
statistically equivalent to these effect sizes. 
 
 
In the proposed design, subjects will be randomized to MIS+rt-PA versus medical 
management using a covariate-adaptive design. The goal of this randomization 
scheme is to obtain an improved balance across study arms in the number of 
subjects with certain pre-randomization variables that are strongly predictive of 
the functional outcomes at 180 days post-stroke. These variables include pre-
randomization clot size and baseline severity of impairment as measured by GCS. 
The design of Pocock and Simon83 will be used, which increases a newly enrolled 
subject’s probability of being assigned to the study arm that improves the overall 
balance in these important prognostic factors.84 The trial will initially enroll ICH 
patients until either a maximum of 500 patients is accrued or the trial is stopped 
early for efficacy or futility using group sequential boundaries described below 
(Table 1).  
 
 
 
 
The above stopping boundaries are used after 250, 375 and 500 patients, 
respectively, have 180-day post-stroke measurements. If the test statistic 
described above exceeds the efficacy boundary, or if it is less than the futility 
boundary, the enrollment of patients is stopped early. The futility boundary at 
each interim analysis corresponds to a one-sided test at level 0.0001 of the 
hypothesis that the probability of a “good” outcome (mRS 0-3) is ≥ 11% under 
assignment to MIS+rt-PA vs medical management.97 These boundaries are more 
aggressive than the efficacy boundaries (the latter of which are based on O’Brien-
Fleming boundaries, but are proportionally increased to strongly control the 
study-wide Type I error rate at the 5% level). 
 
The above design has the following properties as described in Figure 1 and Table 
2: 
 
i) 
At least 88% power to detect a treatment benefit ≥ 13%, assuming the 
probability of mRS 0-3 under medical management is 25%; 
 


 
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ii) 
At least 81% power to detect a treatment benefit ≥ 11%, assuming the 
probability of mRS 0-3 under medical management is 20%. 
 
 
 
9.1.10. Statistical Power for Secondary Aim 2a. Based on MISTIE II data (Table 1), 
the relationship between mRS score and EOT clot size is estimated as an OR 
(95% CI) of 3.82 (0.97-15.1, p=0.056). Simulations were performed on 1000 
generated samples of 250 patients per group based on randomized MISTIE II 
patient data. These simulations indicate that with 500 total patients the estimated 
power to detect an adjusted OR of 3.82 is ≥ 98%. Additional simulations suggest 
that there is ≥ 90% power for detecting an adjusted OR as low as 2.38 to evaluate 
the strength of the relationship between clot size, dichotomized as ≤ 15 vs > 15 
mL and mRS outcome (0-3 vs 4-6). 
 
9.1.11. Innovative Methods. Categorical outcomes such as the mRS, GOS, etc, are 
termed composite outcomes in the statistical literature as they combine outcomes 
of interest such as ability/disability with mortality outcomes. There have been 
recent methods developed to allow simultaneous examination of the 
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mortality in the actual outcome scale. Joint analyses based on generalized linear 
mixed models (GLMM) have been introduced,98 and are proposed to extend these 
models for the brain injury/stroke literature using data from this trial. A latent 
Gaussian process will be posited to represented an individual’s underlying 
propensity to regain ability which describes relationships between a subject’s 
longitudinal outcomes. A random effects model corresponding to the dichotomous 
mRS logistic regression model outlined above may be specified as: 
 
 
 
where Y is the binary outcome for patient i at the time j and Yij=1 if mRSij=0-2 
and Yij=0 if mRSij=3-5. Note that the category mRSij=6, indicating death, has 
been removed from the outcome definition such that Yij describes ability for those 
remaining alive at time j. 
 
9.1.12. Missing Data. Based on previous MISTIE and CLEAR studies performed in this 
group of stroke patients, the CCC will make substantial efforts to ensure complete 
collection of data for all patients, and to accrue minimal LTF to optimize 
evaluation of the primary outcome of 180-day adjudicated mRS post-stroke. In 
the CLEAR III trial, there is a LTF of 2% among the first 100 patients as reported 
to the DSMB. Rates of missing data and LTF will be reported, and no imputation 
of the primary outcome measure will be undertaken. However, multiple 
imputation methods based on regression modeling99 will be used to estimate 
missing covariates incorporated in the logistic regression model for estimating the 
adjusted treatment effect. In addition, the effects of 
incompleteness/noncompliance will be quantified through sensitivity analyses, the 
gold standard in the field.100 
 
9.1.13. Multiplicity. The study design for the primary comparison is a two-arm 
randomized trial with a single-treatment contrast, hence, multiplicity from several 
tests is not an issue. 
 
9.2 
Data Monitoring 
 
Data safety and monitoring procedures will be in place before enrollment begins and 
monitoring will be performed on a regular basis throughout the subject accrual and 
treatment periods.  
 
Medical Monitor: Dr. Carlos Kase, MD, a stroke physician not involved with the study, 
will serve as the Medical Safety Monitor. Dr. Kase is a neurologist with experience 
treating acute ischemic and hemorrhagic stroke as well as clinical trials. He is familiar 
with the proposed study intervention. He will be responsible for ongoing monitoring of 
reports of SAEs and MEOIs submitted by the clinical centers to ensure good clinical care 
and to quickly identify safety concerns. If necessary, he will suggest measures to be taken 
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require frequent measurement of laboratory values predictive of the event. In the event of 
unexpected SAEs or an unduly high rate of SAEs, he will be responsible, with the 
assistance of the CCC, for notifying the DSMB Liaison. 
 
ICU Care Medical Monitor: Dr. J. Ricardo Carhuapoma, MD will serve as the ICU 
Care Medical Monitor. He will review all serious adverse events, focusing on American 
Association of Neurology (AAN) guidelines and ICU protocols prior to, during, and 
following each SAE. He will also review ICU care and drug administration protocol 
deviations and mentor the site PIs on protocol compliance. Dr. Carhuapoma is a member 
of the Johns Hopkins University neurocritical care team and manages critically ill 
patients with neurologic and neurosurgical diseases. She has extensive published 
experience with the CLEAR trials and procedures, and radiologic evaluation of the 
MISTIE procedure. He participates in clinical and basic science research with 
collaborators in the departments of stroke neurology, neurosurgery, and anesthesia. His 
clinical interests include intracranial pressure, ICH and IVH, and ICU resource 
allocation. He has authored multiple MISTIE Phase II publications. He will work closely 
with the leadership and the Safety Compliance Officer to assess ICU protocol 
performance in relation to functional outcomes in MISTIE III. Dr. Carhuapoma will also 
be on call to assist in enrollment and protocol performance decision-making. 
   
10 
DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE       
REPORTING 
 
10.1 
Records to Be Kept 
 
Records Retention. Participation in this study requires that original study documents be 
retained for a minimum of 2 years following notification of the FDA by the study CCC 
that investigations have been discontinued.  This standard complies with U.S. FDA 
regulations (21 CFR §312.62[c]). Records must not be destroyed without first contacting 
the CCC to ensure that the time limits defined in the regulations have been met. Study 
centers in countries other than the US participating in the trial may have to comply with 
different requirements but should comply with whichever requirement is longer.  
 
For the purposes of this section, “original study documents” are defined as: 
 
• 
Subject medical records created at or available to the enrolling center during the 
subject’s participation in the trial, or any other document that supports entries in 
the EDC system and represents the original source of that information, including 
but not limited to applicable sections of medical charts, patient correspondence, 
laboratory data, pharmacy logs and drug accountability forms, as well as any 
forms or documents used to compile or maintain original subject data or study 
procedural information. Intermediary documents and worksheets used to organize 
and compile original records into a form that facilitates easier transcription into 
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directly into the EDC in which case the EDC system represents the original study 
document. 
 
• 
All Essential Regulatory Documents (as defined under Good Clinical Practice 
Regulations) including: all material communications with the IRB; all 
communications with the Sponsor (including the surgical center, reading center, 
outcomes committee, endpoint committee, safety monitor, Emissary’s monitoring 
staff, etc.) that are related to study subjects or which otherwise document material 
study-related procedures or safety issues; and, all training records and 
documentation that all participating staff are suitably qualified and authorized 
(CVs, 1572, Delegation Log, etc.). 
 
• 
Archival copies of the data and electronic documents from the VISION-EDC 
system. 
 
All study documents should be uploaded to the Electronic Trial Master File (eTMF) 
section of the VISION-EDC system. VISION will be used as the master repository for all 
site and Sponsor regulatory documents, and all patient source documents with the 
exception of DICOMs and any records not uploaded to the EDC (perhaps for 
confidentiality reasons or do to specific site discretion, such as might be suitable for 
financial contracts), sites generally do not need to maintain duplicate local files unless 
otherwise mandated by local institutional requirements. 
 
At the conclusion of the study, all entered patient data and uploaded documents (with the 
exception of Modified Rankin videos and DICOMs) in the VISION-EDC system will be 
archived and provided to the site on DVDs. Modified Rankin video interviews uploaded 
to the Glasgow outcomes center will be destroyed at the conclusion of the trial in 
accordance with informed consent commitments. Due to their extreme size, DICOMs 
submitted to the EDC system will not be maintained long-term in the EDC system, but 
rather will be promptly deleted once they have been reviewed by the reading and surgical 
centers. Sites will be responsible for retaining DICOMs via their local PACS system (or 
local copies of CDs). 
 
Regulations require that study documents (including the archive CDs and any study 
documents not uploaded to the EDC) must be retained in the files of the responsible 
investigator for potential review by regulatory agencies. As this is an international study 
conducted under the jurisdiction of multiple regulatory bodies (FDA, NIH, Health 
Canada, ICH, etc.) and for not in support of any one specific regulatory application, 
retention requirements may be considerably longer than what may be required under local 
or regional regulations or other trials being conducted at the site. As such, the principal 
investigator must retain the study documents until otherwise instructed by the 
coordinating center. The expected retention period is a minimum of 2 years after the final 
report is submitted to the FDA after the conclusion of the overall clinical trial, 
irrespective of any particular site’s participation. 
 


 
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10.2 
Role of Data Management 
 
10.2.1 Investigator/Institution will permit trial-related monitoring, audits, IRB/IEC 
review, and regulatory inspections by providing direct access to source data and 
documents. 
 
Data Collection and Reporting: Data for each patient will be reported and 
recorded on electronic case report forms. Electronic case report forms (eCRF) 
must be completed for every randomized patient. This means all patients who 
have a signed informed consent, undergo screening procedures, and fulfill all 
eligibility criteria. 
 
The electronic CRF (eCRF) will be completed by the site investigator(s) listed on 
the Form FDA 1572 or otherwise designated by the site Principal Investigator. If 
any entry on a source document requires change, a single line will be drawn 
throughout the incorrect entry, and the correction will be entered in ink, initialed 
and dated. Whiteout, erasures, or obliteration on source data are not permitted. 
 
10.2.2 Statistical Center responsibilities as the Data Coordination Center (DCC). 
The responsibilities of the DCC in the MISTIE III trial include: trial design 
development and monitoring of trial performance, data management planning, 
review and verification  of CCC data for analysis/presentation, statistical design 
and analysis, and reporting of results for various aspects of trial management 
(e.g., safety, site performance, surgical performance, fidelity of adaptive 
randomization) and trial evaluation (e.g., DSMB reporting, interim analyses, 
publications, resource sharing). The DCC will collaborate closely with CCC 
throughout the duration of the trial, and will rely on CCC leadership to provide 
the appropriate scientific and clinical guidance to ensure the successful 
completion of the responsibilities described above.    
 
10.3 
Quality Assurance 
 
MISTIE III will have a robust safety and data monitoring program in full compliance 
with NIH policy of 10-Jun-1998 as expanded by NINDS guidelines published 14-Sep-
2011 in addition to compliance with all applicable U.S. and international GCP 
regulations. This program, designed to safeguard the well-being of study participants and 
to ensure scientific integrity, will include the following components:  
 
• A NINDS-appointed independent DSMB; 
• A dedicated safety committee comprised of two independent medical monitors (a 
neurologist and a neurointerventionalist/neurosurgeon) with a dedicated 
independent safety compliance officer; 
• Oversight of the CCC and the multicenter trial by an independent IRB in addition 
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• A surgical committee with a dedicated surgical center providing oversight during 
patient enrollment;  
• An outcomes committee composed of an independent monitor to review the 
integrity of the multiple outcome assessments and a centralized, dedicated 
Glasgow outcomes center providing standardized adjudication of mRS 
assessments; 
• An imaging reading center providing independent assessment of clot resolution, 
edema, and mass effect; 
• Automated data quality checks at the time of EDC form completion by the 
investigational site;  
• Dedicated independent data monitoring and QA teams (Emissary International 
and The George Institute); 
• A robust training program prior to site activation, interactively during each 
medical and surgical enrollment, and with monthly advanced training topics, 
monthly newsletters, and quarterly performance reviews. 
 
The components of this multifaceted approach, including each dedicated team’s specific 
responsibilities, are discussed below. 
 
10.3.1. Data and Safety Monitoring Board  
 
A DSMB will provide an independent review of the research, interim safety and efficacy 
data, and progress towards achieving the goals of the study. To enable the CCC to 
properly manage the trial, the project leadership, and key personnel will jointly work on a 
DSMB plan early in the process. After the award but before the project begins, CCC will 
be coordinated with the DCC to develop a detailed monitoring plan. The NIH-appointed 
DSMB will then approve the plan. The monitoring plan will describe the process for 
reporting adverse events to the IRB, FDA, and NIH.  
 
DSMB Administration: DSMB(s) will monitor safety and performance and review 
interim trial analyses. At periodic patient-completion milestones, the DSMB will meet to 
review the data for safety, efficacy, and quality. Investigators and staff involved in the 
interim analyses will attend open sessions of the DSMB meetings to present analyses and, 
if needed, respond to questions and directly obtain requests for new analyses or revised 
presentation formats. The trial leadership will follow the pretrial steps recommended by 
the NIH’s NINDS. The CCC has extensive experience with DSMB preparation and 
reviews. 
 
Interim safety analyses will be prepared for the external DSMB on a pre-arranged 
schedule (such as semi-annually or after enrollment of a fixed number of subjects) to 
evaluate efficacy and safety. Safety measures include: monitoring incidence of 
symptomatic and asymptomatic intracranial bleeding events (i.e., hemorrhage extension, 
new hemorrhage, catheter tract hemorrhage) through daily computerized tomography 
(CT) scans for the first four to five days after enrollment and until day seven (about 24 
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infection, and in-hospital mortality. Safety events will trigger a “suspend recruitment and 
review” by the DSMB. The DSMB will then investigate the presumed cause and impact 
of these events are: 30-day mortality > 60%, a MIS and rt-PA related symptomatic 
bleeding rate > 25% (events identified within the first 30 days and assessed as occurring 
during active treatment or during the 72 hours after treatment will be monitored), first 
week operative death rate > 10%, and a procedure-related infection rate > 15% (over the 
initial 30 days). If any of these events are attributable to the catheter insertion or 
manipulation, or to the rt-PA injection at a 95% confidence level, then the study will be 
suspended for a complete safety and efficacy review. The FDA IND division will be 
notified according to FDA regulations, part 312. 
 
 
Prior to DSMB report generation, the CCC will work with the enrolling sites to 
finalize the case forms, compile the data, conduct all requested analyses, and compile 
suitable reports, tables and graphs. General rules for this analysis are laid out in the DCC 
grant.  All deaths will be reviewed. The most likely complications from this therapy are 
increased mortality, rebleeding, and cerebritis.  We propose to analyze the safety data in 
two groups to approximate complications attributable to surgery and to the ongoing drug 
irrigation.  The first consists of bleeding and complications within the first 24 hours after 
catheter placement.  The second consists of bleeding and procedure-related complications 
in the subsequent six days. 
 
10.3.2. Safety Committee and Safety Officer 
 
Safety Compliance Officer: The DSMB and IRBs (see below) require a process for 
timely communication of adverse events and complication rates to the local sites as well 
as regulatory agencies. Thus, an essential component to the process is the safety 
compliance officer. The safety compliance officer will have the day-to-day responsibility 
for ensuring that adverse events and similar safety-related information are promptly 
collected, medically reviewed by the medical monitor(s) and the MISTIE III safety 
committee, and appropriately reported to regulatory agencies in compliance with GCP 
standards. We have found that assigning an experienced project manager to this 
responsibility allows the physician-experts on the safety team to focus on medical review, 
while the safety compliance officer focuses on maintaining quality, efficiency, and 
regulatory compliance. The safety officer will be responsible for preparing and 
communicating incoming documents and reports to the study leadership. 
Inclusion/exclusion criteria, review-of-system reports, medical history, medical events, 
and radiographic imaging entries will be cross-checked and reviewed by applying real-
time database algorithms, crosschecking sentinel dates and times, procedures, AEs, 
SAEs, and protocol timelines. As aggregate data reports and quarterly and annual 
progress reports are prepared, the safety compliance officer will query the enrolling site 
personnel as needed and follow the data entry tasks to completion.  At the time of each 
review, the safety compliance officer will coordinate the review of the available 
information and imaging with the safety committee members and follow the voting 
process through to consensus. The safety compliance officer will serve as the liaison 
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information as needed and to elicit agreement or disagreement of the site personnel with 
the committee’s assessment.  
 
Online Safety Committee Review: Our safety compliance officer will customize and 
implement a SAE/MEOI reporting/review algorithm, already in use for current trials that 
include online review and electronic signature (using the regulatory-compliant electronic 
signature capability within the EDC) by the medical monitors and safety event committee 
members. The safety compliance officer will manage the development and revision of 
trial protocols, MOP, SOP, and protocol working guidelines with the trial leadership.  
 
Reporting Dictionary and Data Standards: The safety compliance officer will work 
closely with the trial vendors to develop the EDC systems and the corresponding paper 
bedside worksheets, used at the bedside for all safety-related events and processes. The 
Common Terminology Criteria for Adverse Events (CTCAE) dictionary has been 
adapted for the hemorrhage trials to allow for trial-specific reporting using standardized 
Medical Dictionary for Regulatory Activities (MedDRA) coding. The safety compliance 
officer will also produce various presentations to educate clinical site personnel on the 
protocol and the AE/SAE/MEOI reporting process. 
 
10.3.3. Surgical Committee/Surgical Center 
 
Organization: Two neurosurgical teams (Cincinnati and Chicago; neurosurgeon and 
radiology specialist at each site) will share the review of every potential patient just prior 
to randomization to assess eligibility for the trial, assess case-specific risk factors, and 
provide specific guidance to the site investigators regarding the overall stability of the 
clot and patient, surgical procedure, catheter placement, and dosing decisions. 
 
Technical Uniformity: The surgical center will review each procedure for the two 
technical aspects of surgery: catheter placement and drainage.  Reviews will be 
performed in parallel with randomization and scheduled safety reviews. The, CT scans, 
surgical record, surgical case report forms, and the location of the catheter will be 
evaluated.  Adequate catheter location will be achieved when the tip is located in a region 
defined as the “central core,” within two-thirds of the overall hematoma diameter (i.e., 
the catheter tip must have more than one-third of the diameter of the ICH separating it 
from the margin of the clot).  The clot dissolution rate, drainage records, ICP records, and 
nursing case report forms will serve as the data supporting uniformity of drainage.  The 
surgical center will review these data concurrently with the catheter placement data.  
 
Technical Feasibility of Catheter Placement and ICH Drainage: The MIS catheter 
placement will be evaluated for technical feasibility by determining the number of 
catheters placed in one pass with adequate tip location, giving allowance for one-time 
repositioning of the catheter, followed by successful aspiration to first resistance.  Clot 
drainage will be considered technically complete or effective when it reaches the goal of 
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Operative Procedural QA: Quality assurance will be maintained at each treatment site 
by additional review of the medical record by the surgical center after subject treatment. 
This includes: 1) review of the operative report to confirm proper use of the image 
guidance system and ensure the provided introducer cannula and soft ventricular catheter 
were properly used in each case; 2) review of the radiological findings comparing pre-
surgical hematoma volume and post-surgical-intervention hematoma volume to ensure 
accurate blood aspirate; and 3) review of the surgical record, the surgical case report 
forms, and radiographic films to ensure proper catheter placement. 
 
10.3.4. Glasgow University Outcomes Committee/Outcomes Center 
 
We propose, via collaboration with the stroke trials team in Glasgow, to take a robust 
approach to efficacy endpoint assessment through training, certification, and central 
adjudication.  
 
Observer Training: The Glasgow team has published on issues, including the choice of 
outcome scale, the optimal cut-points on these scales and the choice of analysis approach. 
They have also developed a training and certification program for scoring of the mRS, 
which has been used in three major acute stroke trials involving several thousand 
investigators and over 5500 subjects (CHANT, SAINT I & 2). Their preliminary data 
convincingly illustrate the extent of inter-observer variation and endpoint 
misclassification, and suggest that training and centralized adjudication help to limit 
variability.  
 
Efficacy Endpoint Verification: Our Glasgow colleagues have developed and validated 
digital video recording of mRS outcome assessment interviews and duplicate centralized 
review of the outcome score – a method which also delivers objectivity in a trial with 
open design. There are four potential advantages to this method, some of which would 
specifically enhance design of the MISTIE III trial: 1) investigators are aware that they 
are being monitored and will conduct their interview thoroughly, ensuring that they cover 
the crucial elements to justify their score; 2) the video recording permits central scoring 
by independent assessors who can be guaranteed to be completely blinded to treatment 
(objective blinded endpoint); 3) the central assessment can be scored by a committee of 
assessors reviewing responses in the language of the subject; and, 4) to ensure agreement 
over controversial cases and consistency across the trial. While the central assessment 
will primarily be intended to make a rigorous distinction between mRS 0-3 and mRS 4-5, 
it may allow more detailed assessment of disability and the validation of a more 
sophisticated ranking methodology, which they are developing.   
 
Video Recording and Quality Control: The mRS score as well with other assessments 
will be recorded locally during the subject video-interview assessment and entered into 
the EDC system in standard fashion. The digital recording of the assessment will be 
uploaded to the Robertson Centre for Biostatistics in Glasgow via an encrypted secure 
web form. An endpoint assessment committee will convene to review the recording and 
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will be entered into the EDC system and compared to the local score. There are three 
possible conclusions to this process: 1) if there is agreement between the local and central 
mRS scores, this is accepted as the final mRS outcome; 2) if there is disagreement, the 
endpoint committee will reconvene and the case will be reviewed.  If disagreement 
persists and the assessment has been technically adequate, the central score will be 
considered final and feedback will be provided to the local investigator; 3) if there is 
disagreement and the endpoint committee concludes that the recorded assessment is 
inadequate, a data query will be issued and the site will reassess the subject.  This 
information will be considered and a final mRS score then assigned using the same 
process. The use of recording technology does introduce some practical considerations 
that have been addressed in the Glasgow pilot study.  In the pilot, technical problems 
arose in only 2% of assessments; after nearly 200 patients and two years in CLEAR III, 
there have been no technical problems that prevented obtaining the Glasgow mRS score. 
As outlined, all subjects will have a score recorded locally that can be used as a backup.  
 
 
The additional time and cost involved in the recordings is minimal and a fraction 
of that required for screening, selection, recruitment, and treatment. The need for the 
camera, and by implication a restricted group of trained observers, may appear a 
disadvantage but conversely it reinforces the need for endpoint assessments to be 
thorough and undertaken by properly accredited individuals. The addition of observer 
training will minimize inter-observer variability and the risk of endpoint misclassification 
and the few extra minutes and dollars involved in recording of mRS assessments will be 
repaid handsomely in trial power and reliability. Furthermore, if MISTIE III shows 
benefit, comparison of the results of the local and central assessments will provide a 
useful estimate of the observer bias that could be inherent in the mRS assessment. The 
CCC and a majority of the investigators have experience with this method as it is used the 
current CLEAR III trial. We will take procedural steps to ensure the confidentiality of 
patients undergoing these video interviews.  
 
10.3.5. Reading Center: Centralized, Adjudicated CT Analysis 
 
Although routine CT scan determinations will be performed locally, radiographic 
determinations needed for treatment comparisons will be made in a central radiological 
setting and be part of the permanent data files. Central reading will assure a high degree 
of uniformity and standardization of the measurement of the hemorrhage size and 
assessment of edema and mass effect. All imaging studies will be catalogued and 
analyzed, and the results entered into the study database. This process has been tested in 
our prior trials. Measurements are made by experienced radiology technicians and then 
subsequently verified by an independent radiologist. 
 
10.3.6. Automated Data Quality Checks in the EDC System  
 
VISION® EDC System: The EDC system has a robust set of data quality checks that 
will be executed at the time of data entry at the investigational site. This includes the 
standard validations available with most EDC systems such as range checks (e.g., to flag 


 
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a high blood pressure as exceeding inclusion criteria or to ensure a temperature is not an 
impossible value) and data format checks (to flag an invalid date). Additionally, our 
VISION platform will perform very sophisticated cross-form computed calculations that 
would not be available in lesser EDC systems. For example, VISION will conduct a 
series of verifications looking at lab values, CT readings, demographics, etc. and give the 
site guidance regarding the eligibility of the patient for randomization using complex 
cross-page computations. It will also detect when the site has made a protocol variance 
and present a list of such issues to the investigator and the monitoring team for evaluation 
and follow-up. Consequently, our EDC system will handle much of the consistency, 
completeness, and logic checks immediately at the time of data collection that normally 
would have to be done by the monitoring team and/or offline using statistical analysis 
that do not typically occur until weeks or months after the patient visit. This capability 
therefore will result in cleaner data that will be more likely to distinguish a treatment 
effect and significantly reduce the cost of, and delays for, monitoring and data cleaning 
activities. 
 
10.3.7. Independent Data Monitoring and Quality Assurance Team 
 
Emissary: It is important to use an independent Contract Research Organization (CRO) 
for monitoring and quality assurance, to provide the highest level of integrity, industry-
proven best practices, and professionally trained monitors. Our CRO, Emissary 
International, maintains a team of high-caliber, fully-qualified monitors in the U.S. and 
geographically dispersed near most of our international research sites. The Emissary team 
also includes foreign-based monitors and monitors who speak multiple languages. This 
team will be responsible for near real-time review of the clinical data entered into our 
EDC system against source medical records (i.e., Source Document Verification or SDV) 
as well as generation and resolution of the associated data queries.  
 
QA Monitoring Plan: In accordance with recently drafted FDA recommendation for 
risk-based monitoring approaches, this trial will employ centralized monitoring and a 
sophisticated EDC system to: 
• Replace on-site monitoring for activities that can be done better using centralized 
reviewers; 
• Verify source medical records remotely to ensure data integrity, reduce 
transcription errors, and identify any undocumented safety events; 
• Target on-site monitoring at higher risk clinical sites (e.g., sites with high 
frequency of errors, excessive protocol deviations, patient drop-outs, poor data 
timeliness, etc.); 
• Utilize EDC real-time data quality checks to assess range, consistency, and 
completeness of data at the time of entry; and 
• Employ frequent statistical analyses of study data to identify sites that are outliers 
relative to others and to evaluate individual subject data for plausibility and 
protocol compliance. 
 
 


 
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10.3.8. Robust Training and Site Management 
 
Startup Meetings: A series of study start-up meetings will be held. Study personnel 
from the CCC will meet with the other investigator-coordinator teams. Each meeting is 
expected to last one and one-half days. An investigator/coordinator operations manual 
will be developed for these meetings. Overhead images and slides will be presented 
during the start-up meetings. The visual aids provided to each site include slides on 
background and significance, GCP, investigator responsibilities, FDA requirements, 
surgical protocols, case report forms, and other specifics of the protocol. This investigator 
meeting/site initiation process will acquaint the site teams with the design and methods of 
the trial, the study organization, treatment monitoring, and integrity of data collection.  
Prior to each investigator-coordinator meeting, formal mRS, NIHSS, and human subjects 
training certifications will be required of each site investigator and coordinator. A 
specialized training on the EDC system, to include execution of data security and privacy 
protection agreements will be required before anyone may access the EDC system. 
 
Quarterly Site Performance Assessments: Quarterly, the data from the case report 
forms will be organized into a site performance report that assesses enrollment, data 
timeliness, protocol compliance, patient management, and data quality measures. The site 
managers will review these reports with the study coordinator and investigator as part of 
our overall quality program. The site managers will work with the site to develop plans 
for resolving any identified performance issues, which might include additional training 
or site visits, and implementation of a formal Corrective and Preventive Action (CAPA) 
plan. 
 
10.3.9. Data Flow for the Data Safety and Monitoring Board 
 
Each step in the flow of data for this study is discussed below in regards to its importance 
in ensuring data integrity and patient safety. The steps are numbered for reference 
purposes, albeit some steps may occur simultaneously and data for a single patient may 
be in differing stages in this process. 
 
 
1. Regulatory Specialist Verification of Study Documentation: Before the site 
can begin enrolling patients, our Regulatory Document Specialist (RDS) will verify that 
all mandatory startup tasks have been completed and appropriate documentation has been 
uploaded to the EDC system’s Electronic Trial Master File (eTMF). The RDS then will 
set a parameter in the EDC system that will allow the site to randomize a patient and 
grant user access rights to the online case form. This step will ensure that no site may 
enroll patients until all regulatory documentation (i.e., IRB approval, investigator 
qualification), staff training (i.e., Emissary College training certificates, Rankin 
certification, Pharmacist, and Surgical Center Training, etc.) and contractual 
requirements are fulfilled. During the trial, the RDS will work with the site coordinator to 
maintain the study documentation in the eTMF repository, and can stop a site’s ability to 
randomize should there be safety or performance concerns. As all study documentation is 
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document file verifications. At the end of the study, the eTMF content will be provided to 
the site on compact disks, consisting of all the collected patient data and trial 
documentation, for long term regulatory retention. 
 
 
2. Data Entry & Source Document Upload: Once a potential patient is 
identified, the coordinator will register this new patient in the EDC system, triggering an 
automated alert to the CCC, reading center, surgical center and monitoring team. Should 
the patient subsequently fail to qualify for the study, the basic demographic information 
and reason for screen failure will be used to assess potential selection bias at the site, and 
for performance tracking and epidemiologic purposes. 
 
 
Next, the coordinator will upload copies of applicable medical records to the 
eTMF to include the EDC and ambulance records, ICU records, progress notes, 
medication records, radiology, and other procedure reports, surgical reports, dosing 
records, admit and discharge summaries, and adverse event information.  
 
 
Also, each site will collect CT data files (as zipped DICOMs) and upload these to 
the EDC system as well. These will be reviewed by the reading center and surgical 
centers to assess hemorrhage stability, adequacy of dosing catheter placement, clot 
resolution for dosing decision support, and particular patient risk factors (i.e., aneurysm, 
Moyamoya, etc.). The centralized, standardized, adjudicated reading center 
measurements will be used in efficacy determinations, trend analyses for safety reviews, 
and verification of patient eligibility. 
 
 
Sites will be expected to enter critical screening data (and upload diagnostic and 
stability CTs) immediately, and enter post-randomization data within 24 hours. The EDC 
system will be programmed to prevent randomization of the patient if certain data has not 
been entered (such as critical safety/efficacy data points from the CTs) and to send 
automated reminders to the investigator and site managers if sites fail to enter any other 
data in a timely manner. 
 
3. Correction of Automated Errors and Warnings: As data are entered, the 
EDC system will immediately generate automated warnings (yellow highlights) and 
errors (red highlights). Warnings will represent data that is outside expected limits, such 
as an ICH size that exceeds the inclusion criteria, or where required data are missing. 
Errors will indicate conditions that are intolerable (such as an impossibly high body 
temperature) or that are unrealistic (such as an invalid date format).  
 
 
In keeping with FDA requirements for electronic systems, the EDC system will 
not force the investigator/coordinator to immediately change the entered data (as that 
could be misconstrued as encouraging data falsification) but instead simply provide 
feedback via on-screen messages and red/yellow field highlighting. Warnings may be 
unavoidable, due to patient-specific issues, but are documented nonetheless so that they 
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before the case form page can be advanced in the workflow (i.e., signed by the 
coordinator) so the data will be “clean” before it is exported for analysis.  
 
 
Additionally, the EDC system will generate external email notifications in 
response to specific entries; such as to immediately alert the CCC of a possible dosing 
error or to notify the safety officer of a new adverse event. The EDC system also 
produces various instantaneous reports that are useful for data quality and safety 
monitoring purposes both by the site staff and the project teams. 
 
 
4. Site Manager and Study Chairman Verification of Patient Eligibility: Sites 
will be advised to contact the CCC (which also will be notified by the EDC of the 
potential patient) to verify that the patient meets the eligibility requirements and to assess 
safety measures (e.g., INR, PTT, platelets, exclusionary concomitant medications). Site 
managers will go through an enrollment checklist with the coordinator and investigator, 
and consult with the surgical center, study chairman, or safety officer as may be 
appropriate. 
 
 
5. Surgical Center Determination of Catheter Placement and Patient Risk: 
Simultaneously, during the CCC’s review, the surgical center will assess catheter 
placement per the postoperative CTs (using the uploaded DICOM images with findings 
entered directly into the eCRF). This assessment will be made to ensure the catheter is 
best positioned to give optimum drug delivery for rapid/maximum clot resolution and to 
minimize the risk of bleeding complications. 
 
 
6. Reading Center Verification of Hemorrhage Stability: The CT Reading 
Center at JHU will review the uploaded DICOM images to assess patient stability and to 
make the central, standardized volumetric measures used in efficacy analysis. 
 
7. Monitoring Team Source Document Verification and Data Integrity 
Review: Emissary’s and The George Institute’s teams of monitors will review the online 
case forms for completeness, logic, and consistency, then verify the entered data against 
the uploaded source medical records and data collection worksheets. Routine queries 
identified in this process will be entered into the EDC system (triggering an automated 
notice to the site). The monitors, working in conjunction with the site managers in the 
CCC, will then work with the coordinators to obtain correction of all data errors and 
resolution of the corresponding queries. 
 
Reviews will include data from the entire course of each patient’s participation in 
the study. (As noted above, screen failure data will be collected but not actively 
monitored in this fashion because, due to HIPAA restrictions, there is no patient-
identifiable information (source documents) against which it could be verified.) In 
accordance with a formal monitoring plan, this activity will include a review of all 
uploaded source documentation and will entail a 100% source verification of the primary 
safety and efficacy measures. Random sampling will be used to select secondary data for 
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certain minimum expectations in this step, or if any material data integrity or regulatory 
compliance issues are identified, additional data from a patient/site will undergo intensive 
monitoring and the site referred to the CCC for remediation and potential dismissal from 
the trial. 
 
10.3.10. Other Components of Data Management Plan 
 
Randomization and Data Collection: Each subject is assigned a unique study number 
by the EDC, which provides a centralized, web-based randomization system. Treatment 
allocations will be stratified and centralized across all study centers. Daily data collection 
of ICP management, ICU care, catheter monitoring, and neuroimaging will assess the 
subject’s clinical response to treatment as part of the clinical trial. This data will be used 
to assess compliance with the study protocol, intervention stopping rules, and care 
directed at independence. Daily results of routine hematology, chemistry, and coagulation 
studies also will be collected if reported.  
 
Protocol Compliance: Procedures will be implemented to maximize adherence to the 
protocol (meetings, communications via website and teleconferences, individual and 
group training, MOP, and SOP documents). Comprehensive training (approximately 20 
hours each for both the coordinator and investigator, one to 10 hours each for other site 
staff) is required before a site is activated. Early review of data is made possible by real-
time entry of data into a database with validations and daily monitoring.  This is 
particularly important with respect to the mRS, our primary endpoint, as rapid central 
review is anticipated to allow for repeat interview of the subject should an incomplete 
exam be documented.  Site investigators are required to report a protocol deviation within 
24 hours of occurrence or as soon as it is discovered. If the QA monitor discovers an 
undocumented major deviation during a monitoring activity, the monitor will notify the 
CCC immediately. Each site coordinator will report deviations as they are discovered to 
the local IRB in accordance with local requirements. While there may be rational clinical 
reasons for an occasional deviation, a site with serious, continual problems is at risk for 
losing its funding. Routine reporting of protocol deviations will be made to the NINDS, 
DSMB, and other regulatory agencies as required by GCP. 
 
FDA Guidance for Electronic Data Entry Compliance: The design and development 
of the electronic database system will reflect the FDA Guidance for Industry for 
Computerized Systems Used in Clinical Trials (April 1999) as well as the Electronic 
Records/Electronic Signatures rule (21 CFR part 11). The system is currently in use with 
the CLEAR III trial and the earlier MISTIE II study. A secure, computer generated, time-
stamped electronic record will allow reconstruction of the course of events relating to the 
creation, modification, and deletion of an electronic record. Source documents will be 
retained to enable a reconstruction and evaluation of the trial. The system will ensure that 
all applicable regulatory requirements for record keeping and record retention in clinical 
trials are met with the same degree of confidence as are provided with paper systems. 
Clinical investigators will retain the original copy of all source documents uploaded onto 
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tracked by the system. Changes to a required record will not obscure the original 
information. The record will clearly indicate the time a change was made and clearly 
provide a means to locate and read the prior information through the audit trail. This audit 
trail will be in compliance with the 21 CFR 11.10(e). The record, along with supporting 
documentation, will also indicate who made the changes, when changes were made. 
Security measures will be in place to prevent unauthorized access to the system and data. 
To ensure that individuals have the authority to proceed with data entry, the system will 
be designed to verify the electronic signature (user ID and password) at the start of a user 
session. The data entry system will ensure attributability. Each entry to an electronic 
record, including any change, will be made under the electronic signature of the 
individual making that entry. A separate electronic signature will not be required for each 
entry or change; a single electronic signature will cover multiple entries or changes. 
Individuals who maintain the electronic record systems as well as the audit trail will carry 
the responsibilities to protect authenticity, integrity, and confidentiality of electronic 
records. Audit trails will be available for FDA inspectors at the study site or any other 
location where associated electronic study records are maintained. The system will be 
designed to contain the prompts, lookup values, cross-field validations, flags, and on-line 
help to encourage consistent use of clinical terminology and to alert the user in case that 
data entered are out of acceptable range. External safeguards will be in place to ensure 
that access to the computerized system and to the data is restricted to authorized 
personnel. Servers will be stored in a physically secured, guarded data center.  
 
Security Measures: Users at the participating centers will be aware of system security 
measures and the importance of limiting access to authorized personnel. SOPs will be in 
place for handling and accessing the system to prevent unauthorized access. Access to the 
data at a clinical site will be restricted and monitored by the system through required log-
on, security verification procedures, and audit trail. The data cannot be altered, browsed, 
queried, or reported via external software applications without entering through the 
protective software, although computers at each site may also be used for the purposes 
other than the clinical study. Because the system will be largely through remote access, 
all data and applications used for the study will be logically and physically isolated in the 
servers in order to preclude unintended interaction with non-study use software. These 
servers will be strictly monitored and maintained by designated administrators at an 
independent third party (e.g., only Prelude Dynamics, the contracted EDC vender, has 
password access to the database and only its contracted commercial data center, On-
Ramp Systems both of Austin, Texas, has access to the physical hardware); neither 
remote sites nor any member of the project team will have the ability to change such 
logical security of the system. Written procedures describing contingency plans for 
continuing the study by alternate means in the event of hardware or facilities failures with 
alternate hardware or at an alternate site will be provided to each site. It should be noted 
that the data management procedures will reflect the advanced use of computer and 
software technology; include database technology, and electronic file management 
principles; and therefore be of the highest possible standards achievable for data security 
and information integrity. Specifically, the data center is SAS-70 Type II compliant, 
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Backup Recovery: Records will be backed up daily to prevent a catastrophic loss 
compromising the quality and integrity of the data. Data will be backed up onto digital 
media which will be stored at an offsite location. Backup and recovery logs will be 
maintained to facilitate an assessment of the nature and scope of data loss in the event of 
a system failure. Special backup plans for video files at the Glasgow data center will 
include secure offsite tape backup; no clinical data other than the Rankin video interview 
and associated tracking (blinded patient number, visit date, investigator’s score, site, and 
interviewer name) is stored on the Glasgow system and the Outcomes Center has no 
access to the EDC database. 
 
Limited Access: Each user will be assigned an individual account with a unique 
username and password. Any user will be locked out after 10 consecutive attempts, with 
any unauthorized access attempt recorded in a log file. Users will be required to exit the 
system upon leaving a workstation. The computer will automatically log off the current 
session when an idle period reaches 30 minutes. For short periods of inactivity, the 
automatic screensaver will be password protected to prevent unauthorized access to the 
system. 
 
Audit Trails: All changes made to data in the electronic record are tracked and recorded 
in the audit trail. This audit trail will capture the date/time, the contents of the changes 
made, and the login id used to make the change. The audit trails will be created 
incrementally in chronological order, with prevention of overwrite, as such data 
overwriting is in violation of §11.10(e). Audit trail information will be reviewed by pre-
authorized personnel if the need arises to verify the quality and integrity of the data. 
 
Date and Time Stamps: All data will be saved on a central server carrying a time stamp, 
which will be documented in the audit trail. The EDC software will display the 
participating site's time zone but record transactions in exact U.S. Central Time as the 
server is located in that time zone. The date and time on the server will be synchronized 
to the time provided by the U.S. National Institute of Standards. Individual users will be 
unable to change the time on the server. Patient procedure times will be collected in local 
time and recorded in the patient medical record, such as the date/time of a CT scan, lab 
draw or dose. The site’s clocks are not synchronized to any particular standard or even 
synchronized within the site, but such exactness is immaterial for this study, consistent 
with the GCP norms for all multicenter clinical trials and otherwise beyond the 
reasonable control of the CCC. 
 
10.4 
Adverse Experience Reporting 
 
10.4.1. Assessment of Safety 
 
Specification of Safety Variables 
 


 
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Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (SAEs), all events of death, and any study specific issue of 
concern. 
 
Adverse Events 
AE definition: An adverse event is any untoward medical occurrence in a patient entered 
into the study that does not necessarily have a causal relationship with this treatment. An 
adverse event can be any unfavorable and unintended sign (including an abnormal lab 
finding), symptom, or disease temporally associated with the use of the product or 
treatment, whether or not related to the product or treatment. The investigator must 
follow adverse events to resolution whenever possible. 
 
AEs include the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with intracerebral hemorrhage 
that were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as catheter placement).Preexisting medical conditions (other than the 
condition being studied) judged by the investigator to have worsened in severity or 
frequency or changed in character during the protocol-specified AE reporting period. 
 
Serious Adverse Events 
 
SAE definition: A serious adverse event is an adverse event that results in any of the 
outcomes listed below. For purposes of this study, Regulatory Agency reporting 
responsibilities have been designated to the Coordinating Center. 
 
1. Results in death (i.e., the AE actually causes or leads to death). Study Chair agrees to 
adhere to FDA-defined guidelines and submit an expedited report of any death that is 
related (even remotely) to study drug or the MIS procedure and unexpected if the 
death occurs within 30 days from the date of the original ICH event.  
 
2. Life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more 
severe form, might have caused death.). 
 
3. Requires inpatient hospitalization or prolongs inpatient hospitalization. 
 
4. Persistent or significant disability or incapacity: a substantial disruption of a person’s 
ability to conduct normal life functions 
 
5. A congenital anomaly or birth defect in a neonate/infant born to a mother exposed to 
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6. Considered a significant medical event by the investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical intervention to 
prevent one of the outcomes listed above). 
 
 
Medical events of interest (MEOI) definition: MEOIs must be reported to the CCC for 
Medical Monitor and Safety Event Committee review. The AE dictionary, which drives 
the drop down lists on the AE screen in the EDC system, pre-specifies which events are 
defined as MEOIs. A MEOI may or may not satisfy the definition of a SAE but will be 
reported using the same SAE reporting screen in the EDC system and will undergo the 
same review as a SAE. In summary, the MEOIs for the trial are as follows: 
 
1. Ventriculitis/Cerebritis/Meningitis 
2. Cerebral bleeding events (asymptomatic and symptomatic) 
3. Any AE or SAE deemed by the site PI or Medical Monitor as possibly, 
probably, or definitely related to the MIS procedure or rt-PA 
administration(s) 
4. Any AE or SAE requiring discontinuation of dosing or withdrawal 
from follow-up 
 
 
Adverse event intensity grading: A coding dictionary, based on the CTCAE dictionary, 
is developed and will be used at the site-level to code in the EDC system adverse events 
as they occur. The dictionary assigns an intensity code to each event term. The intensity 
codes are event term-specific and usually range from 1-5, with 1 being mild and 5 being 
death. Certain AEs in the coding guide are defined as potentially serious SAEs if there is 
a medically qualifying factor. All AEs coded as a grade 4 or 5 will automatically require 
SAE reporting. These events will be reviewed by the Medical Monitor and, as needed, 
the Safety Event Committee. 
 
10.4.2. Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the MIS procedure and the rt-PA administration(s) (see following 
guidance), and actions taken. 
 
Attributability of AEs to the MIS procedure/rt-PA administrations: Adverse events 
occurring more than 7 days after the MIS procedure are not expected to be considered 
related to the procedure. Also, due to the relatively short half-life of rt-PA, adverse events 
occurring more than 72 hours after completion of the last rt-PA administration are not 
expected to be considered related to the rt-PA administration(s). The investigator and/or 
Medical Monitor will define whether the event is best described as UNRELATED, 
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and/or the rt-PA administration(s) according to the following definitions. To ensure 
consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and the 
administration of the rt-PA, and the AE cannot be readily explained by the subject’s 
clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a 
known pattern of response to the rt-PA; and/or the AE abates or resolves upon 
discontinuation of the rt-PA. 
 
 
• Possibly Related: The adverse event has a temporal relationship to the MIS procedure 
or the rt-PA administration(s). However, an alternative etiology may be responsible 
for the adverse event. Information on drug withdrawal may be lacking or unclear. 
 
• Probably Related: The adverse event has a temporal relationship to the MIS 
procedure or the rt-PA administration(s). The event is unlikely to be related to an 
alternative etiology. There is a reasonable response on withdrawal (dechallenge).  
Rechallenge information is not required. 
 
• Definitely Related:  The adverse event has a temporal relationship to the MIS 
procedure or rt-PA administration(s) and resolves when rt-PA administration is 
discontinued. An alternative etiology is not apparent.  
 
No 
 
Evidence exists that the AE has an etiology other than the rt-PA (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the 
AE has no plausible temporal relationship to rt-PA administration (e.g., cancer diagnosed 
2 days after first dose of study drug). 
 
• Unrelated: There is evidence that the adverse event definitely has an etiology other 
than that assigned to either the MIS procedure or rt-PA administration(s).  
 
Unexpected AE definition: Unexpected events are any adverse events in which the 
specificity or severity is not consistent with the natural history of ICH without the test 
intervention including catheter placement and rt-PA administration. Unexpected will be 
defined as the specificity or severity of an event that is not consistent with the risk 
information described in this protocol. 
 
Expected AE definition. The Medical Events listed in Appendix 5 are published by the 
American Stroke Association and the European Stroke Initiative as natural history events 
of ICH/IVH or are found in the Investigator’s Brochure or Alteplase Package Insert or 
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the disease process or with use of rt-PA. Please enter these expected events on the 
Adverse Event formif they occur. Reports of these events will be analyzed and submitted 
as grouped data by the trial’s statisticians. 
 
10.4.3. Adverse Event Reporting Period 
 
Adverse events must be recorded in the medical chart and in the EDC system. All adverse 
events, serious or otherwise occurring after presentation to the emergency department but 
prior to randomization will be documented on the Medical History form in the EDC 
system. All adverse events and serious adverse events that occur during the acute 
treatment phase (ending at day 6) will be recorded on the Adverse Event form along with 
all neurological AEs and SAEs that occur through the day 365 follow-up visit.  
 
Documentation: Documentation must include the event duration (start/stop) and the 
intensity of each event using the grading definitions and event terms available in the AE 
dictionary in the EDC system. The grades range in intensity from 1 (mild) to grade 5 
(death) and are specific to each event. Specific events will not have all five grades 
available. All AEs coded as a grade 4 or 5 will automatically require SAE reporting. 
 
If a subject is discontinued early from rt-PA administrations for any reason, study site 
personnel must clearly report and document the circumstances and data leading to any 
discontinuation using the electronic case report forms. It must be determined if the reason 
for stopping rt-PA administration is an adverse event, for example, sustained ICP above 
30 mmHg during injection.  
 
Follow up of ongoing AEs: For any untoward event(s) the subject should be followed 
until the event resolves or is explained with the frequency of follow up designated by the 
investigator. 
 
10.4.4. Eliciting AEs during follow up visits 
 
At each follow up visit, the subject will be asked about the occurrence of AEs since the 
last contact. AEs that were ongoing at the last contact will be updated with a stop date or 
confirmed as ongoing. This will continue until the final follow up visit at day 365 or until 
the subject’s death, whichever occurs first.  
 
A consistent methodology for eliciting AEs at all subject evaluation timepoints should be 
adopted.  Examples of non-directive questions include:  
 
• How have you felt since your last clinical visit? 
• Have you had any new or changed health problems since you were last here? 
• Have you (or the patient) had any serious bleeding? Examples of this include 
blood transfusions, a sudden drop in blood pressure, blood in urine or stool, 
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• Have you (or the patient) suffered bleeding on the brain, a stroke, or any other 
change in function of the brain or nerves?  
• Have you (or the patient) had any symptoms such as sudden onset of shortness of 
breath, coughing up blood, purple discoloration of the feet, loss of pulse in legs or 
feet or other problems with blood clots?   
• Have you had any unusual or unexpected worsening your underlying medical  
condition? 
 
10.4.5. Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or 
SAEs. Avoid colloquialisms and abbreviations. 
 
a. Diagnosis vs. Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported rather than individual 
signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, 
asterixis, and elevated transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the 
time of reporting, it is ok to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up information. 
 
b. Deaths 
 
All deaths that occur during the protocol-specified AE reporting period, regardless of 
attribution, will be reported to the CCC. When reporting a death, the event or condition 
that caused or contributed to the fatal outcome should be reported as the single medical 
concept. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, report “Unexplained Death.” 
 
c. Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. Such 
conditions should be reported as medical and surgical history. A preexisting medical 
condition should be re-assessed throughout the trial and reported as an AE or SAE only if 
the frequency, severity, or character of the condition worsens during the study. When 
reporting such events, it is important to convey the concept that the preexisting condition 
has changed by including applicable descriptors (e.g., “more frequent headaches”). 
 
d. Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalizations or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a medical or 
surgical procedure as a result of an AE, the event responsible for the procedure, not the 
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to undergo coronary bypass surgery, record the heart condition that necessitated the 
bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study  
• Hospitalization or prolonged hospitalization for scheduled therapy of the 
target disease of the study 
 
e. Pregnancy 
 
If a female subject becomes pregnant while receiving rt-PA or within 30 days after the 
last dose of study drug, a report should be completed and expeditiously submitted to the 
Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth 
defect in a child born to a female subject exposed to the rt-PA should be reported as an 
SAE. 
 
f. Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a subject has 
completed or discontinued study participation if attributed to prior rt-PA exposure. If the 
investigator should become aware of the development of cancer or a congenital anomaly 
in a subsequently conceived offspring of a female subject who participated in the study, 
this should be reported as an SAE. 
 
g. Reconciliation 
 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor 
will agree to the reconciliation periodicity and format, but agree at minimum to exchange 
monthly line listings of cases received by the other party. If discrepancies are identified, 
the Sponsor and Genentech will cooperate in resolving the discrepancies. The responsible 
individuals for each party shall handle the matter on a case-by-case basis until 
satisfactory resolution. 
 
h. SAE Reporting 
 
General reporting of SAEs: Any alarming, serious, or unexpected adverse event, 
including death due to any cause, which occurs during this study, inclusive of the follow 
up period (day 365), and whether or not thought to be related to the MIS procedure or the 
rt-PA administration(s), must be reported immediately (within 24 hours of learning of the 
event) to the CCC and to the local IRB as required. Completion of a SAE form in the 


 
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EDC system for each SAE or MEOI that occurs is required to formerly report the event to 
the CCC. Once the SAE is reported in the EDC system an email notification is sent to the 
CCC staff, safety officer, and QA monitors. The CCC will then appropriately notify the 
Study Chairman, Genentech, Inc. (subjects receiving rt-PA from Genentech supply only), 
the Medical Monitor, the Surgical Center, Health Canada, the UK and European QA 
Monitors, The George Institute, and the FDA. The UK and European QA Monitors will 
notify the MHRA and Competent Authorities in all other Member States concerned as 
well as to the Ethics Committees concerned as necessary. The table below provides the 
contact information for each of these individuals. 
 
Name 
Title 
Phone Number 
Fax Number 
Email Address 
24-hour study phone 
Coordinating Center 
410-736-1368 
410-502-7869 
 
Daniel F. Hanley, MD 
Principal Investigator 
410-614-6996 
Cell: 410-615-
3749 
410-502-7869 
dhanley@jhmi.edu 
Genentech Drug Safety 
Genentech, Inc. 
800-835-2555 
650-225-4682 or 
650-225-5288 
 
Pat Reilly, RN, MSN 
Sr. Medical Science 
Liaison, Vascular 
Medicine (Genentech) 
717-566-7993 
717-566-7994 
part@gene.com 
FDA fax number for 
IND Safety Reports 
FDA 
 
1 (800) FDA-0178 
 
Carlos S. Kase, MD 
Medical Safety Monitor 
617-638-5102 
617-638-7758 
cskase@bu.edu 
J. Ricardo 
Carhuapoma, MD 
ICU Care Medical 
Monitor 
(410) 955-7481 
(410) 614-7903 
jcarhua1@jhmi.edu 
Marc Lemieux 
Health Canada 
514-398-2667 
514-398-8576 
marc.lemieux@mcgill.ca 
Barbara Gregson, PhD 
QA Monitor, UK; MHRA 
+44 191 233 6161 
ext. 22175 
+44 191 256 3268 
barbara.gregson@ncl.ac.uk 
Alan Cohen 
QA Monitor, Europe 
+32 4 738 650 91 
 
alanscohen@skynet.be 
Michelle Leroux 
The George Institute 
+61 2 9993 4509 
+61 2 9993 4502 
mleroux@georgeinstitute.org.au 
Vandna Kishore 
FDA/CBER (IND File) 
301-796-4193 
301-796-9842 
Vandna.Kishore@fda.hhs.gov  
 
 
An expedited IND safety report will be used to notify the FDA IND division of each 
serious unexpected suspected adverse reactions according to FDA regulations, part 312 
and Guidance for Industry and Investigators: Safety Reporting Requirements for INDS 
and BA/BE Studies effective March 28, 2011. In accordance with these regulations, this 
protocol has a pre-specified monitoring plan for determining if subjects receiving the 
intervention are at higher risk for mortality and will only report a death as an expedited 
IND safety report if there is evidence of a causal relationship between the intervention 
and/or the study drug and the event resulting in death. In addition, an expedited IND 
safety report will be used to notify the FDA if there is an imbalance between the arms 
suggesting there is a reasonable possibility that the intervention or the study drug caused 
any of the safety endpoints: symptomatic bleeding, cerebral infection, mortality occurring 
with seven days of the surgical intervention, 30-day mortality. Otherwise, the occurrence 
of these safety endpoints will be reported on an annual basis. 
 


 
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The CCC will report all AEs and SAEs to the Study Chairman as the IND Sponsor (in 
accordance with CFR 312.32: IND Safety Reports) and the DSMB either immediately or 
as a routine summary report depending upon the severity of the event.   
 
Any study report submitted to the FDA by the Sponsor-Investigator will be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). 
 
The CCC will submit events meeting the following criteria to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports, Genentech Drug Safety using 
the fax cover sheet in Appendix 6 (if the event occurred in a subject receiving rt-PA from 
the Genentech supply), to the UK and European QA Monitors, and The George Institute 
according to the guidance and timelines below. The completed Medwatch/case report will 
be faxed immediately upon completion to the FDA and Genentech Drug Safety. The 
FDA fax number for IND Safety Reports is 1 (800) FDA 0178. All written IND Safety 
Reports submitted to the FDA by the Investigator will also be faxed to Genentech Drug 
Safety at (650) 225-4682 or (650) 225-5288. For questions related to safety reporting, 
please contact the CCC or Genentech Drug Safety by telephone at (888) 835-2555 or by 
Fax at (650) 225-4682 or (650) 225-5288. 
 
Occasionally Genentech may contact the reporter of the SAE for additional information, 
clarification, or current status of the patient for whom an adverse event was reported. For 
questions regarding SAE reporting, you may contact the CCC or the Genentech Drug 
Safety representative noted above or the Medical Science Liaison assigned to the study 
(see table above). Relevant follow-up information should be submitted to the CCC for 
distribution to the FDA, Health Canada, Genentech Drug Safety, the UK and European 
QA Monitors, The George Institute and all participating investigators as soon as it 
becomes available and/or upon request. 
 
7 Calendar Day Telephone or Fax Report: The CCC will notify the FDA, 
Health Canada, Genentech (if the subject received rt-PA from the Genentech 
supply), the UK and European QA Monitors, The George Institute, and all 
participating investigators for local IRB/Ethics Committee review of any fatal or 
life-threatening adverse event that is unexpected (as defined above) and 
assessed by the investigator to be possibly, probably, or definitely related to the 
MIS procedure or the rt-PA administration(s). Such reports will be emailed or 
faxed within 7 calendar days of the CCC first learning of the event. The UK and 
European QA Monitors and The George Institute will submit the reports to the 
MHRA and Competent Authorities in all other Member States concerned as well 
as to the Ethics Committees concerned as necessary. Relevant follow-up 
information will be submitted to all parties as soon as it becomes available.  
 
15 Calendar Day Written Report: The CCC will notify the FDA, Health 
Canada, Genentech (if the event occurred in a subject receiving rt-PA from the 
Genentech supply), the UK and European QA Monitors, The George Institute, 


 
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and all participating investigators for local IRB/Ethics Committee review, in a 
written IND Safety Report, of any serious, unexpected AE (as defined above) 
that is considered possibly, probably, or definitely related to the MIS procedure 
or the rt-PA administration(s). Such reports will be emailed or faxed within 15 
calendar days of the CCC first learning of the event. The UK and European QA 
Monitors and The George Institute will submit the reports to the MHRA and 
Competent Authorities in all other Member States concerned as well as to the 
Ethics Committees concerned as necessary. Relevant follow-up information will 
be submitted to all parties as soon as it becomes available. 
 
15 Calendar Day Written Report: The CCC will notify Genentech Drug Safety 
within fifteen (15) calendar days of the Awareness Date all SAE reports that are 
related to the rt-PA and AEs of Special Interest (regardless of causality) if the 
event occurred in a subject receiving rt-PA from the Genentech supply. 
 
30 Calendar Day Written Report: The CCC will notify Genentech within thirty 
(30) calendar days of the Awareness Date all SAE reports that are unrelated to the 
rt-PA administration(s) and any reports of pregnancy following the start of 
administration of rt-PA if the event occurred in a subject receiving rt-PA from the 
Genentech supply. 
 
Quarterly Written Report: The CCC will notify Genentech of all non-serious 
AEs originating from the study experienced by subjects receiving rt-PA from the 
Genentech supply. 
 
Annual Written Report: The CCC will notify the FDA, Genentech (events 
occurring in a subjects receiving rt-PA from the Genentech supply only), The 
George Institute, and the European Member States in whose territory the clinical 
trial is being conducted and the Ethics Committees concerned as necessary with a 
listing of all suspected serious adverse reactions which have occurred over this 
period and a report of the subjects' safety. Each Member State shall see to it that 
all suspected unexpected serious adverse reactions to an investigational medicinal 
product which are brought to its attention are immediately entered in a European 
database to which, in accordance with Article 11(1), only the Competent 
Authorities of the Member States, the Agency and the Commission shall have 
access. The Agency shall make the information notified by the Sponsor available 
to the Competent Authorities of the Member States. 
 
• Written IND Safety reports will include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32. All safety reports previously filed 
by the investigator with the IND concerning similar events will be analyzed and 
the significance of the new report in light of the previous, similar reports 
commented on. 
 
• Written IND safety reports with Analysis of Similar Events will be submitted to 


 
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the FDA, Health Canada, the MRC, Genentech (if the event occurred in a subject 
receiving rt-PA from the Genentech supply), The George Institute, and all 
participating investigators for local IRB/Ethics Committee review within 15 
calendar days of the CCC first learning of the event. The UK and European QA 
Monitors and The George Institute will submit these reports to the MHRA and 
Competent Authorities in all other Member States concerned as well as to the 
Ethics Committees concerned as necessary.   
 
For questions related to safety reporting, please contact the CCC. 
 
11 
HUMAN SUBJECTS 
 
11.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix 1) and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee responsible 
for oversight of the study. A signed consent form will be obtained from the subject. For 
subjects who cannot consent for themselves, a parent, legal guardian, or person with 
power of attorney, must sign the consent form; additionally, the subject's assent must also 
be obtained if he or she is able to understand the nature, significance, and risks associated 
with the study. The consent form will describe the purpose of the study, the procedures to 
be followed, and the risks and benefits of participation. A copy of the consent form will 
be given to the subject, parent, or legal guardian, and this fact will be documented in the 
subject’s record. 
 
The site investigator will provide the CCC with documentation of institutional review 
board approval of the protocol and the informed consent document before the study may 
begin at the site. The ethical review board(s) will review the protocol as required. 
 
The Investigator is to supply the following to the study site’s institutional review 
board(s): 
 
1. The current clinical investigator brochure or Product Monograph  
2. The current protocol and informed consent document 
3. All updates to the clinical investigator brochure or Product Monograph during 
the course of the study 
4. Relevant curriculum vitae 
5. Human Subjects Training Certification 
6. Any specific information the review board requires. 
 
The Investigator must provide the following documentation to the CCC: 
 
1. The institutional review board’s initial and annual re-approval of the protocol. 
2. The institutional review board’s approvals of any revisions of the informed 
consent document or amendments to the protocol or informed consent. 


 
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11.2 
Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, video recordings, and other records 
that leave the site will be identified only by the Study Identification Number (SID) to 
maintain subject confidentiality. All records will be kept in a locked file cabinet. All 
computer entry and networking programs will be done using SIDs only. Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by IRB, the FDA, the NINDS, the OHRP, the Sponsor, or the 
Sponsor’s designee. 
 
Radiographic Masking: Although determinations for routine patient care will be 
performed locally, radiographic determination needed for treatment comparisons will be 
made in a central radiological setting and be part of the permanent data files. Centralizing 
the CT and MRI scan interpretations ensures that the required masks are maintained. 
Central reading will assure a high degree of uniformity and standardization of the 
measurement of the hemorrhage size and assessment of edema and mass effect. The 
central radiologist and radiology technician will be blinded to clinical information such as 
the response of the patient to MIS with or without rt-PA. All imaging studies will be 
catalogued and analyzed, and the results entered into the EDC system. 
 
11.3 
Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the IRB, the NINDS, the 
Sponsor, the OHRP, the FDA, or other government agencies as part of their duties to 
ensure that research subjects are protected. 
 
12 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by the policies and procedures 
developed by the EC.  Any presentation, abstract, or manuscript will be made available 
for review by the Sponsor and the NINDS prior to submission. 
 
The results of the trial will be published regardless of its outcome. A Publication 
Committee will be established. Publication regarding further analyses performed on the 
data will be by mutual agreement between the EC and the site investigators. 
 
The investigator may publish or present at scientific meetings the results of this study, 
provided that confidential information is not disclosed, and only after obtaining advance 
written consent from the EC.  Consent may be withheld at the sole discretion of 
Executive Committee. 
 
In this regard, a copy of all public disclosures, including but not limited to publication 
manuscripts, abstracts, and seminar presentations, should be provided to the EC for 


 
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review, at least 30 days before the manuscript is submitted to the publisher or a 
presentation is made.  
 
Additionally, the Clinical Study Report (final study report) and any literature articles that 
are a result of the study should be sent to Genentech. Copies of such reports will be faxed 
to the assigned Clinical Operations Contact for the study: Lytics IST central mailbox: 
lytics-gsur@gene.com or fax: 866-283-2263. 
 
13 
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Greenberg SM, Huang JN, MacDonald RL, Messe SR, Mitchell PH, Selim M, Tamargo RJ. 
Guidelines for the management of spontaneous intracerebral hemorrhage: A guideline for 
healthcare professionals from the american heart association/american stroke association. 
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65. Becker KJ, Baxter AB, Cohen WA, Bybee HM, Tirschwell DL, Newell DW, Winn HR, 
Longstreth WT, Jr. Withdrawal of support in intracerebral hemorrhage may lead to self-
fulfilling prophecies. Neurology. 2001;56:766-772 
 
66. Zhou H, Zhang Y, Liu L, Han X, Tao Y, Tang Y, Hua W, Xue J, Dong Q. A prospective 
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67. Hua Y, Keep RF, Hoff JT, Xi G. Deferoxamine therapy for intracerebral hemorrhage. Acta 
neurochirurgica. Supplement. 2008;105:3-6 
 
68. Carhuapoma JR, Barrett RJ, Keyl PM, Hanley DF, Johnson RR. Stereotactic aspiration-
thrombolysis of intracerebral hemorrhage and its impact on perihematoma brain edema. 
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69. Wagner KR, Xi G, Hua Y, Zuccarello M, de Courten-Myers GM, Broderick JP, Brott TG. 
Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of 
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1999;90:491-498 
 
70. Wagner KR, Xi G, Hau Y, Kleinholz M, de Courten-Myers GM, Myers RE. Early metabolic 
alterations in edematous perihematomal brain regions following experimental intracerebral 
hemorrhage. J Neurosurg. 1998;88:1058-1065 
 
71. Volbers B, Staykov D, Wagner I, Dorfler A, Saake M, Schwab S, Bardutzky J. Semi-
automatic volumetric assessment of perihemorrhagic edema with computed tomography. 
European journal of neurology : the official journal of the European Federation of 
Neurological Societies. 2011;18:1323-1328 
 
72. Hua Y, Keep RF, Hoff JT, Xi G. Brain injury after intracerebral hemorrhage: The role of 
thrombin and iron. Stroke. 2007;38:759-762 
 
73. Ducruet AF, Hickman ZL, Zacharia BE, Grobelny BT, Narula R, Guo KH, Claassen J, Lee 
K, Badjatia N, Mayer SA, Connolly ES, Jr. Exacerbation of perihematomal edema and sterile 
meningitis with intraventricular administration of tissue plasminogen activator in patients 
with intracerebral hemorrhage. Neurosurgery. 2010;66:648-655 
 
74. Wei JW, Heeley EL, Wang JG, Huang Y, Wong LK, Li Z, Heritier S, Arima H, Anderson 
CS. Comparison of recovery patterns and prognostic indicators for ischemic and hemorrhagic 
stroke in china: The chinaquest (quality evaluation of stroke care and treatment) registry 
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75. Huang WC, Chen YJ, Chien CL, Kashima H, Lin KC. Constraint-induced movement therapy 
as a paradigm of translational research in neurorehabilitation: Reviews and prospects. Am J 
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76. Klein Kranenbarg E, van de Velde CJ. Surgical trials in oncology. The importance of quality 
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Kusminsky R, Moffat FL, Jr., Noyes RD, Beitsch PD. Prerandomization surgical training for 
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phase iii clinical trial to compare sentinel node resection to conventional axillary dissection 
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78. Krag DN, Ashikaga T, Harlow SP, Skelly JM, Julian TB, Brown AM, Weaver DL, Wolmark 
N. Surgeon training, protocol compliance, and technical outcomes from breast cancer 
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79. Piantadosi S. Clinical trials - a methodologic perspective. Hoboken: John Wiley & Sons, 
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a national symposium on rapid identification and treatment of acute stroke. 1996;2012 
 
81. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI 
Executive Committee. Recommendations for the Management of Intracranial Haemmorrhage 
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82. Bullock R, Chesnut RM, Clifton GL, et al. Brain Trauma Foundation, Inc, American 
Association of Neurological Surgerons, Congress of Neurological Surgeons, Joint Section on 
Neurotrauma and Critical Care. Guidelines for the management of severe traumatic brain 
injury: cerebral perfusion pressure. In New York: Brain Trauma Foundation, Inc.; 2003.   
 
83. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors 
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84. Weir CJ, Lees KR. Comparison of stratification and adaptive methods for treatment 
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85. Rosenblum M, van der Laan MJ. Simple, efficient estimators of treatment effects in 
randomized trials using generalized linear models to leverage baseline variables. The 
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of a marginal structural model. The International Journal of Biostatistics. 2010; 6(2), 1-28. 
 
87. Lachin JM. Biostatistical Methods: The Assessment of Relative Risks. 2011. John Wiley & 
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88. Verbeke G, Molenberghs G. Linear Mixed Models for Longitudinal Data. 2000. Springer 
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90. Rabe-Hesketh S, Skronal A. Multilevel and Longitudinal Modeling Using Stata, 2nd Ed. 
2008. STATA Press, College Station, TX. 
 
91. Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological 
research: Conceptual, strategic, and statistical considerations. J Pers Soc Psychol. 1986; 51, 
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92. Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an 
important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med. 
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93. Diggle PJ, Haegerty P, Liang KY, Zeger SL. Analysis of Longitudinal Data. 2002, 2nd ed. 
Oxford University Press, New York, NY. 
 
94. Reed SD, Blough DK, Meyer K et al. Inpatient costs, length of stay, and mortality for 
cerebrovascular events in community hospitals. Neurology 2001; 57:305. 
 
95. Russell MW, Joshi AV, Neumann PJ et al. Predictors of hospital length of stay and cost in 
patients with intracerebral hemorrhage. Neurology 2006; 67: 1279. 
 
96. Earnshaw SR, Joshi AV, Wilson MR, Rosand J. Cost-effectiveness of recombinant activated 
factor VII in the treatment of intracerebral hemorrhage. Stroke 2006; 37(11):2751-8. 
 
97. Fleming TR, Harrington DP, O’Brien PC. Designs for group sequential tests. Control Clin 
Trials 1984; 5:348–361. 
 
98. Guo X, Carlin BP. Separate and joint modeling of longitudinal and event time data using 
standard computer packages. The American Statistician. 2004;58:16-24 
 
99. Allison PD. Missing Data. 2002. Sage Publications: Thousand Oaks, CA. 
 
100. Rotnitzky A, Scharfstein DO, Su TL, Robins JM. Methods for conducting sensitivity 
analysis of trials with potentially nonignorable competing causes of censoring Biometrics. 
2001;57:103-112. 
 
101. Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM, STICH II 
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2013;382(9890):396. 
 
 


 
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Appendix 1: Sample trial consent form 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title:  
MISTIE III: A phase III, randomized, open-label, 500-subject clinical trial 
of minimally invasive surgery plus rt-PA in the treatment of intracerebral 
hemorrhage. 
 
[Add only if your site is participating in the ancillary study.] 
MTI-M3: Mechanisms of Tissue Injury in MISTIE III  
 
Protocol No.: 
Sponsor protocol number: ICH02 
 
 
 
 
 
Sponsor: 
 
Daniel F. Hanley, MD 
 
 
 
Director, Brain Injury Outcomes Division 
Johns Hopkins University Department of Neurology 
 
 
 
Baltimore, Maryland, USA 
 
Primary funding: National Institutes of Health/ 
 
 
 
National Institute of Neurological Disorders and Stroke 
 
Additional support:  [US and Canadian sites: Genentech, Inc.] 
[Non-US and non-Canadian sites: National Institute for Health 
Research] 
 
 
 
 
 
 
Principal Investigator: 
 
 
1. 
What you should know about this study: 
• You are being asked to join a research study. 
• This consent form explains the research study and your part in the study. 
• Please read it carefully and take as much time as you need. 
• Please ask questions at any time about anything you do not understand. 
• You are a volunteer. If you join the study, you can change your mind later. You 
can decide not to take part or you can quit at any time. There will be no penalty or 
loss of benefits if you decide to quit the study. 
• During the study, we will tell you if we learn any new information that might 
affect whether you wish to continue to be in the study. 
• Ask your study doctor or the study team to explain any words or information in 
this informed consent that you do not understand.  


 
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• A description of the research will be available at www.ClinicalTrials.gov. This 
website will not include information that can identify you. You can search the 
website at any time. 
• The person being asked to be in this research study may not be able to give 
consent to be in this study. You are therefore being asked to give permission for 
this person to be in the study as his/her decision maker. 
• [Add only if your site is participating in the ancillary study.] Biospecimens will be 
collected in this study. These biospecimens may include blood samples as well as 
samples of fluid that would otherwise be discarded. This may include fluid 
collected from the hematoma at surgery or from the drain placed within the 
hematoma as part of the MISTIE trial. Most biospecimens contain DNA, which is 
the genetic code for each person. 
 
2. 
Why is this research being done? 
 
 
This research is being done to evaluate the recovery of participants who receive a study 
drug called rt-PA (recombinant tissue plasminogen activator) when used with minimal 
surgery for the removal of a blood clot from the brain compared to participants who 
receive standard medical care (in other words, no surgery and no study drug). [Add only 
if your site is participating in the ancillary study.] Additionally, this research will help to 
determine if radiographic images, genetic data and markers of inflammation in the brain 
collected from blood and brain fluid samples can help to identify those patients with brain 
hemorrhage who will most likely benefit from the minimal surgery. 
 
People with certain types of bleeding in the brain may join. This includes bleeding that 
happened without warning and which is not caused by a head injury. This unexpected 
bleeding is called ICH or intracerebral hemorrhage. ICH typically occurs in patients with 
high blood pressure or in the elderly due to fragile blood vessels. 
 
The rate of death in patients with ICH is still very high despite the best medical 
treatment. Also, the amount of recovery in those that survive is also very poor. It has 
been shown that the amount and success of recovery is related to the size of the blood 
clot in the head. However, extensive surgery to remove the blood clot has sometimes 
been shown to be more harmful. Therefore, the usual treatment for ICH is to avoid doing 
extensive surgery whenever possible. This usual treatment is called “standard medical 
care.” 
 
Recent studies have shown that a less aggressive method of removing the blood clot - by 
using a small drain tube surgically placed into the brain to give a medicine to break up 
the clot - can be of benefit. This study will allow us to see if this method of clot 
evacuation is more effective at improving recovery than standard medical care, which 
does not involve removing the clot. 
 
Rt-PA is approved by the U.S.A. Food and Drug Administration (FDA) and the European 
Medicines Agency (EMA) for the treatment of heart attacks or ischemic stroke (clot in 


 
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the brain) for dissolving clots. It is not approved for use in hemorrhagic stroke (bleeding 
in the brain) The FDA is allowing the use of rt-PA in this study.  
 
 
How many people will be in this study? 
 
About 500 participants total are expected to take part in this research study, with about 5-
10 subjects from [Your Institution Name]. 
 
3. 
 What will happen if you join this study? 
 
 
If you agree to be in this study, we will ask you to do the following things: 
 
Screening: With your consent, you will have the following screening procedures to find 
out if you are eligible for this study: 
 
• A CT scan will be done at least 6 hours after the first CT scan that diagnosed the 
bleeding in your brain. If this second CT scan shows more blood in the brain when 
compared to the first CT scan, another CT scan will be repeated at least 6 hours later. 
This is done to make sure the bleeding has stopped. A CT scan is a test that produces 
an image of your body using a small amount of radiation. The image shows the body 
tissues and structure in three dimensions (“3-D”). These CT scans may already have 
been done per standard clinical care.  
 
• A MRI (magnetic resonance imaging) scan and a MRA (magnetic resonance 
angiogram) or a CTA (computed tomography angiogram) will be done. These 
procedures are part of the standard clinical care to see if the bleeding is caused by 
abnormal blood vessels, such as an aneurysm. You will not be eligible for this study 
if this is the cause for your bleeding.  
 
• A pregnancy test will be done if you are a female of childbearing potential. You must 
not be pregnant to be in this study. This test is part of the standard clinical care. 
 
Randomization: If, after these tests, you are found to be eligible for this study, you will 
be randomly assigned (50%-50% chance, similar to flipping a coin) to one of the two 
methods being compared in this study. You will either continue to receive standard 
medical care, or a small tube will be surgically placed into the clot to allow it to drain. 
You will have 1 chance out of 2 to be selected to have surgery. The drug rt-PA may be 
given through this tube to help break-up the clot if the drain alone does not remove 
enough of it.  
 
Standard medical care: If you are randomly assigned to continue to receive standard 
medical care: 
 


 
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• Your vital signs, such as, heart rate, blood pressure, temperature, and neurological 
condition will be monitored daily for the next 6 days. This is done as part of 
standard clinical care but will be reviewed for study purposes. 
• Blood samples, about 3 to 4 teaspoons, will be drawn daily for the next 6 days to 
monitor natural chemical levels in the blood related to the bleeding in your brain. 
This is done as part of standard clinical care but will be reviewed for study 
purposes. 
• CT scans will be done daily for the next 4 to 5 days to monitor the remaining 
blood clot in your brain. This is done as part of standard clinical care but will be 
reviewed for study purposes. 
• An MRI will be performed at day 7. This is done for study purposes only and only 
if you are able to have an MRI (see Risks section below). At some point during 
the MRI exam, the scanning procedure will be interrupted to give you a contrast 
agent through a needle in your arm. 
• [Add only if your site is participating in the ancillary study.] Blood will be drawn 
(2 teaspoons each time) from a needle in the arm or from an intra-arterial or 
intravenous line once daily for 5 days. This will be done at the same time as other 
routine blood collection and using the same sterile technique for usual blood 
draws. 
• [Add only if your site is participating in the ancillary study.] Blood will be drawn 
(four teaspoons) once while you are in the hospital or during a scheduled follow-
up visit. 
 
Surgery plus study drug: If you are randomly chosen or assigned to the group that will 
get the drain:  
 
• You will be taken to an operating room or other designated area and given an 
appropriate, general anesthetic. A neurosurgeon will make a skin incision over the 
site of the blood clot. Following this, a hole will be drilled in the skull through the 
skin opening and an unbendable, hollow tube will be passed into the clot. When 
the tube is in the right place, suction will be applied to the drain using a syringe to 
remove as much of the blood clot as possible. A soft rubber drain tube (called a 
catheter) will be passed through the tube and the unbendable tube will be 
removed. The soft rubber drain tube will be left in the clot in the head and the skin 
will be closed around it.  
• Another CT scan will then be done to see how much clot is left and to make sure 
that the soft drain tube is in the middle of the remaining blood clot.  
• You will then be taken to the intensive care unit.  
• If there is enough blood clot remaining in the brain after the surgery, rt-PA (a 
drug that breaks up blood clots) along with a saline (salt water) fluid (to flush the 
tubing) will be given into the drain every 8 hours to break up the clot. In-between 
injections, the drain tube will be attached to a drainage system to allow the clot to 
come out on its own.  


 
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• Once a day you will be taken to have another CT scan. Injections of rt-PA will 
stop after 9 doses have been given or when enough blood has been removed from 
the clot, whichever comes first.  
• Your vital signs, such as, heart rate, blood pressure, temperature, and neurological 
condition will be monitored daily for the next 6 days. This is done as part of 
standard clinical care but will be reviewed for study purposes. 
• Blood samples, about 3 to 4 teaspoons, will be drawn for the next 6 days to 
monitor natural chemical levels in the blood related to the bleeding in your brain. 
This is done as part of standard clinical care but will be reviewed for study 
purposes. 
• CT scans will be done daily for the next 4 to 5 days to monitor the remaining 
blood clot in your brain. This is done as part of standard clinical care but will be 
reviewed for study purposes. 
• An MRI will be performed at day 7. This is done for study purposes only and only 
if you are able to have an MRI (see Risks section below). At some point during 
the MRI exam, the scanning procedure will be interrupted to give you a contrast 
agent through a needle in your arm. 
• [Add only if your site is participating in the ancillary study.] Blood will be drawn 
(four teaspoons) once while you are in the hospital or during a scheduled follow-
up visit. 
• [Add only if your site is participating in the ancillary study.] Blood will be drawn 
(2 teaspoons each time) from an intravenous line once daily for 5 days. This will 
be done at the same time as other routine blood collection and using the same 
sterile technique for usual blood draws. 
•  [Add only if your site is participating in the ancillary study.] The blood clot 
removed during the placement of the brain catheter will be collected. 
• [Add only if your site is participating in the ancillary study.] Blood clot drainage 
will be collected (2 teaspoons) from the drainage bag/chamber once daily while 
the brain catheter is in place. This will be done using sterile technique. 
 
[Add this section only if your site is participating in the ancillary study.] 
Genetic and Inflammatory Marker Testing 
 
• We will prepare the blood collected for genetic and inflammatory marker testing 
and analysis. The study staff will send the blood samples to be stored with 
specific investigators for 10 years. You will have the choice to allow your stored 
blood samples to be used in future related studies for brain bleeding strokes. 
• The Genetic Information Nondiscrimination Act (GINA) may help protect you 
from health insurance employment discrimination based on genetic information. 
• The law provides that health insurance companies and group health plans 
o May not ask for genetic information from this research and 
o May not use genetic information when making decision about eligibility or 
premiums 


 
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o The law will not stop health insurance companies from using genetic 
information to decide whether to pay claims. The law does not apply to 
other types of insurance (such as life, disability or long-term care). 
• Request to collect and store biospecimens for future research 
o As part of this research study, we would like to ask you to let us store your 
biospecimens and health information for future research. This research 
could include other diseases and involve research tools such as gene 
sequencing or the creation of cell lines. 
o Gene sequencing of your DNA provides researchers with the code to your 
genetic material. 
o Cell lines are living tissue samples that can be grown in a laboratory. A 
cell line can provide an unlimited supply of cells in the future without 
requiring more samples from you. Each cell contains your complete DNA. 
o The study doctor can provide you with additional information if you have 
questions. Also, further information about our use of your biospecimens 
can be found in this consent document under the heading What happens to 
Data and Biospeciments that are collected in the study? 
o Will you allow us to store the biospecimens we collect for this study for 
use in future research? 
 
YES    ___________________                                                                  
Signature of Participant 
 
NO 
___________________ 
Signature of Participant 
 
Study follow visits: Study participants will be followed for 1 year after randomization. 
Regardless of what group you are assigned to: 
 
• You will be asked to return to the clinic 30, 180, and 365 days from today. Your 
neurological condition and blood pressure will be checked and you will be asked 
questions about how well you are doing. These visits will take about 2 hours and 
will be video recorded. This video will be sent to an expert doctor in the United 
Kingdom for review. If during the 30-, 180- and 365-day follow-up visit, we are 
unable to interview you directly, we will ask permission to interview the person 
accompanying you during the visit. There will be a separate consent form for the 
person accompanying you to sign at that time, if it is necessary. 
• During the clinic visits at 30 and 180 days from today you will have CT scan to 
look at how your brain is healing.  
• You will be contacted by telephone 90 and 270 days from today. You will be 
asked questions about your condition and how well you are doing.  
 
How long will you be in the study? 
 
You will be in this study for 12 months. 


 
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4.  
What are the risks or discomforts of the study? 
  
STANDARD MEDICAL CARE GROUP:  
 
Likely risks: 
• Approximately 70% of ICH patients receiving standard medical care will 
normally have further bleeding in the brain. This is called rebleeding. We will 
review daily CT scans to watch for rebleeding. We will also review daily 
blood tests to watch for bleeding disorders. 
• You will have daily CT scans. The radiation exposure from the CT scans you 
will receive by participating in this study is equivalent to an exposure of 1.4 
rems (14 mSv) to your whole body. For comparison, naturally occurring 
radiation from the environment exposes people to about 0.3 rems (3 mSv) per 
year and people exposed to radiation in their occupations are permitted to 
receive whole body exposures of 5 rems (50 mSv) per year. 
 
 
Less likely risks: 
• Approximately 10% to 20% of ICH patients receiving standard medical care 
will normally develop infection. If you develop signs and symptoms of 
infection, your clinical care team will take samples of your spinal fluid to look 
for infection if necessary. 
• Worsening of your neurological condition. 
• The effects of magnetic fields in an MRI scanner have been extensively 
studied, and there are no known significant risks with an MRI exam. You 
may, however, be bothered by feelings of confinement (claustrophobia), and 
by the noise made by the magnet during the procedure. You will be asked to 
wear earplugs or earphones while in the magnet. You will not have an MRI if 
you have a pacemaker, an implanted defibrillator or certain other implanted 
electronic or metallic devices. It is important for you to advise the MRI staff if 
you have had brain surgery for a cerebral aneurysm, or if you have implanted 
medical or metallic devices, shrapnel, or other metal, such as metal in your 
eye. 
• The contrast agent you will receive is FDA-approved and used routinely for 
MRI exams. It contains a material called gadolinium. About 1 in 100 people 
may notice discomfort, tingling or warmth in the lips, metallic taste in the 
mouth, tingling in the arm, nausea, or headache. These symptoms go away 
quickly. There is a small risk of an allergic reaction to gadolinium. However, 
a severe allergic reaction occurs in less than one in 300,000 people. The 
placement of the needle (small plastic tube) to give you the gadolinium may 
cause minor pain, bruising and/or infection at the injection site. 
• People with severe kidney failure who receive gadolinium are at risk of 
developing Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing 
Dermopathy (NSF/NFD). This disease causes fibrosis (the formation of too 


 
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much connective tissue in the skin and internal organs). This is a serious 
disease which can result in death. You should notify the study team or MRI 
staff if you are allergic to gadolinium or if you have kidney problems. 
• Drawing blood from your arm may cause pain, bruising, lightheadedness, and, 
on rare occasions, infection. 
• [Add only if your site is participating in the ancillary study.] Despite the 
GINA protections and the best efforts of the research team, there may still be 
a risk if information about you were to become known to people outside of 
this study. 
• [Add only if your site is participating in the ancillary study.] Genetic 
information is unique to you, even without your name or other identifiers. For 
this reason, genetic information like DNA may be used to identify you and 
possibly your family members. We have procedures (such as, labeling your 
biospecimens with a password protected code known only to select research 
staff) to prevent people working with your DNA from discovering if it 
belongs to you. However, there is the risk this can happen as new ways of 
tracing genetic information are being developed that may make re-
identification of genetic information possible. 
• Death. 
 
 
Discomforts: 
• You may experience discomfort that is part of the routine medical care for 
participants with your condition in the intensive care unit.  
• During the follow up visits, you may get tired or bored when we are asking 
you questions or you are completing questionnaires. You do not have to 
answer any question you do not want to answer. 
 
There may be side effects and discomforts that are not yet known. 
 
 
SURGERY PLUS STUDY DRUG GROUP: 
 
 
 
Likely risks: 
• In this study, the risk of rebleeding could be higher than normal. Certain 
procedures such as inserting the drain tube into the clot, injecting the clot-
dissolving drug, and removing the drain tube may increase the risk. We will 
review daily CT scans to watch for rebleeding. We will also review daily 
blood tests to watch for bleeding disorders. If you have rebleeding in the brain 
that causes a worsening of your neurological condition, we will stop injecting 
the study drug.  
• You will have daily CT scans. The radiation exposure from the CT scans you 
will receive by participating in this study is equivalent to an exposure of 1.4 
rems (14 mSv) to your whole body. For comparison, naturally occurring 
radiation from the environment exposes people to about 0.3 rems (3 mSv) per 
year and people exposed to radiation in their occupations are permitted to 
receive whole body exposures of 5 rems (50 mSv) per year. 


 
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Less likely risks: 
• In this study, the injection of the study drug (rt-PA) could increase the risk of 
infection. If you develop signs and symptoms of infection, your clinical care 
team will take samples of your spinal fluid to look for infection if necessary. 
• The placement of the drain tube and leaving it in place for 3 days may further 
increase the risk of infection.  
• We do not yet know if your overall risk is higher or lower if you get the drain 
tube and the study drug.  
• Worsening of your neurological condition. 
• The effects of magnetic fields in an MRI scanner have been extensively 
studied, and there are no known significant risks with an MRI exam. You 
may, however, be bothered by feelings of confinement (claustrophobia), and 
by the noise made by the magnet during the procedure. You will be asked to 
wear earplugs or earphones while in the magnet. You will not have an MRI if 
you have a pacemaker, an implanted defibrillator or certain other implanted 
electronic or metallic devices. It is important for you to advise the MRI staff if 
you have had brain surgery for a cerebral aneurysm, or if you have implanted 
medical or metallic devices, shrapnel, or other metal, such as metal in your 
eye. 
• The contrast agent you will receive is FDA-approved and used routinely for 
MRI exams. It contains a material called gadolinium. About 1 in 100 people 
may notice discomfort, tingling or warmth in the lips, metallic taste in the 
mouth, tingling in the arm, nausea, or headache. These symptoms go away 
quickly. There is a small risk of an allergic reaction to gadolinium. However, 
a severe allergic reaction occurs in less than one in 300,000 people. The 
placement of the needle (small plastic tube) to give you the gadolinium may 
cause minor pain, bruising and/or infection at the injection site. 
• People with severe kidney failure who receive gadolinium are at risk of 
developing Nephrogenic Systemic Fibrosis/Nephrogenic Fibrosing 
Dermopathy (NSF/NFD). This disease causes fibrosis (the formation of too 
much connective tissue in the skin and internal organs). This is a serious 
disease which can result in death. You should notify the study team or MRI 
staff if you are allergic to gadolinium or if you have kidney problems. 
• Drawing blood from your arm may cause pain, bruising, lightheadedness, and, 
on rare occasions, infection. 
• [Add only if your site is participating in the ancillary study.] The removal 
of hematoma drainage may be associated with a small increased risk of 
infection in the brain. We will minimize the risk of infection by using a 
standardized sterile technique to remove the hematoma drainage.  
• [Add only if your site is participating in the ancillary study.] Despite the 
GINA protections and the best efforts of the research team, there may still be 
a risk if information about you were to become known to people outside of 
this study. 


 
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• [Add only if your site is participating in the ancillary study.] Genetic 
information is unique to you, even without your name or other identifiers. For 
this reason, genetic information like DNA may be used to identify you and 
possibly your family members. We have procedures (such as, labeling your 
biospecimens with a password protected code known only to select research 
staff) to prevent people working with your DNA from discovering if it 
belongs to you. However, there is the risk this can happen as new ways of 
tracing genetic information are being developed that may make re-
identification of genetic information possible. 
• Death. 
 
Discomforts: 
• You will have to stay in bed while the drain tube is in place.  
• You may experience discomfort that is part of the routine medical care for 
participants with your condition in the intensive care unit.  
• During the follow up visits, you may get tired or bored when we are asking 
you questions or you are completing questionnaires. You do not have to 
answer any question you do not want to answer. 
 
There may be side effects and discomforts that are not yet known. 
 
5.  
Are there risks related to pregnancy? 
 
Because of the need for head CT and MRI scans, you will have a pregnancy test if you 
are a female of childbearing potential. You may not take part in this study if you are 
pregnant or nursing. 
 
If you become pregnant during the 12 month follow up period, we will ask you to 
complete the interviews and questionnaires, but you will not have the CT scans done. 
 
 
This research may hurt an embryo or fetus in ways we do not currently know.  
 
6.  
Are there benefits to being in the study? 
 
Your intracerebral hemorrhage (ICH) may improve while you are in this study; however, 
this cannot be promised. The results of this study may help people with ICH in the future. 
There is no guarantee that you will receive any medical benefits from being in this study. 
 
There may be no benefit to you from use of the study drug. We hope to show that rt-PA 
in combination with minimal surgery, will decrease the size of the blood clot in your head 
allowing you to recover faster. If you are assigned to receive standard medical care, you 
may not have this benefit.  If this study shows that the use of rt-PA in combination with 
minimal surgery is more effective than medical treatment, it could be of benefit to many 
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It cannot be promised that you will receive any medical benefits from being in this study. 
 
7. 
What are your options if you do not want to be in the study? 
 
If you decide not to join this study, there are no other specific treatments available. 
Currently the only alternative to this treatment is standard medical management without 
removal of the blood clot. Ask the study doctor to discuss possible medical and surgical 
options with you.  
 
You do not have to join this study. If you do not join, your care at [Your Institution 
Name] will not be affected. 
 
8. 
Will it cost you anything to be in this study? 
 
The following procedures, tests, drugs or devices are part of this research study and will 
be supplied free of charge by the study: 
• Pregnancy test (if a second test is done post-consent) 
• Activase administrations (via intraclot catheter; surgical group only) 
• ICU interviews and clinic visits to evaluate neurological function and your recovery 
 
[US and Canadian Sites: This study and the procedures listed below qualify under CMS 
rules for Medicare/Medicaid coverage. Most private insurers follow CMS rules for 
coverage of procedures related to being in a clinical study. Your health insurer will be 
responsible for all other procedures, tests, drugs, or devices that are part of this study 
such as the following:] 
 
[Non-US and non-Canadian Sites: All patients are insured according to the Medicines 
Act. Your health insurer will be responsible for all other procedures, tests, drugs, or 
devices that are part of this study such as the following:] 
 
• Diagnostic CT 
• Stability CT (6 hours or more after diagnostic CT) 
• Blood pressure control sustained over a minimum of 6 hours 
• 
Pregnancy test 
• 
MRI/MRA and CTA 
• 
Image-Guided Catheter Placement + Aspiration (Surgical Group Only) 
• 
Post catheter placement CT scan 
• 
Daily CT scan 
• 
CT obtained 24 h post catheter removal 
• 
Neurocheck 
• 
Lab Assessments- Coagulation tests: PT, aPTT, INR 
• 
Lab Assessments- CBC including platelet counts 
• 
Lab Assessments- Chemistries 
 


 
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[US and Canadian sites: If an insurer denies coverage for any of the above listed 
procedures, the study will pay for the denied claim. If you have private health insurance, 
you will be responsible for deductibles. If there are co-pays for study related charges, the 
study will cover the co-pays. If you have received a medical bill related to this research 
participation, please contact [Study Coordinator Name] at [Study Coordinator Phone 
Number]. 
 
 
Funds for MISTIE III are provided by the National Institutes of Health (NIH), National 
Institute for Neurologic Disorders and Stroke (NINDS). These funds are not available to 
cover the costs of any other medical care, and you are responsible for the cost of your 
hospitalization and care not related to research. If for some reason your insurance denies 
the claim for your hospital bill, there may be services available to you, if you choose, to 
help you through the claims appeal process. If you have questions about your medical bill 
not relative to research participation, you may contact [Study Coordinator Name] at 
[Study Coordinator Phone Number], who can refer you to hospital sources that may help 
with your hospital charges.] 
 
[Non-US and non-Canadian sites: If you have received a medical bill related to this 
research participation, please contact [Study Coordinator Name] at [Study Coordinator 
Phone Number]. [Add country-specific insurance information] 
 
 
9. 
 Will you be paid if you join this study? 
 
You will not be paid for participation in the study. The study will reimburse $50 per visit 
for travel expenses as part of the 30, 180, and 365 day follow-up visits only. All other 
visits will take place while you are in the hospital or over the telephone. 
 
10.  
Can you leave the study early? 
 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care. 
• If you leave the study early, [Your Institution Name] may use or give out your health 
information that it already has if the information is needed for this study or any 
follow-up activities. 
 
11. 
Why might we take you out of the study early? 
 
 
You may be taken out of the study if: 
• Staying in the study would be harmful. 
• You need treatment not allowed in the study. 
• The study is cancelled. 


 
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• There may be other reasons to take you out of the study that we do not know 
at this time. 
 
If you are taken out of the study early, [Your Institution Name] may use or give out your 
health information that it already has if the information is needed for this study or any 
follow-up activities. 
 
12. 
How will your privacy be protected? 
 
[US and Canadian sites: [Your Institution Name] has rules to protect information about 
you. Federal and state laws also protect your privacy. This part of the consent form tells 
you what information about you may be collected in this study and who might see it. 
 
Generally, only people on the research team will know that you are in the research study 
and will see your information. However, there are a few exceptions that are listed later in 
this section of the consent form. 
 
The people working on the study will collect information about you. This includes things 
learned from the procedures described in the consent form. They may collect other 
information including your name, address, date of birth, and other details. 
 
The research team will need to see your information. Sometimes other people at [Your 
Institution Name] may see or give out your information. These include people who 
review the research studies, their staff, lawyers, or other [Your Institution Name] staff. 
 
People outside of [Your Institution Name] may need to see your information for this 
study. Examples include government groups (such as the Food and Drug Administration), 
safety monitors, other hospitals in the study and companies that sponsor the study. 
 
We cannot do this study without your permission to use and give your information. You 
do not have to give us this permission. If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside of [Your Institution Name] who 
receive your information may not be covered by this promise. We try to make sure that 
everyone who needs to see your information keeps it confidential – but we cannot 
guarantee this. 
 
The use and disclosure of your information has no time limit. You can cancel your 
permission to use and disclose your information at any time by contacting the Principal 
Investigator of this study. The Principal Investigator can be reached by phone at [Phone 
Number] or by sending a letter to: 
 
[PI name] 
[PI address] 


 
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[PI fax number] 
 
You may also choose the option of contacting the [Your Institution Name] Privacy 
Officer. The [Your Institution Name] Privacy Officer can be reached by phone at [Phone 
Number] or by sending a letter to: 
 
[Your Institution Name] Privacy Officer 
[Address] 
[Fax number] 
 
If you send a letter, please be sure to include the study number and your contact 
information. 
 
If you do cancel your permission to use and disclose your information, your part in this 
study will end and no further information about you will be collected. Your cancellation 
would not affect information already collected in this study.] 
 
[Non-US and non-Canadian sites: Insert country-specific privacy language.] 
 
13. 
Will the study require any of your health care providers to share your 
health information with the researchers of this study? 
 
As part of this study, the researchers may ask to see your health care records from your 
other health care providers. 
 
14. 
What treatment costs will be paid if you are injured in this study? 
 
The costs for any treatment or hospital care you received as the result of a study-related 
injury will be billed to your health insurer. Any costs that are not paid for by your health 
insurer will be billed to you. 
 
15. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) [Ethics Committee (EC)] and how 
does it protect you? 
 
The [Your Institution Name] IRB is made up of: 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community. 
 
The IRB [EC] reviews human research studies. It protects the rights and welfare of the 
people taking part in those studies. You may contact the IRB [EC] if you have questions 
about your rights as a participant or if you think you have not been treated fairly. The 


 
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IRB [EC] office number is [Phone Number]. You may also call this number for other 
questions, concerns or complaints about the research. 
 
b. What do you do if you have questions about the study? 
Call the principal investigator, Dr. _________ at [Phone Number]. If you wish, you may 
contact the principal investigator by letter at [Address] or by fax at [Fax Number]. If you 
cannot reach the principal investigator or wish to talk to someone else, call the IRB [EC] 
office at [Phone Number]. 
 
c. What should you do if you are injured or ill as a result of being in this study? 
Call Dr. ________ at [24 hour Phone or Pager Number] if you have an urgent medical 
problem related to your taking part in this study.  
 
If this number is a pager number, after the tone, enter the phone number where you can 
be called, press the # key, and hang up. 
 
d. What happens to Data, Imaging (CT, MRI, etc.) scan copies, and biospecimens 
that are collected in the study? 
The data, imaging scan copies, and biospecimens collected from you during the study are 
important to both this study and to future research. 
 
If you join this study: 
• You will not own the data or copies of imaging scans given by you to the 
investigators for this research. 
• Both [Your Institution Name] and any Sponsor of this research may study your data 
and imaging scan copies collected from you. 
• If data or imaging scan copies are in a form that identifies you, [Your Institution 
Name] may use them for future research only with your consent or IRB [EC] 
approval. 
• All biospecimens will be stored at [Your Institution Name] before secure transfer to 
one or more of the central study laboratories for analysis:  University of Manchester, 
UK, Massachusetts General Hospital, Boston, USA, and/or Yale University, New 
Haven, Connecticut, USA. 
• You will not own any product or idea created by the researchers working on this 
study. 
• You will not receive any financial benefit from the creation, use or sale of such 
product or idea. 
 
Often it is helpful for scientists to share information they get from studies in order to 
learn more about health and disease. Combining information from different studies in one 
place may help them learn even more. This collection of information is called a databank. 
Your study data may be sent to one or more databanks, where it will be stored with data 
from other studies. The databanks may be kept at universities, government agencies (such 
as the National Institutes of Health), or private companies. The data may include health 


 
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information and images (for example, X-rays, MRIs, or CT scans). Results of this study 
will also be published in a medical journal(s). 
 
Your name and any other identifying information will NEVER be included in 
information that is published in a medical journal(s) or sent to a databank(s) (this is called 
de-identification). Researchers will ALWAYS have a duty to keep your information 
confidential.] 
 
e. What are the Organizations that are part of [Your Institution Name]? 
[Your Institution Name] includes the following: 
• [List out any other names or locations that serve your institution] 
 
16. 
What does your signature on this consent form mean? 
  
 
Your signature on this form means that: 
• you understand the information given to you in this form 
• you accept the provisions in the form 
• you agree to join the study 
You will not give up any legal rights by signing this consent form. 
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
Signature of Participant 
 
 
 
 
 
 
 
 
Date/Time 
 
 
Signature of Person Obtaining Consent 
 
 
 
 
 
 
Date/Time 
 
 
Signature of Legally Authorized Representative (LAR) for ADULTS NOT 
 
 
Date/Time 
CAPABLE of GIVING CONSENT (Persons from the following categories in order of 
priority may be a Legally Authorized Representative: Health Care Agent; Legal Guardian; 
Spouse; Adult child; Parent; Adult sibling; Friend or other relative) 
 
 
 
Relationship of LAR to Participant (indicate why the LAR is authorized 
 
 
Date/Time 
to act as a surrogate health care decision-maker under state law) 
 
 
 
Signature of Witness to Consent Procedures (optional unless IRB or Sponsor required) 
 
Date/Time 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE 
PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN TO THE PARTICIPANT; AND, IF 


 
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APPROPRIATE A COPY OF THE CONSENT FORM MUST BE PLACED IN THE 
PARTICIPANT’S MEDICAL RECORD. 
 
ONLY CONSENT FORMS THAT INCLUDE THE [Your Institution Name] LOGO CAN BE 
USED FOR CONSENTING RESEARCH PARTICIPANTS. IF THIS CONSENT FORM DOES 
NOT HAVE A [Your Institution Name] LOGO, DO NOT USE IT TO CONSENT RESEARCH 
PARTICIPANTS. 
 


 
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Appendix 2: Sample HIPAA authorization form for international research 
 
HIPAA Authorization Form for International Research 
 
Principal Investigator: 
 
Application Number: 
 
Study Title:  
MISTIE III: A phase III, randomized, open-label, 500-subject 
clinical trial of minimally invasive surgery plus rt-PA in the 
treatment of intracerebral hemorrhage. 
 
Some of your health information collected in this study will be sent to the United States. The 
U.S. has privacy laws that will protect your information and your identity. 
 
If you want to be in the study, you must agree to let us use and send details about you and your 
health as part of this study. This study uses a drug. The U.S. Food and Drug Administration 
(FDA) may need to see your health information when it is sent to the U.S. 
 
If you join the study, you can decide later that you want to leave the study and you do not want 
to have your health information sent to the U.S. If you decide to leave the study, we will not be 
able to take back any health information that has already been sent to the U.S. To leave the 
study, tell the principal investigator. 
 
Please sign this form (or make your mark) if you agree to let us use and give out details about 
your health. 
 
 
Signature of Participant 
 
 
 
 
 
 
 
 
Date/Time 
 
 
Signature of Person Obtaining Consent 
 
 
 
 
 
 
Date/Time 
 
 
Signature of Legally Authorized Representative (LAR) for ADULTS NOT 
 
 
Date/Time 
CAPABLE of GIVING CONSENT (Persons from the following categories in order of 
priority may be a Legally Authorized Representative: Health Care Agent; Legal Guardian; 
Spouse; Adult child; Parent; Adult sibling; Friend or other relative) 
 
 
 
Relationship of LAR to Participant (indicate why the LAR is authorized 
 
 
Date/Time 
to act as a surrogate health care decision-maker under state law) 
 
(This form is to be kept with the consent document signed by the study participant or LAR.) 
 


 
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Appendix 3: Medical management guidelines 
 
1. ICP management: The American Academy of Neurological Surgery’s (AANS) Head 
Injury Guidelines will be used as the standardized approach for both the medical and 
surgical treatment groups. This approach has been previously employed. (Clifton GL, 
Miller ER, Choi SC, et al: Lack of effect of induction of hypothermia after acute brain 
injury. N Engl J Med 344:556-563, 2001) Intracranial hypertension is defined as pressure 
within the cranial vault elevated > 30 mm Hg for five or more minutes. A patient will be 
monitored if he or she demonstrates obtundation, which we define as GCS ≤ 8 on a 
minimum of two observations over eight hours of time. All eligible patients will be 
monitored, independent of medical or surgical treatment. The treating surgeon will use 
standardized clinical criteria to select the ICP monitoring device. The Camino 
parenchymal catheter has been pre-specified as the device of choice. However the 
intraventricular catheter could be a choice, if it offers clinical advantage in the presence 
of non-compressed ventricles, or a subarachnoid screw could be chosen, if there is risk of 
infection.  
Interventions include: 1) head positioning (usually 30o elevation HOB), 2) 
euthermia with core temperature < 38o, 3) normoxia and normocapnia, and 4) sedation 
and analgesia, to maintain HR < 120 with concurrent absence of agitated motor activity. 
When standard interventions are not effective, mannitol in doses of 1 gm/kg load and 
0.25 gm per kg maintenance will be administered. In response to acute sustained ICP 
elevation (> 40 mm Hg or refractory ICP elevation), hyperventilation to a PaCO2 < 25 
mm Hg will be performed. Ventilation parameters, including FiO2 and tidal volume, 
respiratory rate, and ventilation mode, will be set to produce SaO2 > 90% saturation and 
mean airway pressures < 20 cm H2O. Prolonged sedation with propofol will be used for 
transient or sustained ICP > 30 mm Hg, where agitation is deemed a possible factor. 
Surgical management of uncontrollable ICP to control ICP is allowed but not encouraged 
in the absence of full medical therapy. Surgery may be considered if hemorrhage 
extension or rebleeding occurs, if ICP > 30 mmHg, with optimal medical management, 
for acute compartment syndrome, or other life-saving consideration. When ICP is 
controlled at < 20 mm Hg for one or more days, sequentially withdraw treatment 
modalities from highest level of intervention to lowest level of intervention. Every effort 
will be made to avoid long term hyperventilation, in keeping with the AANS head injury 
guidelines (American Association of NS: Guidelines for the management of severe head 
injury.  Brain Trauma Foundation, American Association of Neurological Surgeons, Joint 
Section on Neurotrauma and Critical Care. J Neurotrauma 13:641-734, 1996) and the 
ASA ICH treatment guideline statement. (Broderick JP, Connolly S, Feldman E: 
Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for 
healthcare professionals from a special writing group of the Stroke Council, American 
Heart Association. Stroke 38:2001-2023, 2007)  
ICP monitoring devices will be removed when ICP is maintained < 20 mm Hg 
without pharmacological therapy.   
 
2. Neurological status: The GCS goal is 15 or 10T sustained for 8 hours of observation. 
Sedation will be used for agitation. The sedations of choice are Propofol or Lorazepam 


 
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0.5 mg, IV, Q1-2 hr., to maintain a sedation score of 1. Sedation will be discontinued 
when ICP is successfully controlled. 
 
3. Cardiovascular management: Beta-blockade with Metoprolol, 20 to 80 mg IV Q8 hrs, 
will be the primary therapeutic modality. Transient elevations of BP > 160 mm Hg will 
be treated with labetalol 5-10 mg IV. A second agent will be initiated where coronary 
artery disease is suspected by EKG or by historical criteria.  Where renovascular 
hypertension appears likely, the angiotension converting enzyme inhibitor enalapril will 
be administered. When necessary for sustained BP control, a constant infusion of esmolol 
will be the first line drug, heart rate permitting (HR > 90 beats per min). 
 
4. Respiratory care: A trial of independent breathing will be undertaken and/or the level 
of mechanical ventilatory support will be diminished, when no pooled secretions exist, 
the LOC is > 10 GCS points, and oxygenation is sustained. The absence of ongoing ICP 
elevation and the presence of independent sustained mechanical ventilatory activity for > 
12 hours will be considered sufficient criteria to consider removal of the endotracheal 
tube in all patients with intact airway reflexes. 
 
5. Nutritional support: Ranitidine and/or reglan may be used to suppress gastric acid. For 
patients with persistent ileus, after pharmacologic motility enhancement for > 48 hours, a 
trial of parenteral nutrition will be undertaken.  The presence of established independent 
ventilation and the absence of aspiration on bedside swallowing tests will be considered 
the necessary prerequisites for a trial of oral feeding. Enteral or parenteral feeds will not 
be discontinued until a minimum of 80% of daily caloric needs is consistently met by oral 
intake. 
 
6. Thromboembolic prophylaxis: Deep venous thrombophlebitis and pulmonary embolus 
prophylaxis will be undertaken on the day of admission with the use of SCDs. For 
patients at high risk of thromboembolism, study center standard of care policies may 
govern the use of low molecular weight, fractionated and unfractionated heparins for 
DVT prophylaxis during the acute treatment and follow-up periods (criteria established 
by the American Orthopedic Association). 
 
7. Withdrawal of care: Withdrawal of care discussions of prognosis and decisions to 
continue or limit, or to withdraw, life-sustaining interventions will be conducted 
according to each institution’s policies for end-of-life decision-making, as well as their 
institutional codes of medical ethics. The study assumes any such discussion will reflect 
the patient’s wishes and the known facts regarding prognosis. Where the PI is not the 
managing physician it is assumed that those individuals will confer prior to presentation 
of the consensus prognosis and planned course of treatment. In some situations, the 
investigator may choose to select a colleague to serve in the clinician role or request a 
review by the hospital’s ethics committee or other knowledgeable expert. 
 
 


 
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Appendix 4: Sample consent form for videotaping a proxy during the modified Rankin Scale 
interview. 
 
MISTIE III Proxy Videotaping Consent 
 
The purpose of this document is to obtain your consent to talk with you on videotape 
 
1. In the MISTIE III study, we record each patient at three follow-up visits 
 
2. Today, we are unable to record an interview with the patient who is enrolled in the MISTIE 
III study but is too ill to speak 
 
3. We would like to record you instead while you briefly describe the patient’s condition 
 
4. The purpose of the recording is to have the same central readers at the University of 
Glasgow evaluate every patient’s condition  
 
5. Only physicians and staff at the University of Glasgow will see the video in a professional 
hospital research setting 
 
6. The recording will not be broadcast or used for any other purpose and no other copies will be 
made 
 
7. The recording may be stored on a computer server for 2 years after the end of the study 
 
 
 
Videotape Consent  
 
I, the undersigned, hereby give my permission to be videotaped for the purposes described 
above. 
 
Name: ___________________________________________________ 
 
Signature:  ___________________________________________________ 
 
Relationship to study patient:  _____________________________________ 
 
Date: ___________________________________________________ 
 
Signature/role of MISTIE III interviewer: ______________________________ 
 
Date: ___________________________________________________  
 
 
 


 
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Appendix 5: Expected adverse event frequencies based on MISTIE II trial data.  
 
Event 
% Events (n=573) 
Blood and lymphatic system disorders  
 
3.14% 
Anemia 
2.27% 
Leukocytosis 
0.87% 
Cardiac disorders 
 
 
 
5.89% 
Atrial fibrillation 
0.87% 
Atrial flutter 
0.35% 
Bradycardia 
0.52% 
Cardiac arrest 
0.70% 
Chest pain 
0.35% 
Congestive heart failure 
0.17% 
Dysrhythmia 
0.17% 
Myocardial infarction 
0.52% 
Prolonged QT interval on EKG 
0.17% 
Pulmonary vascular congestion 
0.17% 
PVC's; bigemeny 
0.17% 
Sinus bradycardia 
0.17% 
Sinus tachycardia 
0.52% 
Supraventricular tachydysrhythmia 
0.52% 
Ventricular extrasystoles 
0.17% 
Ventricular fibrillation 
0.35% 
Endocrine disorders  
 
 
0.17% 
Hypothyroid 
0.17% 
Eye disorders 
 
 
 
0.17% 
Vision abnormalities 
0.17% 
Gastrointestinal disorders 
 
 
5.89% 
Abdominal pain 
0.35% 
Colitis 
0.17% 
Constipation 
1.22% 
Diarrhea 
0.87% 
Dysphagia 
0.70% 
Esophagitis 
0.17% 
Gall bladder thickening 
0.17% 
Gastritis 
0.17% 
Gastrointestinal bleeding 
0.70% 
Ileus 
0.17% 
Increased gastric outputs 
0.17% 
Intraoperative hemorrhage (PEG) 
0.17% 
Peptic ulcer 
0.17% 
Rotten tooth extraction 
0.17% 
Small intestine infection 
0.17% 
Vomiting 
0.35% 
General disorders and administration site conditions 
6.44% 
Death due to index bleeding event 
1.05% 
Fever 
4.19% 
Generalized edema 
0.17% 
Localized edema 
0.52% 
Phlebitis 
0.17% 
Sudden death NOS 
0.17% 
Transient arm weakness 
0.17% 
Immune system disorders 
 
 
0.35% 
Anaphylaxis 
0.17% 
Angioedema 
0.17% 
Infections, non-neurologic 
 
 
7.13% 
Bacteremia 
0.87% 
Bronchial infection 
0.17% 
Clostridium difficile 
0.35% 
Endocarditis 
0.17% 
Enterocolitis infectious 
0.35% 
Pleural infection 
0.17% 
Sepsis 
0.52% 
Sinusitis 
0.35% 
Skin infection 
0.17% 
Upper respiratory infection 
0.52% 
Urinary tract infection 
3.32% 
Vaginal infection 
0.17% 
Investigations 
 
 
 
2.57% 
Coagulopathy 
0.17% 
Creatinine increased 
0.17% 
Eosinophilia 
0.17% 
Increased ALT 
0.17% 
Increased AST 
0.17% 
Increased bilirubin, direct 
0.17% 
Increased chloride 
0.17% 
increased d-dimer 
0.35% 
Increased fibrinogen 
0.35% 
Increased PT 
0.17% 
Patelet count decreased 
0.17% 
Thrombocytopenia 
0.17% 
Thrombocytosis 
0.17% 
Metabolism and nutrition disorders 
 
11.67% 
Acidosis (metabolic or respiratory) 
0.35% 
Dehydration 
0.17% 
Electrolyte imbalance 
0.17% 
Hyperglycemia 
1.22% 
Hyperkalemia 
0.52% 
Hypernatremia 
0.70% 


 
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Hypertension 
2.44% 
Hypoalbuminemia 
0.17% 
Hypocalcemia 
1.05% 
Hypoglycemia 
0.87% 
Hypokalemia 
1.40% 
Hypomagnesemia 
0.70% 
Hyponatremia 
0.87% 
Hypophosphatemia 
0.87% 
Metabolic alkalosis 
0.17% 
Musculoskeletal and connective tissue disorders 
0.17% 
Back pain 
0.17% 
Nervous system disorders 
 
 
27.71% 
Anoxic brain injury 
0.17% 
Aphasia 
0.35% 
CSF leak 
0.17% 
Depressed level of consciousness 
1.92% 
Dizziness 
0.17% 
Edema cerebral 
0.87% 
Headache 
1.57% 
Herniation 
0.17% 
Hydrocephalus 
0.35% 
Intracranial hemorrhage: Catheter Tract, 
Enlargement 
0.70% 
Intracranial hemorrhage: Catheter Tract, 
New 
4.01% 
Intracranial hemorrhage: Hematoma, 
subdural 
0.17% 
Intracranial hemorrhage: Tissue, 
Enlargement 
4.01% 
Intracranial hemorrhage: Tissue, New 
1.40% 
Intracranial hemorrhage: Ventricular 
system, Enlargement 
1.75% 
Intracranial hemorrhage: Ventricular 
system, New 
1.57% 
Intracranial hypertension 
1.75% 
Ischemia cerebrovascular 
1.92% 
Mass effect 
0.17% 
Meningitis 
0.17% 
Muscle twitching 
0.70% 
Seizure 
2.27% 
Somnolence 
0.17% 
Stroke 
0.17% 
Syncope 
0.70% 
Ventriculitis, non-bacterial 
0.17% 
Wound reclosure after serous fluid leak 
0.17% 
Psychiatric disorders  
 
 
1.04% 
Agitation 
0.87% 
Labile sleep wake cycle 
0.17% 
Renal and urinary disorders 
 
 
2.61% 
Acute kidney injury 
0.35% 
Acute renal insufficiency 
0.87% 
Hematuria 
0.35% 
Left renal mass 
0.17% 
Urinary incontinence 
0.17% 
Urinary retention 
0.70% 
Respiratory, mediastinal and thoracic disorders 
19.84% 
Adult respiratory distress syndrome 
1.22% 
Aspiration 
1.22% 
Atelectasis 
0.87% 
Bronchospasm 
0.17% 
Dyspnea 
0.17% 
Epistaxis 
0.87% 
Hemothorax 
0.17% 
Hypoxemia 
0.70% 
Increased respiratory secretions 
0.17% 
Lung infection 
1.22% 
MRSA infection 
0.17% 
Pleural effusion 
1.05% 
Pneumonia 
5.76% 
Pneumothorax 
0.17% 
Pulmonary edema 
0.70% 
Respiratory arrest 
0.17% 
Respiratory failure 
3.14% 
Shortness of breath 
0.35% 
SIADH 
0.17% 
Stridor 
0.17% 
Tachypnia 
0.52% 
Tracheal stricture 
0.17% 
Tracheitis 
0.35% 
Wheezing 
0.17% 
Skin disorders 
 
 
 
0.35% 
Rash maculo-papular 
0.35% 
Vascular disorders 
 
 
 
4.02% 
Hypotension 
1.05% 
Thromboembolic event 
2.97% 
 
 
 
 


 
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Appendix 6: Genentech Drug Safety: Safety Reporting FAX Cover Sheet 


 
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Appendix 7: Abbreviation List 
AAN:
American Association of Neurology
GOSE:
Glasgow Outcome Scale Extended
AANS:
American Academy of Neurological Surgery
GRE:
Gradient echo
ADL:
Activities of Daily Living
HIPAA:
Health Insurance Portability and Accountability Act
AE:
Adverse event
HOB:
Head of bead
AHA:
American Heart Association
hr, h, or hrs:
Hour(s)
AIC:
Akaike Information Criterion
HR:
Heart rate
aPTT:
Activated partial thromboplastic time
ICES:
Intraoperative CT guided Endoscopic Surgery for intracerebral hemorrhage trial
ASA:
Aspirin
ICH:
Intracerebral hemorrhage
ATACH:
Antihypertensive Treatment of Acute Cerebral Hemorrhage Trial
ICH:
International Conference on Harmonisation
AVM:
Arteriovenous malformation
ICP:
Intracranial pressure
BA:
Bioavailability
ICU:
Intensive care unit
BE:
Bioequivalence
IEC:
Independent Ethics Committee
BP:
Blood pressure
Inc:
Incorporated
CAPA:
Corrective and preventative action plan
IND:
Investigational new drug
cc:
Cubic centimeter
INR:
International normalized ratio
CCC:
Clinical Coordinating Center
INTERACT:
Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial
CD:
Compact Disc
IRB:
Institutional Review Board
CES-D:
Center for Epidemiological Studies – Depression 
IST:
Investigator sponsored trial
CFR:
Code of Federal Regulations
ITT:
Intention-to-treat
CHANT:
Cerebral Hemorrhage and NXY-059 Treatment
IV:
Intravenous
CI:
Confidence interval
IVH:
Intraventricular hemorrhage
CLEAR III:
Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage: Phase III
JHMI:
Johns Hopkins Medical Institutions
cm:
Centimeter
JHU:
Johns Hopkins University
CRO:
Contract research organization
kcal:
Kilocalorie
CSF:
Cerebrospinal fluid
kg:
Kilogram
CT:
Computerized tomography
LOC:
Level of consciousness
CTA:
Computed tomography angiogram
LTF:
Lost to follow-up
CTCAE:
Common Terminology Criteria for Adverse Events
MAP:
Mean arterial pressure
CV:
Curriculum vitae
MD:
Doctor of Medicine
CVD:
Cardiovascular disease
med:
Medical
DBP:
Diastolic blood pressure
MedDRA:
Medical Dictionary for Regulatory Activities
DCC:
Data Coordinating Center
MEOI:
Medical event of interest
dCT:
Diagnostic Computed Tomography
mg:
Milligram
Diag:
Diagnostic
MHRA:
Medicines and Healthcare products Regulatory Agency
DICOM:
Digital imaging and communications in medicine
min:
minutes
DNI:
Do not intubate
MIS:
Minimally invasive surgery
DNR:
Do not resuscitate
MISTIE II:
MISTIE Phase II (precursor to MISTIE III)
DSMB:
Data Safety and Monitoring Board
MISTIE III: 
Minimally Invasive Surgery plus rt-PA for ICH Evacuation Phase III
DVD:
Digital video disc
mL:
Milliliter
DVT:
Deep vein thrombosis
mmHg:
Millimeters of mercury
DWI:
Diffusion weighted imaging
MMSE:
Mini-Mental State Exam
EC:
Executive Committee
MOP:
Manual of Operations and Procedures
eCRF:
Electronic case report form
MR:
Magnetic resonance
ED:
Emergency Department
MRA:
Magnetic resonance angiogram
EDC:
Electronic data capture
MRI:
Magnetic resonance imaging
EKG:
Electrocardiogram
mRS:
Modified Rankin Scale
EOT:
End of treatment
MTI:M3
Mechanisms of Tissue Injury in MISTIE III (ancillary study)
EQ-5D:
Euroquol-5D
NIH:
National Institutes of Health
eTMF:
Electronic trial master file
NIHSS:
National Institutes of Health Stroke Scale
EUSI:
European Stroke Initiative
NINDS:
The National Institute of Neurological Disorders and Stroke
EVD:
Extraventricular drainage
OHRP:
Office of Human Research Protection
FAST:
Factor Seven for Acute Hemorrhagic Stroke Trial
OR:
Odds ratio
FDA:
Food and Drug Administration
OR:
Operating room
FFP:
Fresh frozen plasma
PACS:
Picture Archiving and Communication System
Fig:
Figure
PBSI:
Preference Based Stroke Index
G:
Gram
PHI:
Protected health information
GCP:
Good Clinical Practice
PI:
Principal investigator
GCP:
Good clinical practice
PT:
Prothrombin time
GCS:
Glasgow Coma Scale
Pts:
Patients
GEE:
Generalized estimating equations
Q:
Every
GLMM:
Generalized Linear Mixed Model
QA:
Quality assurance
gm:
Gram
QD:
Every day
GOS:
Glasgow Outcome Scale
QOL:
Quality of life
RDS:
Regulatory document specialist
RCT:
Randomized clinical trial
ROC:
Receiver Operating Characteristic
SIS:
Stroke Impact Scale
rt-PA:
Recombinant tissue plasminogen activator
SIS:
Stroke Impact Scale
SAE:
Serious adverse event
SOP:
Standard operating procedure
SAINT:
Stroke-Acute Ischemic NXY Treatment
SPRG:
Stroke Progress Review Group (NINDS Advisory and Peer Review Group)
SBP:
Systolic blood pressure
STICH:
Surgical Trial in Lobar Intracerebral Hemorrhage 
SCDs:
Sequential compression devices
surg:
Surgical
SD:
Standard deviation
TIL:
Therapy intensity level
SDV:
Source document verification
t-PA:
Tissue plasminogen activator
SID:
Study identification number
VISTA:
Virtual International Stroke Trials Archive
Vol:
Volume
 


 
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Appendix 8: MTI-M3 Ancillary Study Protocol 
 
Participation in the MTI-M3 ancillary study is optional. Study centers outside of the US and 
Canada will not participate in the portion of the protocol that requires overnight shipment of 
samples to Yale University. Otherwise, all study centers are eligible to participate but may opt-
out. 
 
Mechanisms of Tissue Injury in MISTIE III: Rebleeding and inflammation: Predicting risk of 
excessive bleeding in minimally invasive surgery and inflammatory marker evaluation. 
 
1. Abstract 
 
Intracerebral hemorrhage (ICH) is the most deadly and disabling form of stroke. One treatment 
option is surgical hematoma evacuation; however, two large trials of this intervention have failed 
to show benefit. The most promising current intervention is minimally invasive surgery (MIS), the 
subject of the MISTIE III clinical trial. This ancillary protocol, Mechanisms of Tissue Injury in 
MISTIE III: Rebleeding and Inflammation (MTI:M3) will be an ancillary study to the MISTIE III 
trial. The overriding goals of this ancillary study are to determine which patients are most likely 
and least likely to benefit from MIS and whether the level of activation of central nervous system 
inflammatory mediators is associated with ICH severity, perihematomal edema, and recovery.  
 
2. Study Objectives 
 
MTI:M3 will examine neuroimaging together with blood and intrahematomal fluid biomarkers in 
patients enrolled in MISTIE III. The objectives are as follows: (1) First, we will determine 
whether the presence of the CTA spot sign, a marker of bleeding risk, can mark those patients 
at highest risk of perioperative bleeding and lowest likelihood of benefit following MIS. (2) We 
will determine whether markers of small vessel disease, including cerebral microbleeds (CMB) 
and white matter hyperintensities, are associated with perioperative complications and 
opportunity to benefit from MIS. (3) We will determine whether intrahematomal and peripheral 
markers of inflammation and the cellular immune response are associated with hematoma and 
intraventricular clot volume, perihematomal edema and outcomes; (4) We will determine 
whether genetic markers are associated with perioperative complications, the central 
inflammatory response and outcome following MIS. The results of the proposed study will have 
direct impact on both clinical care and research. If MISTIE III shows improved outcome after 
ICH, our results will provide neurosurgeons with the data to determine which patients are the 
most optimal candidates for the procedure. If MISTIE III does not show a benefit for the overall 
cohort, our results may still highlight that certain patient subgroups can in fact benefit, and that 
those patients can be identified in the acute phase. The investigation of intracranial 
inflammatory cascades in MISTIE III represents a unique opportunity to understand immune 
responses and potentially identify new targets to limit inflammation and improve outcomes 
following ICH. Simultaneous analysis of peripheral and central inflammatory responses will for 
the first time provide direct clinical correlation between the brain and serum inflammatory 
responses in spontaneous ICH. If an association does exist, then blood surrogates could help 
gauge the degree of central inflammation. 
 
Overall, MTI:M3 offers a tremendous opportunity to leverage clinical trial data to bring novel 
insights from ICH pathophysiology into the clinical realm, using neuroimaging, genetic and 


 
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inflammatory markers of disease to provide clinicians with powerful new tools to guide surgical 
therapy and develop new therapeutic targets.    
 
• 
Specific Aim 1. To determine whether CTA spot sign is associated with perioperative 
bleeding and hematoma reduction after MIS 
 
• 
Specific Aim 2. To determine whether white matter hyperintensity burden and cerebral 
microbleeds are associated with perioperative bleeding and outcome after MIS.  
 
• 
Specific Aim 3a. To identify the association between acute phase levels of intracranial 
and peripheral inflammatory mediators and hematoma volume, and perihematomal 
edema as determined by cerebral imaging. 
 
• 
Specific Aim 3b. To determine whether acute phase levels of intracranial inflammatory 
markers are associated with 90/180 day functional outcomes in intracerebral 
hemorrhage. 
 
• 
Specific Aim 4a. To determine if specific genotypes are associated with perihematomal 
edema and outcome after MIS. 
 
• 
Specific Aim 5a. To determine the cellular immune responses to acute brain 
hemorrhage and how these responses change over time. 
 
• 
Specific Aim 5b. To determine whether cellular immune responses transition from pro-
inflammatory to those that aid in resolution of inflammation are associated with ICH 
clearance and improved functional recovery. 
 
3. Background 
 
Intracerebral hemorrhage (ICH) hematoma size is a potent predictor of poor outcome in ICH. 
Minimally invasive surgery (MIS) to aspirate and reduce hematoma volume is a promising 
therapy that may reduce neurotoxicity and brain injury. MISTIE III is a randomized controlled 
trial examining the relationship between outcome following ICH and MIS. It builds on MISTIE II, 
which found that one limitation to MIS was variable success in hematoma volume reduction.  In 
some patients, portions of the clot could not be aspirated, or blood re-accumulated, or 
secondary effects from clot formation may be greater, mitigating the benefit of this procedure. 
While catheter placement plays a fundamental role, accumulating evidence suggests that 
patient-specific factors influence the extent of bleeding in ICH and the therapeutic response to 
ICH surgery. 
 
Our team has demonstrated that contrast extravasation on CT angiography (CTA spot sign) 
identifies ICH patients at highest risk for hematoma expansion and ongoing bleeding. 
Furthermore, among patients undergoing surgical hematoma evacuation, CTA spot sign 
strongly predicted peri-operative and post-operative re-bleeding.  Additional genetic and 
imaging data support the hypothesis that the type and severity of the underlying cerebral small 
vessel disease associated with ICH will influence outcomes, side effects, and the extent of 
bleeding. Our team has also demonstrated that in cerebrospinal fluid of patients with 
spontaneous intraventricular hemorrhage (IVH) treated with external ventricular drainage, 
maximally elevated mean levels of interleukins, IL-1beta, IL-10 and IL-8 occur on post bleed day 


 
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1, which subsequently plateaued around post bleed day 5, before returning to normal by day 10. 
Levels of monocyte chemo-attractant protein (MCP-1) showed persistent elevation over 2 
weeks. The time trends of these markers support experimental data that suggests inflammation 
is a contributor to acute brain injury after ICH/IVH. 
 
4. Study Procedures 
 
MTI:M3 is a prospective and observational, nested study within the MISTIE III randomized 
controlled clinical trial. This design provides tremendous leverage of the existing workload for 
MISTIE III, promising major insight into neuroimaging and genetic and inflammatory biomarkers 
of ICH pathophysiology and response to surgical intervention without affecting the execution of 
the parent study. 
 
The primary goal of MTI:M3 is to determine whether radiologic and genetic and inflammatory 
marker data can help identify those ICH patients most likely to undergo successful clot reduction 
after the MIS intervention and most likely to derive clinical benefit from the procedure. Details of 
MISTIE III are not reprinted here. Incorporation of MTI:M3 will require an additional informed 
consent section in the MISTIE III consent for lab draw and collection of hematoma fluid from the 
collection bag/chamber. All patients enrolled in MISTIE will be eligible for MTI:M3.  
 
a. The study will be completed as part of the participants’ hospitalization and follow-up. 
 
b. Imaging required for the MTI:M3 study will be done as part of the MISTIE III protocol. 
Image files will be uploaded to the MISTIE III coordinating center via the electronic 
data capture system. Image files collected from subjects who also consent to MTI:M3 
will then be de-identified and electronically transferred to MTI:M3 investigators for 
analysis as described below in section 6. 
 
c. There are 2 types of blood draws: 
 
(i) 
A daily blood draw (two teaspoons, 12 mL) on the day of enrollment into 
MISTIE III (Day 0) (for both medical and surgical patients) and daily for up 
to 4 days timed with routine collection of blood for daily blood tests 
(medical patients), or with hematoma fluid aspiration (surgical patients).  
Samples will be collected in two separate tubes, one shipped immediately 
and the other locally processed (centrifuged and aliquoted), frozen at -
70°C, and shipped to specific investigators for storage and analysis.  
 
(ii) 
A separate single blood draw (approximately 1 teaspoon, one 6 mL tube) 
will be collected from medical and surgical MISTIE III subjects at any time 
during the hospitalization or during follow-up. The 6mL tube of blood will 
be locally processed (centrifuged and the plasma aliquoted into cryovials) 
and frozen at -70°C. For sites not able to participate in part (d) below: 
during this separate blood draw, two additional tubes (10 mL each, 
approximately 4 teaspoons total) of whole blood will also be collected and 
frozen at -70°C. The frozen whole blood and plasma from this single draw 
will be shipped to specific investigators for storage and analysis. 
 


 
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d. A 1-10 cc sample of the patient’s hematoma drainage from the existing brain 
catheter will be collected on the following schedule: 
(i) 
At time of initial placement of the brain catheter (at clot aspiration and 
catheter insertion= “Hematoma aspirate”). 
 
(ii) 
Once daily from the drainage bag/collection chamber to be timed 
immediately prior to injection of rtPA through the brain catheter (= “Drain 
sampling”).  
 
(iii) 
From the drainage bag/collection chamber at the time of removal of the 
brain catheter. 
 
(iv) 
Samples will divided and collected in two separate tubes, one shipped 
immediately and the other locally processed (centrifuged and aliquoted), 
frozen at -70°C, and shipped to the specific investigators for storage and 
analysis.  
 
 
 
 
 
e. Additional data collected as part of the MISTIE III protocol will also be made 
available to MTI:M3 investigators. These data include but are not limited to: study 
subject ID number, demographic and baseline variables including recent infection 
Procedures for Perihematomal Fluid Sampling in 
MISTIE 
Days 
2 
4 
3 
1
 clot aspiration  
and catheter  
insertion 
 = tPA dose 
= Haematoma aspirate 
= Drain and peripheral blood 
sampling 
0 


 
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and underlying inflammatory conditions, MIS procedure, rt-PA dosing, outcomes 
scales scores (blinded data; available after database lock), and adverse events.  
 
5. Inclusion/Exclusion Criteria 
 
The participant must be an adult (older than 18 years of age) enrolled in the parent trial for this 
proposal, MISTIE III. 
 
6. Drugs/Substances/Devices 
 
None. 
 
7. Study Statistics 
 
• 
For Aim 1a, to evaluate whether Spot Sign absence predicts clot reduction after MIS, 
we will analyze clot reduction in two ways: first as a continuous variable compared 
using a two-sample t-test, then as a dichotomized variable (<60% vs. ≥60%, with 
≥60% defined as successful clot reduction) compared using a chi-square test.  
 
• 
For Aim 1b, we will evaluate whether Spot Sign is associated with increased 
frequency of neurological complications.  
 
• 
For Aim 2a, we will evaluate whether white matter disease burden is associated with 
neurologic complications after MIS.  
 
• 
For Aim 2b, we will evaluate whether patients with CMBs have less frequent 
neurological complications.  
 
• 
For Aim 3a, we will compare serially measured inflammatory markers from serum, 
and hematoma drainage with ICH, IVH and PHE volumes using standard statistical 
techniques. 
 
• 
For Aim 3b, we will assess the association between mean levels of inflammatory 
mediators and 90/180-day mRS. 
 
• 
For Aim 4, we will evaluate whether genotype predicts neurological complications 
after MIS.  
 
• 
For Aim 5, we will determine the infiltration of peripheral leukocytes into the 
hematoma and the transcriptional profile of multiple leukocyte subsets in order to 
determine how leukocyte responses correlate with outcome. 
 
Data analysis for Aim 1 (Clot reduction and rebleeding).  To evaluate whether Spot Sign 
absence predicts clot reduction after MIS. Clot reduction will be analyzed in two ways: first as a 
continuous variable compared using a two-sample t-test, then as a dichotomized variable 
(<60% vs. ≥60%, with ≥60% defined as a successful clot reduction) compared using a chi-
square test. This analysis will focus on the surgical management arm. Based upon prior work, 
we expect 34% of patients to show a Spot Sign. With a conservative estimate of 30% for the 


 
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SD of clot reduction and a sample size of 85 and 165 for Spot Sign positive and negative, 
respectively, the study will have 80% power to detect a mean difference of 11.3% in clot size 
reduction. When dichotomized at 60%, the study will have 82% power to detect a difference of 
20% (40% for the spot sign positive and 60% for the spot sign negative) with a 0.05 two-sided 
significance level.  
 
Secondary analyses will include outcomes of severe rebleeding with neurologic deterioration 
(expected to occur 3.6% of the time), rebleeding into the surgical bed as a radiographic 
outcome (expected to occur 15% of the time), and bleeding along the MIS catheter tract 
(expected to occur 30% of the time).  
 
Data analysis for Aim 1 (Clinical outcomes). To evaluate whether Spot Sign is associated 
with improved clinical outcome associated with MISTIE III study intervention. 
 
The primary outcome in MISTIE III is good functional outcome, defined by modified Rankin 
Score (mRS) of 0-3 at 180 days following treatment. We hypothesize that treatment effect will 
be more profound among patients who are absent of a Spot Sign. This will be tested using 
Wald’s test for the interaction effect between treatment and Spot Sign in a generalized linear 
model.  The MISTIE III study has 88% power to detect a 13% difference in the dichotomized 
outcome between the control and intervention group. Our assumptions on the proportion with 
mRS 0-3 for the four groups are shown in the table below.  
 
 
Medial management 
arm 
Surgical management 
arm 
Spot Sign 
present 
18% (N=85)  
18% (N=85)  
Spot Sign 
absent 
27% (N=165) 
44% (N=165) 
Total 
24% (N=250) 
35% (N=250) 
 
With a simulated sample, we found that the study has only 43% power for testing the 
interaction between treatment and spot sign. However, among the 330 patients without spot 
sign, the study will have 87% power to detect the 17% difference between treatment arms with 
a two sided 0.05 significance level. 
 
Specific Aim 2 (White matter disease burden). To determine the association between white 
matter disease burden with successful clot reduction after MIS.   
 
Local MISTIE III sites will electronically transfer MRI images to the MISTIE III coordinating site 
via the electronic data collection system, which will then be electronically transferred to the 
MTI:M3 investigators.  Specific scanner type and GRE imaging parameters will be 
documented. 
 
Volumetric analysis of white matter disease will be performed. This analysis will focus on the 
surgical management arm and white matter disease burden will be compared between those 
with and without successful clot reduction (≥60%) using a two-sample t-test. Assuming 53% of 


 
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the patients will achieve successful clot reduction and a SD of 6.9cc, the study will have 80% 
power to detect a mean difference as small as 2.5cc with a 0.05 two-sided significance level. 
 
Specific Aim 2 (Microbleeds).  To determine whether patients with microbleeds have a higher 
likelihood of successful clot reduction after MIS.   
 
Identification of CMBs and determination of their number, size, and distribution will be 
performed by two trained reviewers blinded to clinical and radiographic information. CMBs will 
be identified according to criteria proposed  by  the  Microbleed  Study  Group  and  in  long-
term  use  at  the  MTI:M3 coordinating  center. Briefly,  these  criteria  require  that  identified  
CMB  be  black  or  substantially hypointense on T2*-weighted MRI, round or ovoid (excluding 
tubular or linear structures that may represent flow voids or resorbed macrobleeds), blooming 
(i.e. larger on T2*-weighted than spin-echo MRI), devoid of T1- or T2-weighted hyperintensity, 
and at least half surrounded by brain parenchyma (to exclude primarily subarachnoid 
bleeding). Our group has previously reported very high inter-rater reliability for detection of 
CMB using either conventional T2*-weighted gradient-echo MRI (intra-class correlation 
coefficient =0.97) or the more sensitive susceptibility-weighted imaging technique (SWI; intra-
class correlation coefficient =0.93). Other parameters to be measured on MRI will include the 
presence of perihematomal edema, extravasation of MRI contrast, and presence of 
diffusion/perfusion abnormalities. Volumetric analysis of white matter hyperintensity will be 
performed as previously described, as will  evaluation for  CAA using  the  Boston criteria 
(originally developed by our group).  
 
The primary hypothesis is that presence of CMBs on GRE-MRI is associated with more 
successful clot reduction. This analysis will focus on the surgical management arm. We predict 
there will be an association between absence of CMBs, and proportional change in hematoma 
volume. Similar to Aim 1a above, clot reduction will be analyzed as a continuous variable 
compared using a two-sample t-test, and as a dichotomized variable compared using a chi-
square test. We expect 31% of patients to show signs of CMBs. Assuming a SD of 30% and a 
sample size of 77 and 173 for any CMBs and no CMBs, respectively, the study will have 80% 
power to detect a mean difference of 11.6% in clot size reduction. When dichotomized at 60%, 
the study will have 80% power to detect a difference of 20% (67% for the any CMBs group and 
47% for the no CMBs group) with a 0.05 two-sided significance level.  
 
Finally, we propose to evaluate whether the difference in neurologic outcome between the 
MISTIE III intervention and control is greatest in those with CMBs on GRE-MRI. Secondary 
analyses will examine the interaction between CMBs, Spot Sign, white matter burden, and 
neurologic outcome. The model for clinical benefit (i.e. mRS 0-3 vs. 4-6) will include effects for 
treatment, CMBs, and the interaction between treatment and CMBs. Wald’s test will be used to 
assess the significance of the interaction effect. These results can be confirmed using the 
CMH test. 
 
Specific Aim 3a/b. To identify the association between acute phase levels of intracranial and 
peripheral inflammatory mediators and hematoma volume, peri-hematomal edema and 
neurologic outcomes as determined by cerebral imaging and mRS. 
 


 
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The primary outcome measure of this aim is serial levels of inflammatory mediators in 
hematoma fluid/surgical aspirate. The secondary outcome measures are: (i) ICH/IVH clot 
burden on admission and end of treatment and absolute/relative perihematomal edema (PHE) 
at admission and end of treatment (24 hrs post brain catheter removal) compared to time of 
brain catheter placement; (ii) functional outcomes measured by mRS at 90 and 180 days after 
admission; and (iii) serial levels of inflammatory mediators in serum.  Hematoma aspirate and 
serum inflammatory markers (see Table below) will be determined by the following methods: 
 
White blood cell count and differential, CRP, glucose, protein, red blood cell count, fibrinogen, 
and fibrin D-dimer (DD) will be measured using routine laboratory assays.  
 
Concentrations of IL-1α, IL-2, IL-6, TNFα, IL-8, IL-10, (MCP)-1, (MIP)-1α,IL-1 receptor 
antagonist, IL-10, TGF-β  and IFNγ will be quantified using immunoassays. 
 
 
Levels of matrix metalloproteinases (MMPs) will be assayed by two-step sandwich enzyme- 
linked immunosorbent assay methods. 
 
Glutamate concentrations will be analyzed by high-performance liquid chromatography. 
 
Inflammatory Marker Studies 
 
Serum Studies 
D-dimer, C-reactive protein (CRP), fibrinogen, matrix 
metalloproteinases (MMPs),  Interleukin-6 (IL-6), tumor necrosis 
factor-α (TNF-α), glutamate 
Hematoma Aspirate Studies 
White blood cell count and differential, glucose, protein, red blood 
cell count, Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin-6 
(IL-6), Interleukin-8 (IL-8), IL-10, monocyte chemoattractant 
protein(MCP)-1, macrophage inflammatory protein (MIP)-1α, tumor 
necrosis factor-α (TNFα), Interferon-gamma (IFNγ), transforming 
growth factor(TGF)-β, matrix metalloproteinases (MMPs)  
 
Statistical plan: Analysis of categorical variables will be performed using the Pearson’s Chi-
square test. The Fisher exact test will be used when applicable. Continuous variables will be 
analyzed using one-way Analysis of variance if data is normally distributed or with Kruskall-
Wallis test if not normally distributed. Trend statistic of inflammatory markers will be calculated 
using the Mantel-Haenszel test for linear association, with the catheter day plotted on the X-
axis and levels of specific inflammatory mediators on the Y-axis.  
 
For analysis of secondary outcome measures, inflammatory markers will be expressed as AUC 
(area under the curve) and included in a multifactorial linear regression model to test for 
associations with ICH/IVH/PHE volumes and with 90/180-day mRS. The models will include 
age, sex, and ICH score as covariates. Given the anticipated small sample size of the study 
population, a total of four or fewer confounders can be controlled in regression models. All 
tests will be two-tailed, with significance defined by p<0.05. Statistical analysis will be 
performed using STATA 12.0 (Stata, College Station, Texas). 
 
 


 
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Specific Aim 4a. ApoE Genotype 
Secondary analyses will explore whether imaging and genetics are associated with specific 
subcategories of neurological complications, whether they predict improved neurological 
outcome, and whether they stratify who will receive the most clinical benefit from the MIS 
intervention 
 
We will test the hypothesis that specific ApoE genotype predicts successful clot reduction after 
MIS. This analysis will focus on the surgical management arm. We predict those patients with 
an E2 allele will have less clot reduction. Similar to Aim 1a, clot reduction will be analyzed as a 
continuous variable compared using a two-sample t-test, and as a dichotomized variable 
compared using a chi-square test. We expect 9% of patients will have an ApoE E2 allele. 
Assuming a SD of 30% and a sample size of 22 and 228 for presence of an ApoE E2 allele vs. 
absence, respectively, the study will have 80% power to detect a mean difference of 18.8% in 
clot size reduction. When dichotomized at 60%, the study will have 84% power to detect a 
difference of 24% (22% for the ApoE E2 allele group and 56% for the no ApoE E2 allele group) 
with a 0.05 two-sided significance level. 
 
 
Specific Aim 4b. Haptoglobin phenotype 
We will test the hypothesis that haptoglobin 1-1 predicts better outcome. For our analysis of 
haptoglobin, patients will be categorized as Hp1-1, 1-2, or 2-2 phenotype. Our primary analysis 
will examine whether Hp1-1 predicts a higher likelihood of good neurologic outcome (defined 
as above) using a chi-square test. Our preliminary data suggests that that 13% of patients will 
have the Hp1-1 phenotype, 48% will have Hp 1-2, and 38% will have 2-2. We do not anticipate 
interaction between haptoglobin genotype and treatment effect; therefore, the analysis will be 
conducted combining the two treatment arms. Assuming a sample size of 65 and 435 for Hp1-
1 and Hp (1-2 + 2-2), respectively, the study will have 82% power to detect a difference of 19% 
(46% for the Hp 1-1 group and 27% for the other 2 genotypes) with a 0.05 two-sided 
significance level. 
 
Specific Aim 5.  Leukocyte infiltration and outcomes.  Our preliminary data from both mice 
and human patients demonstrates a robust recruitment of peripheral leukocytes into the 
hematoma and perihematomal region over the first seven days after ICH.  During this time, 
blood derived macrophages transition from a pro-inflammatory phenotype to a reparative 
phenotype that aids in phagocytosis of the hemorrhage and wound healing.  Cell surface 
markers on macrophages involved in phagocytosis, including CD36, and inhibition of T cell 
response, including PDL2, increase over this time.  Our primary hypothesis is that this 
transition to repair is critical to good outcome after ICH, and that patients who transition to 
reparative macrophage profiles and shifts from effector to regulatory T cell responses earlier 
after ICH onset will have improved outcomes.  
 
Hematoma aspirate and blood samples will be shipped ambient priority overnight to Yale 
University and immediately analyzed to prevent degradation of samples. Mononuclear cells will 
be isolated by Ficoll gradient, stained with fluorophore-conjugated antibodies to CD45, CD11b, 
CD16, CD3, CD4, CD8, CD25, and CD127.  Leukocytes will be quantified by flow cytometry 
and cell sorting (FACS) to isolate populations of interest (see Table below for the gating of the 
populations to be sorted).  In a single batch, RNA from each population of interest will be 
converted to cDNA and analyzed by RNAseq to fully characterize the transcriptional profile of 


 
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each cell population at each time point after ICH onset.  Peripheral blood samples will be 
processed and analyzed in the identical fashion to allow for direct comparison of the 
differences in cellular phenotypes that occur once the cells have migrated into the brain.  
Analyses will compare (1) blood to brain transcriptional profile differences at each time point, 
(2) changes in transcriptional profiles within leukocyte populations over time, (3) initial 
transcriptional profiles of macrophage population and ICH severity, (4) transcriptional profile 
shifts to reparative/suppressor macrophage and T cell phenotypes and outcome at 90/180 
days.  RNA sequencing and analysis will be performed by collaborator J. Christopher Love, 
PhD, at the Broad Institute of MIT and Harvard. 
 
Cell surface markers
Leukocyte population
Analysis plan
CD45hiCD3-CD11b+CD16+ 
Blood derived 
macrophage 
Quantified, sorted, and 
analyzed by RNAseq 
CD45hiCD3+CD4+CD25-CD127hi 
Effector TH1 
lymphocytes 
Quantified, sorted, and 
analyzed by RNAseq 
CD45hiCD3+CD4+CD25+CD127- 
Regulatory T cells 
Quantified, sorted, and 
analyzed by RNAseq 
CD45hiCD3+CD4-CD8+ 
Cytotoxic T cells 
Quantified, sorted, and 
analyzed by RNAseq 
CD45loCD11b+ 
Microglia 
Quantified by flow 
cytometry 
(brain only) 
CD45hiCD3-CD11b+CD14hi 
Blood classical 
monocyte 
Quantified by flow 
cytometry 
(blood only) 
 
8. Risks 
 
Blood draws: There are no known medical risks to the patient except those associated with a 
blood draw from an indwelling line or a peripheral blood draw (both medical and surgical arms). 
We have minimized the number of blood draws so that they are timed with routine blood draws 
or with hematoma fluid aspiration and this will occur through an existing in-dwelling line or 
peripheral blood draw. 
 
Drainage collection: In the surgical arm, the hematoma drainage in patients with a brain catheter 
will initially be obtained as part of its placement in the operating room during which the blood 
clot is aspirated as part of the MISTIE III parent protocol. This poses no additional risk or 
exposure of the volunteer to additional procedures. The subsequent samples will be collected 
daily from the spontaneous hematoma drainage into the collection bag/chamber using sterile 
technique. The only risk is infection, which is minimal for both hematoma fluid and peripheral 
blood collection. 
 
No additional CT scans are required. 
 
There are no legal ramifications to the participant. 
 
There are no financial risks to the participant. 
 


 
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All unanticipated problems or study deviations will be reported to the PI who will be responsible 
for reporting them to the IRB. 
 
9. Benefits 
 
This may result in improved treatment of ICH for society in general. The participant will have the 
satisfaction of helping others through their participation. 
 
10. Payment and Remuneration 
 
There are no forms of compensation to the participant. The participants’ care and ability to 
participate in the MISTIE III trial will not be impacted if they decide not to participate in this 
ancillary study. 
 
11. Costs 
 
There are no costs to the patients. Any costs associated with the blood draw will be paid by the 
investigator. The imaging will be done as part of the MISTIE III protocol.