1. CLEAR III Monthly Broadcast
December 2011

2. Agenda Enrollments and Announcements….Mark A. Macek
MISTIE Outcomes…………………………..Gayane Yenokyan
Good news for Randomization!……….Natalie Ullman

3. CLEAR III Recent Enrollments
November-December 2011

4. Congratulations to November-December 2011 Enrollments
Dr. Sagi Harnof (PI), 
Yulia Wasserman,
Tali Kimchi
Shiri Fischler (coordinators),
Chaim Sheba Medical Center
 9th enrollment on
(the trial's 179th enrollment)

5. Congratulations to November-December 2011 Enrollments
Dr. Carsten Hobohm(PI), 
Rita Lachmund and Daniela Urban (coordinators),
University of Leipzig
1st enrollment on
(the trial's 180th enrollment)

6. Congratulations to November-December 2011 Enrollments
Dr. Thomas Kerz (PI/Coordinator), 
University of Mainz
3rd enrollment on
(the trial's 181st enrollment)

7. Congratulations to November-December 2011 Enrollments
Dr. Sayona John(PI), 
Terry Cole (coordinator),
Rush University
13th enrollment on
(the trial's 182nd enrollment)

8. Congratulations to November-December 2011 Enrollments
Dr. David Ledoux(PI), 
Oleg Rivkin(coordinator),
Northshore, Long Island
4th enrollment on
(the trial's 183rd enrollment)

9. Congratulations to November-December 2011 Enrollments
Dr. Paul Vespa (PI), 
Maria Fillipou and Maria Etchepare (coordinator),
UCLA
4th enrollment on
(the trial's 184th enrollment)

10. Congratulations to November-December 2011 Enrollments
Dr. Stephan Mayer(PI), 
Noeleen Ostapkovich(coordinator),
Columbia
4th enrollment on
(the trial's 185th enrollment)

11. Congratulations to November-December 2011 Enrollments
Dr. Venkatesh Aiyagari (PI), 
Maureen Hillmann(coordinator),
University of Illinois at Chicago
3rd enrollment on
(the trial's 186th enrollment)

12. Congratulations to November-December 2011 Enrollments
Dr. Robert Hoesch (PI), 
Julie Martinez(coordinator),
University of Utah
7th enrollment on
(the trial's 187th enrollment)

13. Outcomes and trajectory for recovery after intracerebral hemorrhage
Presented by Gayane Yenokyan
Assistant Scientist, Biostatistics Center
4/3/2019

14. Presentation Plan Goal of the analysis
Stroke outcome measures included in the analyses
Data
Results
Implications
Summary and conclusions
4/3/2019

15. Goals of the Analysis Main goals are:
To assess the relationships between outcomes measures at various times post stroke
To evaluate variability of one measure at various levels of another
To understand recovery in ICH
4/3/2019

16. Data MISTIE I and II 117 MISTIE patients (with available outcomes):
80 surgical and 37 medical patients (3 ICES patients)
26 “Run-in’s” and 91 randomized
59 Stage I and 58 Stage II
Follow-up visits (days post stroke): 30, 90, 180, 270, and 365
4/3/2019

17. MISTIE I and II
MINIMALLY INVASIVE SURGERY plus T-PA for INTRACEREBRAL HEMORRHAGE EVACUATION
Study Hypothesis: Clot reduction with minimally invasive surgery plus rt-PA decreases mortality and increases good outcomes
4/3/2019

18. MISTIE Trial Design Stage I N = 60 Stage II n = 60 Medical Arm
Minimally
Invasive
Surgery +
0.3 mg
rt-PA
1.0 mg
ICES
Stage II
n = 60
Medical Arm
Image Guided
Surgical
Arm
3Trajectory options

19. Main Characteristics of MISTIE Trial
First prospectively randomized MIS + rt-PA trial in ICH
Prospectively defined, standardized surgical task
Independent ICH Surgical Center
Fully monitored, independent adjudication of image guided surgery
25 clinical sites

20. Outcomes Included in the Analysis
Death (mRS = 6)
Stroke Scales:
mRS
Barthel index
NIHSS score
SIS and its subscales
4/3/2019

21. Plan for the Results Mortality and factors that affect mortality rate
Pair-wise correlations of Stroke Scales by follow-up visit
Variability of SIS subscales by mRS (cut-offs of mRS)
Trajectories (and summaries) of Stroke Scales over time post stroke
Predicting Outcome at 180 days
4/3/2019

22. Part I: Mortality Research Question: What factors predict Mortality?
4/3/2019

23. Distribution of Deaths by Follow-up
Time of Death (days post stroke) 30 90
180
270
Total
Alive - 86
Deaths 14 11 3 31
Missing status
120
4/3/2019

24. Mortality in MISTIE I and II cohorts
Status
Stage I*
Stage II
Total Cohort
N(%) N
Alive
46 (78.0)
40 (69%) 86
Died
13 (22%)
18 (31%) 31 30 6 8 14 90 5 11
180 1 2 3
270 -
365
* Includes ICES (n = 3)
4/3/2019

25. Availability of Follow-up Visits, Stage I (N = 59)
Follow-up Visit (days post stroke)
Number of Patients
Number of Patients who died
Number of Patients Lost to Follow-up or no Information 30 59 6 1 90 52
180 45 44
4/3/2019

26. Availability of Follow-up Visits, Stage II (N = 58)
Follow-up Visit (days post stroke)
Number of Patients
Number of Patients who died
Number of Patients Lost to Follow-up or no Information 30 58 8 3 90 47 5
180 34 2 10
270 22 4
365 15 -
4/3/2019

27. Two Stages Can be Combined
Result of the Log-rank test: p-value = 0.507
4/3/2019

28. Multivariate Analyses
Predictors of Death
Covariate*
Bivariate Analyses
Multivariate Analyses
HR (95%CI)
P-value
Age of onset (per 5 years)
1.2 (1.1, 1.4)
0.034
1.2 (1.0, 1.4)
0.041
ICH
(per 10cc)
1.3 (1.1, 1.5)
0.003
1.2 (1.0, 1.5)
0.053
Enrollment GCS (per 1 score increment)
0.8 (0.8, 1.0)
0.019
0.9 (0.8, 1.0)
0.020
Men
2.2 (0.9, 5.4)
0.080
Cardio-vascular disease
1.9 (0.9, 3.8)
0.083
Other factors evaluated: randomization group, location, ethnicity, medical history, hypertension, diabetes, alcohol etc.
* Selected at alpha = 0.1 in the bivariate analysis
4/3/2019

29. II. Pair-wise Correlations of Outcome Measures by Follow-up Visit
4/3/2019

30. Research Question: How do different Stroke scales correlate with each other over the course of recovery?
4/3/2019

31. mRS vs. Barthel by time post stroke
Pearson Correlation Coefficients: (30, 90, and 180 days) ≥ 0.81 (p-value <0.0001)
Barthel improves earlier than Rankin. Barthel measures ability, Rankin measures disability/dependence
4/3/2019

32. mRS vs. SIS by time post stroke
Pearson Correlation Coefficients: (30, 90, and 180 days) ≥ 0.83 (p-value <0.0001)
4/3/2019

33. mRS vs. SIS Mood Stability
Pearson Correlation Coefficients: (30, 90, and 180 days) 0.4 to 0.5 (p-value <0.0001)
Mood stability improves earlier and is already pretty high at 30 days
4/3/2019

34. mRS vs. SIS Social Participation
Pearson Correlation Coefficients: (30, 90, and 180 days) from 0.4 to 0.6 (p-value <0.0001)
Correlation with social participation is low, but it improves dramatically.
4/3/2019

35. Summary of Findings for Parts I and II
ICH volume predicts death – supports the hypothesis that getting the blood out will improve the outcomes
Low linear correlation between SIS sub-scales: Mood, Emotion, Social Participation and Disability Measures at 30 days post-stroke (Barthel and SIS ADL)
These correlations increase over time
Data seem to support the notion of “gradual improvement”:
Initial improvement of Barthel Index (at 30 days), followed by improvement in modified Rankin Score
4/3/2019

36. III. Variability of SIS subscales by mRS
4/3/2019

37. Variability of SIS physical sub-scales (y-axis) by mRS (x-axis) at 30 days
30-day outcomes
4/3/2019

38. Variability of SIS physical sub-scales (y-axis) by mRS (x-axis) at 180 days
30-day outcomes
4/3/2019

39. Variability of SIS emotion/social sub-scales (y-axis) by mRS (x-axis) 30 days
30-day outcomes
Red circle indicates high variability and overlap of communication memory and emotion at mRS=3 and 4
4/3/2019

40. Variability of SIS emotion/social sub-scales (y-axis) by mRS (x-axis) 180 days
30-day outcomes
Red circle indicates high variability and overlap of communication memory and emotion at mRS=3 and 4
4/3/2019

41. Summary of Findings (Part II)
SIS physical subscales correlate well with Rankin score
There appears to be good separation between mRS 3 and 4 based on the physical subscales
There is lots of variability in SIS emotion, communication, memory and social participation at mRS = 3 and 4
Social participation is affected the most by stroke; it correlates better with Rankin
Social participation improves at 180 days
4/3/2019

42. IV. Outcome Trajectories
4/3/2019

43. Modified Rankin Score Over Time
Overall better improvement in Rankin scores in the surgical arm
4/3/2019

44. SIS Physical Domain Sub-scales over Time
Functions that improve the best after surgery are Strength and Mobility
4/3/2019

45. SIS Social Domain Sub-scales over Time
Memory and mood seem to improve in Surgical patients much better than in medical: Communication seem to improve earlier
4/3/2019

46. Summary of Findings (Part III)
Most of functions improve over time
Surgery seems to be better at improving physical domains (as measured by Barthel score, Rankin or SIS physical) and memory and mood
There is quite a bit of heterogeneity in response in both treatment arms
Next: look at predictors of “better response”
4/3/2019

47. V. Predict Outcomes at 180 days
4/3/2019

48. Strategy Rankin as the outcome Exclude deaths
Continuous
Dichotomous (dependence vs. not)
Exclude deaths
Available data: 117 – 39 (Deaths before 180) – 3 (Deaths at 180) = 75 observations
4/3/2019

49. Distribution of Rankin at 180 days
4/3/2019

50. Distribution of NIHSS at 180 days
4/3/2019

51. (Continuous) Rankin Score at 180
Covariate
Multivariate Analyses
Multivariate Analyses*
beta (95%CI)
P-value
Surgery
-0.5 (-0.9, -0.2)
0.007
-0.5 (-0.8, -0.1)
0.017
ICH
(per 10cc)
0.1 (0.0, 0.2)
0.028
0.1 (-0.02, 0.2)
0.140
Age of onset (per 5 years)
0.2 (0.1, 0.3)
<0.0001
0.2 (0.1, 0.2)
0.001
Enrollment GCS (per 1 score increment)
-0.2 (-0.2, -0.1)
Lobar Location
-0.5 (-1.0, -0.1)
0.020
-0.5 (-1, -0.1)
0.027
Diabetes
0.8 (0.3, 1.2)
0.7 (0.3, 1.1)
CVD
0.6 (0.2, 1.0)
0.002
0.6 (0.2, 0.9)
This model explains about 50% variability in Rankin Scores
* Excluding deaths
4/3/2019

52. Independence at 180 (Rankin <4)
Covariate
Multivariate Analyses
Multivariate Analyses*
OR (95%CI)
P-value
Surgery
3.5 (0.8, 15.5)
0.096
3.4 (0.8, 15.1)
0.108
Age of onset (per 5 years)
0.6 (0.5, 0.9)
0.010
0.7 (0.5, 0.9)
0.012
Enrollment GCS (per 1 score increment)
1.7 (1.3, 2.3)
<0.0001
CVD
0.2 (0.1, 0.8)
0.019
0.022
* Excluding deaths
4/3/2019

53. Question: Should one separate survival from recovery when talking about outcomes after ICH?
Answer: There seem to be evidence that predictors of survival and recovery at 180-day are different (slides 16 vs. 39 and 40)
4/3/2019

54. Question: What are the most prominent predictors of survival vs
Question: What are the most prominent predictors of survival vs. predictors of better Rankin scores are 180 days?
Answer: Pre-randomization ICH volume seem to be negatively correlated with survival. Other less modifiable factors of survival are age at onset, sex, and GCS at enrollment. When looking at better Rankin scores among the survivors, surgical intervention, lobar location, and absence of diabetes and CVD are associated with better outcomes.
4/3/2019

55. Question: Which scales are most correlated with modified Rankin score
Question: Which scales are most correlated with modified Rankin score? Do these correlations “improve” over time?
Answer: Barthel index, SIS total score and its “physical” subscales (strength, mobility, hand function and ADL) are better correlated with Rankin scores, compared to SIS emotion, mood, memory and social participation subscales. These relationships become stronger over time.
4/3/2019

56. Question: Which scales demonstrate more variability in the process of recovery after ICH?
Answer: SIS emotion, mood, memory, hand function and social participation subscales
4/3/2019

57. Thank you!

58. Making your life easier during randomization

59. The options… 2. Upload jepgs
Site Team: Enter age, gender, ICH location, IVH Graeb score, and date/time of all diagnostic and stability scans.
Upload DICOMs EARLY (>2hrs before randomizing)
Site Team: Enter basic demographic information & CT date/times
Reading Center: we will enter everything else necessary for you to be able to randomize

60. 2012 CLEAR III Webinars Will host 3 per month:
3rd Thurs. of every month at 8am & 2pm EDT
4th Thurs. of every month at 9am EDT
No longer held on 4th Fridays!
MUST re-register for all! Visit our new website to do so