ENRICH Trial - Clinial Outcomes for surgical treatment of ICH

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ENRICH is the
FIRST Positive Surgical Trial
in the Deadliest Type of Stroke
3 P u b l i c a t i o n s C o m i n g S o o n !

ICH Surgical Trials (2004-2023)
1. Early surgery vs. initial conservative treatment in patients with spontaneous supratentorial intracerebral hematomas in the International Surgical Trial in intracerebral hemorrhage. Lancet. 2005;365(9457):387-397
2. Early surgery vs. initial conservative treatment in patients with spontaneous supratentorial lobar ICH: a randomized trial. Lancet. 2013;382(9890):397-408
3. Hanley DF. MISTIE II Trial Results: Safety, Efficacy and Surgical Performance. Presentation at ISC 2013
4. Hanley DF. MISTIE III Trial Results. Lancet 2019
5. MIND – DSMB Letter
Year Surgical Trial Outcome Aim Evacuation Method Patients Result
2004 STICH Failed
Early surgery vs. Initial
Conservative TX for sICH
Any method available 1033 Did not achieve primary endpoint
2005 STICH II Failed
Early surgery vs. Initial
Conservative TX for LOBAR sICH
Any method available 601 Signal – not statistically significant
2013 MISTIE II N/A
Safety of MIS and rtPA to remove
ICH
Intraclot catheter and
rtPA
118
N/A - Drug safety study,
not powered for efficacy
2019 MISTIE III Failed
Safety & Efficacy of MIS and rtPA
for 3 days to remove ICH vs MM
Intraclot catheter and
rtPA
506
Achieved 4% difference,
goal was 12%
2023 ENRICH Positive
Improve functional outcome
>97.5% for MIPS over MM at 180
days using UWmRS
MIPS – BrainPath and
Myriad
300
98.1% posterior probability of
superiority of MIPS over MM.
Analogous to p-value 0.032
2023 MIND Failed
Safety and Efficacy of MIS with the
Artemis Neuro Evacuation device
Endoscope – with
Artemis
236/500 Stopped by Sponsor

Independent of disease, location of lesion, or approach taken,
resection/removal should be:
SAFE
EFFECTIVE
EFFICIENT
EASY
Access
Removal
Collection
Defining Resection Wants
What is Ideal

Minimally Invasive Parafascicular Surgery
A Deficit Sparing Approach
ACHIEVE SURGICAL GOALS
EFFICIENTLY
POWER
PRECISION MEDICINE
SPARE HEALTHY TISSUE

MIPS Approach Designed to Overcome Limitations of
Prior ICH Evacuation Procedures
Early
Intervention
Minimally Invasive Procedure
using Systems Approach
with Specialized Tools
Maximum
Clot Removal
Systems approach easily adopted, augmented by training
Requires specialized, FDA-cleared tools: NICO BrainPath® and Myriad®

ENRICH Trial
Early miNimally-invasive Removal of ICH

ENRICH Outcomes
Primary Outcome Measure:
• UWmRS scale at 180 days post-
randomization
• Bayesian posterior probability of
MIPS benefit ≥0.975
Secondary Outcomes:
• Postoperative rebleeding associated with
deterioration following MIPS
• ICU and in-hospital length of stay
• mRS at discharge, 30 and 90 days
• Impact of percent ICH reduction with
MIPS on mRS at 180 days
• Impact of end-of-treatment (EOT)
volume with MIPS on mRS at 180 days
• Proportion of patients with mRS at 180
days equal to 0, 1, 2, or 3
• Ordinal mRS at 180 days
• Overall survival through 180 days

ENRICH: Early MiNimally-Invasive Removal of ICH
 300 patient, multicenter, randomized, adaptive clinical trial
o Compared standard medical management (MM) to early surgical hematoma evacuation with
minimally invasive parafascicular surgery (MIPS) to treat intracerebral hemorrhage (ICH)
 Primary endpoint
o Functional outcome with utility-weighted modified Rankin scale (UW-mRS) score at 180 days
o UW-mRS converts the 7-point scale into a continuous variable (0 to 1)
o Better reflects patient-centered values about the desirability of an outcome
 Trial design
o Adaptive trial with location Enrichment
 Pre-planned analyses and simulations with the ability to enrich on a particular hemorrhage location
 Encouraged by FDA and NIH to modernize clinical trials by improving speed, efficiency and
protecting patient safety

MIPS Superior to Medical Management
2
4
9
21
15
22
31
27
31
30
16
13
35
30
0 10 20 30 40 50 60 70 80 90 100
Medical
Management
(N=139)
MIPS
(N=147)
0 1 2 3 4 5 6
mRS at 180 Days
MIPS
(N=147)
Medical
Management
(N=139)
Percent of Patients
Mean UW-mRS at 180 Days
0.46
0.37
Difference 0.084
(95% CrI: 0.005 – 0.163)
98.1% posterior
probability of superiority
Analogous to
p = 0.032

Posterior Distribution of Treatment Effect
Location Estimate (95% CrI)
Probability of
Superiority
ABG -0.013 (-0.147, 0.116) 0.4301
Lobar 0.127 (0.035, 0.219) 0.9968
Combined 0.084 (0.005, 0.163) 0.9813

MIPS Benefits on mRS Observed Early, Consistent
Through Follow-up
Time Point
Ordinal Logistic Regression Analysis
(odds of higher mRS with MIPS vs MM)
Odds Ratio (95% CI) P-value
Discharge 0.362 (0.224, 0.578) <0.001
30 days 0.475 (0.311, 0.723) <0.001
90 days 0.629 (0.415, 0.952) 0.029
180 days 0.636 (0.421, 0.959) 0.032
0.1 1 10
Favors Medical Management
Favors MIPS

Lower 30-Day All-Cause Mortality with MIPS
9.3
18.1
0
5
10
15
20
25
30
35
40
MIPS Medical Management
Δ = 8.8 percentage points
p = 0.027
All-Cause
Mortality at
30 Days (%)

Lower 180-Day All-Cause Mortality with MIPS
Overall
Survival
(%)
MIPS
Medical Management

Significantly Shorter Lengths of Stay in ICU and
Hospital
7.0
9.6
0
5
10
15
20
25
ICU Length of Stay (days)
Δ = 2.6 days
p < 0.001 14.7
17.1
0
5
10
15
20
25
In-Hospital Length of Stay (days)
Δ = 2.4 days
p = 0.021

Significantly Fewer Ventilator Days with MIPS
5.4
8.9
0
1
2
3
4
5
6
7
8
9
10
Ventilation Days
Δ = 3.5 days
p < 0.001

Parameter
ENRICH MIPS
(N=150)
MISTIE
(N=250)
EOT ICH volume (mL) 14.9 16
EOT ICH volume (mL), median 7.2 12.5
Change in ICH volume (mL) -43.9 -32
% ICH reduction 73.2% 69%
% ICH reduction, median 87.7%
Patients with EOT volume ≤15 mL 72.7% 58%
ENRICH vs MISTIE Outcomes
Hanley, D. F., Thompson, R. E., Rosenblum, M., Yenokyan, G., Lane, K., McBee, N., Mayo, S. W., et al. MISTIE III Investigators. (2019). Efficacy and safety of minimally invasive surgery with thrombolysis in
intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet, 393(10175), 1021–1032. https://doi.org/10.1016/S0140-6736(19)30195-3
**Planned Secondary Analysis

 Clinical outcomes
o Statistically significant:
 98.1% posterior probability of superiority
of MIPS over MM in UW-mRS (statistical
significance threshold > 97.5%)
 Analogous p-value = 0.032
 Includes both lobar and ABG ICH
locations
 Superior in lobar ICH, neutral in ABG
 Improvement in traditional mRS at
discharge, 30, 90, and 180 days with p-
values
 Improved 30-day mortality in MIPS (9.3%)
vs MM (18.1%), p=0.027
o Benefit:
 Improved 180-day mortality in MIPS
 Economic outcomes
o Statistically significant:
 ICU length of stay shorter in MIPS (2.6
days difference), p<0.001)
 Hospital length of stay shorter in MIPS
(2.4 days difference), p=0.021
 Ventilator days shorter in MIPS (3.5 days
difference), p<0.001
 Technical outcomes
o Median EOT volume of 7.2 mL (mRS improved
with every 10 mL reduction)
o Median ICH reduction of 88% (mRS improved
with every 10% reduction)
First positive trial to show functional benefit of ICH evacuation
(Level 1b evidence)
Summary

ENRICH Trial - Clinial Outcomes for surgical treatment of ICH

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Editor's Notes