ENRICH_ICH Trial_Outcomes_2023.pdf

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ENRICH Trial
Improving Treatment for Patients with Hemorrhagic Stroke (ICH)
Block Out
Penny Sekerak, MBA, BA, RN
Vice President, Clinical Affairs
NICO Corporation

ENRICH: First and Only Positive Randomized Trial to
Demonstrate Benefit of Surgical Intervention for ICH
• Innovative, adaptive trial design
• Demonstrated that Minimally Invasive Parafascicular Surgery (MIPS) is superior to
standard Medical Management (MM)
• Met primary and secondary efficacy endpoints
• Showed MIPS was cost effective
• Proved that surgeons can consistently, safely, and predictably access and evacuate an ICH
using MIPS approach

MIPS: Unique Approach Designed to Overcome
Limitations of Prior ICH Evacuation Procedures
• MIPS incorporates several key differentiators
• Early intervention
• Minimally invasive, trans-sulcal systems approach
• Maximal clot removal with specialized instruments
• NICO BrainPath® and Myriad®
Combination of MIPS technology and approach
changes the paradigm for treatment of ICH

ICH Epidemiology

ICH: Most Costly, Deadly, and Debilitating Form
of Stroke
• ICH comprises ~10-15% of all strokes and disproportionate amount of stroke-
related morbidity and mortality1-3
• 40% of patients with ICH die within 30 days4
• Significantly higher than ischemic stroke and subarachnoid hemorrhage
• Among those who survive, ~4/5 left with significant disability5
• US rate of ICH nearly doubled over past 40 years6
• Annual US admission rate ~ 63,000 cases per year
1. Greenberg et al, 2022; 2. Benjamin et al, 2017; 3. Macellari et al, 2014; 4. Adeoye & Broderick, 2010; 5. Macellari et al, 2014; 6. Rincon et al, 2013.

ICH Survival Rates Unchanged Since Mid-1980s
• Treatment guidelines recommend medical management
• Prompt diagnosis and work-up
• Aggressive coagulopathy and blood pressure management
• Prevention and control of secondary brain injury and intracranial pressure
• Despite intuitive rationale for MIS approaches for addressing moderate to large
ICHs, results from RCTs have not been definitive
• No proven benefit for functional outcomes
• Suggestive benefit for mortality vs standard of care
Greenberg et al, 2022

Previous Clinical Trials for
Surgical ICH Intervention

All Randomized Surgical Trials Failed to Show Functional,
Cognitive Improvements over Medical Management
Limitations possibly due to:
Delayed
Intervention
Heterogeneity in
Surgical Approach
Insufficient
Clot Removal

Negative Conventional Surgical ICH Trials
• STICH I & II began ~20 years ago
• Utilized open craniotomy in vast majority of cases
• Median time from onset to treatment of about 30 hours
• Invasive surgical approach creates enough trauma to negate any benefit of
hematoma evacuation
• Question: Role of less invasive surgery to remove ICH
• Particularly at early time periods
STICH = Surgical Trial in Lobar Intracerebral Haemorrhage

MISTIE Procedure Has Not Shown Significant
Functional Outcome Benefit for ICH
• MISTIE surgical management
• Minimally-invasive surgery to place catheter
• Clot lysis using intermittent dosing of recombinant tissue plasminogen
activator (rt-PA) – once every 8 hours up to 72 hours
• MISTIE III found no significant benefit of surgery on primary endpoint (mRS 0-3)1
• MISTIE: 45%
• Medical management: 41%
• Difference not statistically significant: p = 0.33
1. Hanley et al, 2019; 2. Awad et al, 2019.
MISTIE: minimally invasive catheter evacuation followed by thrombolysis

0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 15 30 45 60 75 90 105 120
Greatest Benefit: ≤ 15 mL EOT Volume
MISTIE III: Strong Suggestion of Benefit with Greater
Extent of Clot Removal and Lower EOT Volume
Adapted from Awad et al, 2019.
Probability of
mRS 0-3
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
-45 -30 -15 0 15 30 45 60 75 90
Greatest Benefit: ≥ 70%
End of Treatment ICH Volume (mL) Percent Hematoma Volume Removed
Greatest Benefit: ≤ 15 mL EOT Volume Greatest Benefit: ≥ 70% ICH Reduction
Surgical success not achieved
in 40% of patients

Minimally Invasive
Parafascicular Surgery (MIPS)
Overview

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®

NICO BrainPath®: Minimally-invasive Navigable
Port-based Access to the ICH
• Clinical benefits achieved
• Minimally disruptive access
• Avoid cannulation injuries
• Tip design gently dilates sulcal
opening
• Vent allows ICP to be dissipated
during cannulation
Two components
Inner obturator and outer sheath

NICO Myriad NOVUS®: Automated, Multi-functional
Instrument Designed Specifically for MIS Corridors
• Effectively removes liquefied or
crosslinked clots through cutting,
suction, and blunt dissection
• Automation and multi-functionality
allows for:
• Greater clot evacuation
• Fewer rebleeds
• Lower EOT volume
• Reduced surgical time

ENRICH Trial
Early miNimally-invasive Removal of ICH
Innovative, adaptive trial designed to evaluate the efficacy, safety and economics of
a standardized MIPS approach for patients with an ICH

ENRICH Designed to Evaluate Whether MIPS Improves
Functional Outcomes and Economic Benefit vs MM
• 1:1 randomization to MIPS or medical management (MM)
• Randomization stratified by
• Hemorrhage location (anterior basal ganglia or lobar)
• Index Glasgow Coma Score (<9 or ≥9)
• No restrictions on enrollment by hemorrhage location at beginning
• MIPS: clot evacuation within 24 hours of symptom onset, with goal of arrival in
OR within 8 hours of symptom onset
• Planned enrollment between 150-300 patients at 37 US sites

37 Clinical Sites Selected Based on MIPS Experience, Annual ICH Patient Volume,
Partnership with Neurocritical Care, and Research Experience

Key Inclusion and Exclusion Criteria
Inclusion Criteria
• Aged 18 to 80 years
• Head CT: acute, spontaneous, primary
ICH
• ICH volume 30-80 mL
• Intervention can be initiated within 24
hours of symptoms
(≤8 hours preferred)
• GCS 5-14
• Historical mRS 0 or 1
Exclusion Criteria
• Recurrent ICH or other vascular
abnormality
• NIHSS ≤5
• IVH >50% of the lateral ventricles
• Uncorrected coagulopathy or known
clotting disorder
• Anticoagulants not rapidly reversible
• No reasonable expectation of recovery,
DNR/comfort measures, or life
expectancy <6 months

Standardized Medical Management (MM)
Protocol Based on AHA/ASA Guidelines
• Procedures included aggressive
resuscitation, control of blood pressure,
correction of clinically significant
bleeding diatheses
• Traditional surgical techniques
permitted if medically necessary
• Patients randomized to MM not
permitted to crossover to MIPS

MIPS Training Ensured Correct Application of
Uniform Systems Approach
• All participating neurosurgeons
• Completed training course
• Participated in Mi SPACE registry or reviewed ≥ 10 MIPS cases outside of trial
• Verified hospital privileges in stereotactic and image-guided procedures
• All surgeries video recorded
• First two surgical cases from each site reviewed by trial’s lead neurosurgeon to
assess adherence with surgical protocol
• Prescriptive training protocol and oversight ensured correct application of MIPS
systems approach

ENRICH Endpoints
• Efficacy
• Safety
• Cost-effectiveness

Primary Efficacy Endpoint: Utility-Weighted
Modified Rankin Score (UW-mRS) at 180 Days
mRS Utility Weight
0 (no symptoms) 1.0
1 (no significant disability) 0.91
2 (slight disability) 0.76
3 (moderate disability) 0.65
4 (moderate-severe disability) 0.33
5 (severe disability) 0
6 (dead) 0
• Discharge and Day 180 assessments
performed in person
• Others by structured telephone interview
• Primary ITT analysis evaluated if mean UW-
mRS score at 180 days in MIPS group was
superior to MM group
• Bayesian statistical analysis: posterior
probability for success > 97.5%
• Analogous to one-sided p < 0.025

FDA and NIH Have Encouraged Adaptive Trial
Designs to Increase Speed, Efficiency
• Neurological trials have successfully used adaptive trial designs
• DAWN and Swift Prime trial used adaptive design and is now part of evidence that favors
endovascular approach for acute ischemic stroke1
• ENRICH allowed for enrichment based on ICH location
• Enrichment based on interim analyses to predict location that had greatest
magnitude of benefit with MIPS
• Ultimate design goal to reach overall study conclusion as quickly as possible
1. Saver et al, 2015.

Key Secondary Endpoints to Provide Context for
Primary Endpoint
• ICU length of stay (LOS)
• In-hospital LOS
• mRS at discharge, 30 days, 90 days, and 180 days
• Proportion of patients with mRS of 0-3 at 180 days
• Overall survival through 180 days
• Impact of %ICH reduction with MIPS on mRS at 180 days
• Impact of EOT volume with MIPS on mRS at 180 days

Safety Endpoints to Evaluate Safety Profile of
MIPS vs MM
• Mortality at 30 days
• Change in hemorrhage volume between index and 24-hr CT
• Postoperative rebleeding associated with clinical deterioration following MIPS

ENRICH Included Several Economic Endpoints to
Evaluate Cost-Effectiveness of MIPS
• Primary: cost per quality-adjusted life year (QALY) gained with MIPS
• Secondary
• Cost per 30-day readmission avoided through MIPS
• Cost per infection avoided through MIPS per inpatient stay
• Cost of healthcare utilization pathways
• Cost per death avoided
• Cost per gain in UW-mRS
• Cost per gain in mRS
• Estimated initial global budget per patient
*Outcomes being
analyzed

ENRICH Efficacy and Safety
Results
Demonstrated that surgeons can consistently, safely, and predictably access and
evacuate an ICH using MIPS

Interim Analyses Resulted in Enrichment for Lobar
Region
0 50 100 150 200 250 300
Number of Patients Enrolled
No change
Enrich for lobar
Stop AGB enrollment
150 175 200 220 250
No change
No change*
* Interim analysis performed early due to COVID-19
275 300
No change Final analysis
No change

ENRICH CONSORT Diagram
Assessed for Eligibility (N=*11,603)
Randomized (N=300)
MIPS (n=150)
102 Lobar
48 BG
Medical Management (n=150)
106 Lobar
44 BG
Excluded (n=11,303)
9,510 Did not meet entry criteria
1,506 Other reasons
168 Refused to participate
Allocation
Follow-up
Analysis
1 Lost to follow-up
2 Withdrawal of consent
7 Lost to follow-up
4 Withdrawal of consent
150 analyzed in ITT analysis
147 observed mRS at 6 months
150 analyzed in ITT analysis
139 observed mRS at 6 months
*Sites were not compensated
for screening. Logs highly
variable.

Demographics and Baseline Characteristics
MIPS
(N=150)
Medical Management
(N=150)
Age (years) 66.5 ± 12.3 65.5 ± 12.2
Female sex 48.0% 52.0%
Race
White 70.7% 68.7%
Black / African American 24.0% 26.7%
Other 6.0% 5.3%
Hispanic/Latino ethnicity 6.0% 6.7%
Diabetes 22.7% 22.0%
Hypertension 77.3% 74.7%
Prior ischemic stroke/TIA 10.7% 8.0%
Current/former tobacco use 39.3% 35.3%

Clinical Presentation
MIPS
(N=150)
Medical Management
(N=150)
Index GCS 11.4 ± 2.5 11.1 ± 2.5
Index NIHSS 16.7 ± 6.5 17.8 ± 6.0
Index ICH volume (cm3) 58.9 ± 25.6 59.4 ± 22.5
ICH location
Lobar 68.0% 70.7%
Basal ganglia 32.0% 29.3%
Hours from LKN
ED arrival 5.0 ± 4.6 5.6 ± 4.9
Randomization 13.3 ± 5.9 12.7 ± 5.9
Surgery 16.6 ± 6.3

Primary Endpoint: MIPS Superior to Medical
Management
1
3
6
14
11
15
22
18
22
20
12
9
25
20
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 of MIPS
over MM
Analogous to statistically
significant p-value 0.032

Efficacy:
Posterior Distribution of the Treatment Effect
Positive
Neutral
Positive

Lower Rate of 30-Day All-Cause Mortality and
Significant Reduction in Hemorrhagic Volume with
MIPS
Outcome
MIPS
(N=150)
Medical Management
(N=150)
Difference
(95% CI) P-value
Death from any cause at 30 days 14 (9.3%) 27 (18.1%) -8.8 (-16.5, -0.1) 0.027
Difference in hemorrhagic volume (mL)
between index procedure and 24 hours
-43.9 (30.09) 3.6 (17.70) <0.001
Postoperative rebleeding associated with
clinical deterioration – no. (%)
5 (3.3%) n/a

No. at risk
MIPS 150 136 131 126 124 118 79
Medical Management 150 122 116 115 110 107 69
Lower All-Cause Mortality with MIPS through 180
Days
Overall
Survival
(%)
MIPS
Medical Management

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

Post MIPS Volumes
*
*
* Planned Secondary Analysis

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

Conclusions
• ENRICH is the first clinical trial to demonstrate functional benefit of surgical
ICH evacuation in patients with supratentorial ICH presenting within 24 hours of LKN
• MIPS approach is trans-sulcal, parafascicular, and requires the use of NICO BrainPath and
Myriad NOVUS devices
• MIPS is safe, resulted in substantial clot evacuation, and improved the UW-mRS at 6
months relative to standard medical management in both the Bayesian primary analysis
and the secondary ordinal logistic regression
• The overall benefit of MIPS appears to be from the strong positive effect observed for
participants with lobar ICH
• Basal Ganglia – neutral
• Lobar – Positive
• Combined – Positive
• MIPS was associated with improved 30-day mortality and shorter ICU/hospital LOS

ENRICH_ICH Trial_Outcomes_2023.pdf

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