1
A pivotal, randomized, controlled, and single-blinded
trial of the hemoglobin-based oxygen carrier (HBOC),
bovine polyme...
2
Outline of NMRC/RESUS Advisory Board
presentations
1. Introduction: Daniel Freilich, MD, CDR, MC, USN
2. Importance of R...
3
Hemorrhagic Shock
Lewis J. Kaplan, MD, FACS, FCCM, FCCP
Associate Professor Of Surgery
Yale University School of Medicin...
4
OBJECTIVES
• Hemorrhagic shock (HS)
– Pathophysiology
– Clinically relevant indicators of HS
– Acute therapeutic goals
•...
5
HEMORRHAGIC SHOCK
• Results from acute blood loss
– Trauma (blunt and penetrating)
– Emergency general surgery
– Electiv...
6
PATHOPHYSIOLOGY
• Acute blood loss
– Reduced red cell mass
– Reduced plasma volume
• Reduced tissue oxygen delivery
• Im...
7
PATHOPHYSIOLOGY
• Unbalanced utilization and delivery
– Anaerobic metabolism
– Systemic lactic acidosis
– Cellular hypox...
8
SHOCK CLASSES: ATLS 2004
Class I Class II Class III Class IV
EBL (ml) < 750 750-1500 1500-2000 > 2000
EBL (%) < 15% 15-3...
9
CLINICAL CORRELATES:
Standard Field Criteria PHTLS 2004
• Discoverable by all EMS providers
– Tachycardia (HR > 100 bpm)...
10
INTERVENTION OPPORTUNITY
• Intervene during the evolution of
hemorrhagic shock to avoid severe
sequelae
• Survival dire...
11
UNIVERSAL THERAPY (HS):
Trauma Bay
• ABCDE – ATLS driven
• Airway control + 100% O2
• Resuscitation (IVF + PRBC’s)
• La...
12
SHOCK IDENTIFIERS
• Vital signs
• Core temperature
• Peripheral temp
• Urine output
• ABG, arterial lactate
• Derived i...
13
INTERVENTION CHALLENGES:
Field and Transport
• Lack of definitive control, plasma, RBC
• US standard of care = crystall...
14
FLUIDS FOR SMALL VOLUME
RESUSCITATION
• Hextend
– 6% HES in balanced salt solution
– Special Forces, US civilian center...
15
OPTIMAL FLUIDS FOR SMALL
VOLUME RESUSCITATION
• Ideal fluid
– Small volume
– Repeatedly doseable
– Free of electrolyte ...
16
SURVIVAL AND LACTATE
CLEARANCE AFTER TRAUMA
Abramson et al., J Trauma, 1993; 35:584-9
17
RESUS: In-hospital Trauma Care
Assumes resuscitation is ongoing . . .
Hemorrhagic Shock
Ongoing Bleeding
Bleeding Contr...
18
RESUS ALGORITHM:
PVE and Component Therapy
Volume Depletion Volume Replete Volume Overload
IVF / Colloid PRBC/FFP
Hemod...
19
HEMORRHAGIC SHOCK, MSOF,
AND MORTALITY RISK
0
50
Mortality
Injury
MSOF
I ncreasing time
Injury
MSOF
Kaplan L, et al. Cu...
20
CONCLUSION
• Hemorrhagic shock
– Known pathophysiology
– Targeted intervention
• Survival is enhanced with early hemorr...
21
RESUS
Richard P. Dutton, MD MBA
Chief, Trauma Anesthesiology
R Adams Cowley Shock Trauma Center
University of Maryland ...
22
Objective
To compare HBOC-201 with
lactated Ringers solution for
prehospital resuscitation of
patients with severe hemo...
23
Trial Design
• Part I (Phase 2b trial): 50 subjects
• Part II (Phase 3 trial): 1,108 subjects
24
Inclusion Criteria
• Adults 18 to < 70 years old
• Injury with suspected bleeding
• SBP < 90 mmHg
• Revised Trauma Scor...
25
Revised Trauma Score
• Blood pressure
• Respiratory rate
• Glasgow Coma Scale (GCS) score
26
“Blood transfusion available”
exclusion criterion
• Intent
– To exclude subjects with short transportation delay
• Who ...
27
Exclusions
• Penetrating brain injury
• Paralysis
• Known pregnancy
• Burns
• Cardiac arrest
• Allergy
• Known oppositi...
28
Pre-Hospital Procedures
• Screening
• Pre-enrollment disclosure or informed consent
(when feasible)
• Enrollment and ra...
29
RESUS EMS interventions
Inclusion/exclusion criteria not met
DO NOT ENROLLDO NOT ENROLL
If do NOT agree to participate
...
30
In-Hospital Procedures
• Finish incomplete trial product infusion
• Routine initial care (ATLS)
• “Best practice” conti...
31
RESUS In-Hospital Trauma Care
Guidelines
• Fluid resuscitation
– Prior to hemorrhage control target SBP of 90 mmHg, the...
32
Primary Outcomes
• Reduced 28 day mortality
• Safe and tolerable
33
Other Outcomes
• Key Clinical Parameters:
1. Hemodynamics 11. Hemostasis
2. Tissue oxygenation (lactate) 12. Blood tran...
34
Consent
• Exception from informed consent per 21CFR50.24
• Community consultation & disclosure:
– media public service ...
35
36
Some potential serious side effects/risks of getting
HBOC-201
(Each less than 6% in phase III orthopedics trial)
 Car...
37
Pre-enrollment disclosure script
1. You appear to have severe bleeding, are in shock, and need treatment with
fluids.
2...
38
Data Monitoring Committee
• Will review the study for efficacy and safety
• Planned interim analyses in accordance with...
39
Stopping Criteria: Efficacy
• Absolute: Significantly decreased 28-day
relative risk of mortality
– Intent-to-treat [IT...
40
Stopping Criteria: Safety
• Absolute: Increased risk of death,
disability or birth defects in the HBOC-201
group
• Rela...
41
RESUS Summary
• A pivotal trial of HBOC-201 for prehospital
resuscitation of severe hemorrhagic shock
• Comparison to t...
42
Pre-Clinical Data:
HBOC-201 Swine
Hemorrhagic Shock Studies
Susan A. Stern, MD
Associate Professor
Associate Chair for ...
43
Preclinical Hemorrhagic Shock (HS) Studies
22 Trauma Related HS Studies:
– 12 Controlled Hemorrhage Models
• Fixed volu...
44
Study Methodologies
• Animal preparation
– Swine were anesthetized and fasted
– One study in which animals were dehydra...
45
Data
• Survival
• Hemodynamics
• Tissue oxygenation (direct and
indirect)
• Blood loss
• Organ function
46
Survival
47
HBOC-201
Control
p = 0.004
Survival was Significantly Improved with HBOC-201
88
53
0
10
20
30
40
50
60
70
80
90
100
103...
48
Survival - All Models
0
10
20
30
40
50
60
70
80
90
100
Y
ork
Sam
pson
K
nudson
M
cN
eilPhilbin
(2)
R
ice
PhilbinFitzpat...
49
Hemodynamics
50
Mean Arterial Pressure was Significantly Improved
with HBOC-201
HBOC-201
HEX/LR
= simulated hospital arrival
= baseline...
51
Mean Pulmonary Artery Pressure was Significantly
Greater with HBOC-201
HBOC-201
HEX/LR
= simulated hospital arrival
= b...
52
Cardiac Index was NOT Different with HBOC-201
HBOC-201
HEX/LR
= simulated hospital arrival
= baseline for HBOC-201
40% ...
53
Tissue Oxygenation
54
Transcutaneous Tissue Oxygen Tension was
Significantly Improved with HBOC-201
HBOC-201
HEX/LR
= simulated hospital arri...
55
Invasively Measured Tissue Oxygen
Tension
Brain Deltoid Liver Jejunum
Lee et al
Knudson et al
York et al.
Stern et al.
...
56
Arterial Lactate was Improved with HBOC-201 in
the Severe Hemorrhage Models
HBOC-201
HEX/LR
= simulated hospital arriva...
57
Blood Loss
58
Total Blood Loss
HBOC-201
HEX/LR
Uncontrolled HS
0
10
20
30
40
50
60
70
80
90
100
ml/kg
Uncontrolled HS/TBI - Short Del...
59
Organ Function and Histopathology
60
Organ Function and Histopathology
• Johnson et al. Crit Care Med. 2006.
– 40% Controlled HS
– 55% Controlled HS
– Uncon...
61
HBOC-201: Effects in Animal Models of Combined
Hemorrhagic Shock (HS) and
Traumatic Brain Injury (TBI)
Potential Advant...
62
HBOC-201: Effects in Animal Models of
HS & TBI
Potential Concerns with HBOCs for Combined HS
and TBI:
– Increased vasoa...
63
Studies of HBOC-201 in the Setting of
Combined HS and TBI
• UTHSCSA (Kerby et al. Shock, in press)
– rat, moderate cont...
64
Pre-hospital Resuscitation with HBOC-201 in a
Swine Model of Severe Uncontrolled HS/TBI
(Stern et al. submitted)
• Unco...
65
Survival was Significantly Improved with
HBOC-201 for the Long Delay Cohort
(Stern et al: HBOC-201 in severe uncontroll...
66
Cerebral Perfusion Pressure
(Stern et al: HBOC-201 in severe uncontrolled hemorrhage and TBI)
Uncontrolled HS/TBI - Sho...
67
Brain Tissue Oxygen Tension was Significantly Greater
with HBOC-201
(Stern et al: HBOC-201 in severe uncontrolled hemor...
68
Other Studies of Controlled HS and TBI Demonstrate
Improvement in Multiple Parameters with HBOC-201
CPP Brain Tissue
O2...
69
Summary
• Adverse Effects
– Mild to moderate vasoactivity
– Transiently elevated LFTs
– Minimal hepatobilliary and rena...
70
A Gerson Greenburg, MD PhD FACS
VP, Medical Affairs Biopure Corporation
MD University of Chicago
PhD Northwestern Univ....
71
Overview of Clinical Trials: HBOC-201
*Includes two non-surgical studies in Sickle cell anemia subjects
Trials Study
Po...
72
Overview of Clinical Trials: HBOC-201
Trials Type Studies
N
Subjects
N
Uncontrolled Phase 1 3 15
“Colloid Control” Phas...
73
The majority of experience with HBOC-201 is
with doses of ≤ 6 units
Dose
HBOC-201 Units (g Hb)
Low
≤ 2 U
(≤ 60 g Hb)
Mi...
74
Quantitative assessment of safety data rather than
subjective evaluation of safety signals is necessary
•Detection of s...
75
Phase 3 Orthopedic Surgery Study: HEM-0115
• Largest trial; 688 subjects (350 vs. 338)
• Powered to detect 1-2% differe...
76
The overall pattern of serious and non-serious
adverse events is accurately reflected in study
HEM-0115
HBOC-201
(n=350...
77
Randomization
100%
The study design of HEM-0115
RBC
Treatment
No Further
Treatment
40%
60%
HBOC
Treatment
RBC
Treatment...
78
• Total fluid crystalloid/colloid administration
• Total RBC administered
• Higher estimated blood loss
• Longer anesth...
79
• First treatment before the end of anesthesia
• More cell-saver blood
• Time to first treatment shorter
• More total A...
80
Major contributors to imbalances in adverse events
between treatment arms concentrated in the
HBOC-201 plus RBC group
•...
81
Adverse Events: Age Dependence
Patients > 70 years of age
n (%)
Patients < 70 years of age
n (%)
SAEs
HBOC-201
(n=111)
...
82
*System organ class and preferred terms from MedDRA
Cardiac Serious Adverse Events
All Subjects < 70 Years of Age
Cardi...
83
*System organ class and preferred terms from MedDRA
Cardiac Serious Adverse Events
All Subjects < 70 Years of Age
Cardi...
84
*System organ class and preferred terms from MedDRA
Renal Serious Adverse Events
All Subjects <70 Years of Age
Renal an...
85
*System organ class and preferred terms from MedDRA
CNS Serious Adverse Events
All Subjects <70 Years of Age
Nervous Sy...
86
*System organ class and preferred terms from MedDRA
Respiratory Serious Adverse Events
All Subjects < 70 Years of Age
R...
87
*System organ class and preferred terms from MedDRA
Hepatobiliary Serious Adverse Events
All Subjects <70 Years of Age
...
88
Changes In Systolic Blood Pressure
0
5
10
15
20
25
Baseline Post CTM Day 1 Post Day 2 Post Day
6/Dischage
6 w eek
Follo...
89
LFT Activity Over Study Period
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 0
1 8 0
2 0 0
B a s e l i n e D u r i n g C T M ...
90
Lipase Activity Over Study Period
Error bars = ± SE
0
20
40
60
80
100
120
140
160
Baseline During CTM Day 1 Day 2 Day 6...
91
Creatinine & BUN Levels Over Study Period
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Baseline During CTM Day 1 Day 2 Discharge 6-Weeks...
92
Conclusions
• In 22 clinical trials 826 subjects have received HBOC-201
• 87% of the clinical experience with HBOC-201 ...
93
Given there is reasonable risk associated with
the use of HBOC-201
and the potential benefits to patients in
hemorrhagi...
94
RESUS IND and Clinical Hold
Daniel Freilich, MD, CDR, MC, USN
RESUS Sponsor Lead Investigator
Naval Medical Research Ce...
95
“FDA has placed the RESUS IND on Clinical Hold
for three primary reasons”
1. Safety concerns based on
i. AEs seen in pr...
96
Outline of discussion points
1. Traumatic HS: public health problem, unsatisfactory treatment
2. RESUS: program evoluti...
97
Outline of discussion points—continued
6. Clinical database: benefit, reasonable safety in overall pop.,
especially in ...
98
Background
99
Improved prehospital HS resuscitation is an urgent
unmet medical need
• Trauma is the leading cause of death in young a...
100
HBOC-201 may equilibrate prehospital and in-
hospital resuscitation
Current standard HS treatment:
• Prehospital: resu...
101
HBOC-201 is one component of a comprehensive
strategy to diminish morbidity/mortality from HS
after 911 and in The War...
102
HBOC-201 (Hemopure®
)
(bovine polymerized hemoglobin)
• Modified bovine hemoglobin 32.5 g in 250 ml bag modified LR
• ...
103
Objective criteria were used to select HBOC-201
for development for a traumatic HS indication
• Improved resuscitative...
104
RESUS protocol under review is product of 5 years
of comprehensive deliberation
2001 Sep Program conceived
2003
Apr RE...
105
RESUS may have a transformational effect on
trauma care
Potential lives saved annually if RESUS is successful
(15% mor...
106
HBOC-201 clinical database
Pivotal Phase 3 Orthopedic Trial
(HEM-0115)
107
The HEM-0115 trial enrolled mostly older adults
undergoing orthopedic surgery
• Trial design
– Randomized, controlled,...
108
High blood transfusion avoidance confirmed
efficacy in HEM-0115
> 95% in first 24 hours, 59% overall
 Predicts transf...
109
There were a number of key adverse safety signals
in HEM-0115
Overall
• AEs
• SAEs
Cardiac
• Cardiac SAEs
• MI AEs
• T...
110
Overall safety signals were more frequent
with HBOC-201 than RBC in HEM-0115
(overall population)
HBOC-201
%
RBC
%
Gro...
111
Some cardiac safety signals were more frequent
with HBOC-201 than RBC in HEM-0115
(overall population)
HBOC-201
%
RBC
...
112
Cerebral ischemic AEs were more frequent
with HBOC-201 than RBC in HEM-0115
(overall population)
HBOC-201
%
RBC
%
Grou...
113
Elevated BP safety signals were more frequent
with HBOC-201 than RBC in HEM-0115
(overall population)
HBOC-201
%
RBC
%...
114
Mortality was not significantly different
in HEM-0115
(overall population)
HBOC-201
%
RBC
%
Group
difference
%
P
Morta...
115
NMRC conclusions from HEM-0115 trial
“…in a relatively older population undergoing
orthopedic surgery, overall clinica...
116
HEM-0115 clinical database
Pivotal Phase 3 Orthopedic Trial
(younger sub-populations)
117
Sub-populations stratified by age
Population
Mean age
(yrs)
N
HBOC-201
N
RBC
> 70 years
old# 77.0 111 111
Overall
popu...
118
Key adverse safety signal group differences were
decreased or absent in younger subjects
0
5
10
15
20
25
O
verallSA
Es...
119
No unreasonable overall SAE risk in younger subjects
HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.005
35...
120
No unreasonable cardiac SAE risk in younger subjects
HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.002
12...
121
No unreasonable MI AE risk in younger subjects
MI in HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.01
3.6...
122
No unreasonable heart failure/fluid overload risk in
younger subjects
HBOC-201 subjects: > 70 years old vs. < 70 year ...
123
No unreasonable cerebral ischemic risk in younger
subjects
3.6
1.7
0.8
00 0 0 0
3.6
1.7
0.8
0
0.0
0.5
1.0
1.5
2.0
2.5
...
124
No unreasonable cardiac arrest or mortality risk in
younger subjects
7.2
2.9
0.8
0.0
5.4
1.8
0.0 0.0
1.8
1.1
0.8
0.0
0...
125
NMRC conclusions from HEM-0115 trial
“Our finding of an improved safety profile in sub-
populations of subjects more c...
126
Assumptions used to assess
21 CFR 50.24
benefit:risk requirements for RESUS
127
Benefit:risk requirements of 21 CFR 50.24
1. “human subjects are facing a life-threatening situation”
2. “available tr...
128
1. Predicted mortality is 58.1% in the RESUS
target population receiving standard care
Two redundant and confirmatory ...
129
2. & 3. Preclinical HS studies with HBOC-201 show
improved outcome and predict potential for
benefit, including decrea...
130
4. As efficacy data from preclinical and prior clinical trials
show that HBOC-201 effectively transports oxygen,
simil...
131
5. In the prior Phase 3 HEM-0115 trial, the AE profile
of HBOC-201 was inferior to RBC in the overall
mainly older pop...
132
6. Safety data in overall populations in prior HBOC-201
surgery/orthopedics trials are unlikely to accurately
predict ...
133
6a. Even if one assumes prior trials accurately predict
benefit:risk in RESUS, safety data in overall
populations pred...
134
6b. Even if one assumes prior trials accurately
predict benefit:risk in RESUS, key safety signal
group differences wer...
135
7. Favorable interim data from HEM-0125 S. Africa
traumatic HS ER trial further predict reasonable risk
in RESUS
• Pop...
136
8. Safety data from prior Diaspirin Cross-linked
Hemoglobin (DCLHb) trauma trials are
unlikely to accurately predict b...
137
9. Preclinical and clinical data support
RESUS Dosing Guidelines
• Multiple HS preclinical studies: improved outcome w...
138
10. Multiple protocol risk mitigation strategies further
diminish risk in RESUS
I. Optimization of target population s...
139
I. Target population selection maximizes benefit
and minimizes risk
1. Targeting a population with severe HS without a...
140
II. Standardization and optimization of care, training,
and allowance for standard care minimize risk
4. Thorough EMS ...
141
III & IV. Comprehensive surveillance methods allow
early detection and action and minimize risk
9. Prospective “increa...
142
RESUS IND Clinical Hold*
* Note: all consultant reports included in FDA’s BPAC Issue
Summary were completed prior to i...
143
FDA:
“There is inadequate information to assess
whether risks and benefits are reasonable…”
144
There is more information than usual for an IND
• Substantial preclinical database
– 41 trauma-related studies (mainly...
145
FDA:
“The toxicity profile of HBOC-201 precludes
study in field trauma…unless the target
population is projected to ha...
146
RESUS targets a population meeting OBRR’s
criteria
• “Exsanguinating hemorrhage”
– Severe HS with projected mortality ...
147
FDA:
“Entry criteria for RESUS suggests that the
patient population likely to be heterogeneous”
148
• Mortality high in all RTS stratifications (reasonably homogeneous pop.) (left)
• Target pop. has normalized (bell-sh...
149
Stratification of RESUS target population based on
RTS ranges reveals reasonable mortality
homogeneity and distributio...
150
FDA:
“For crystalloid/colloid controlled surgery
studies…, the imbalances…persisted”
151
“Crystalloid/colloid” studies have minimal impact
on prediction of benefit:risk in RESUS
• Key adverse signal: MI: HBO...
152
FDA:
“…preclinical studies do not support…
potential…to provide… direct benefit…”
153
Preclinical data predict reduced mortality in
RESUS
• Mortality: reduced in all models combined
– HBOC-201 12% vs. con...
154
Preclinical data predict improved hemodynamic
stabilization without unreasonable risk in RESUS
• More rapid stabilizat...
155
Preclinical data predict tissue oxygenation benefit
in RESUS
• Improved direct measures
– Increased transcutaneous*, b...
156
Preclinical data predict equivalent or improved
myocardial effects in RESUS
• No evidence of heart failure/fluid overl...
157
Preclinical data predict equivalent or improved
respiratory effects in RESUS
• No evidence of hypoxemia
– Mildly decre...
158
Preclinical data predict mild GI/hepatic side effects
without unreasonable risk in RESUS
• No evidence of jejunal inju...
159
Preclinical data predict mild renal side effects
without unreasonable risk in RESUS
• Mildly decreased urine output
– ...
160
Preclinical data predict neurologic benefit without
unreasonable risk in RESUS
• No neurotoxicity in vitro
• Improved ...
161
Preclinical data predict hematologic benefits in
RESUS
• Hematology
– Improved blood oxygen content
– Decreased transf...
162
Preclinical data predict significant benefit without
unreasonable risk in RESUS
• Overall results
– Beneficial surviva...
163
FDA:
“…our concerns that when a vasoactive HBOC (DCLHb
or HBOC-201) is infused…, the two endpoints typically
used by E...
164
Vasoactivity is characteristic of all HBOCs
Mechanism
– Nitric oxide binding by tetrameric Hb
– Mean mw effects on dis...
165
As HBOC-201 elicits mainly mild to moderate BP
responses, risk of adverse effects on prehospital
monitoring of fluid s...
166
RESUS fluid re-infusion criteria (hypotension and tachycardia):
– Preclinical HS studies*
• Hypotension is sensitive i...
167
Summary: HBOC-201 is unlikely to significantly
adversely affect prehospital monitoring in RESUS
• Low a priori risk du...
168
FDA:
“…increases in SBP to 220 mm Hg have been
noted with HBOC-201”
4 out of 826 subjects (< 0.5%)
169
Rare hypertension SAEs in euvolemic and
hypertensive subjects do not affect benefit:risk in
hypovolemic/hypotensive su...
170
FDA:
“There are very limited clinical data on dose and
rate of administration using HBOC-201 to
support the RESUS dosi...
171
RESUS Dosing Guidelines
– Dose 500 ml (2 units) (7 ml/kg)
– Default* infusion duration 10 min
– Default* infusion rate...
172
Extensive preclinical HS data establish evidence
basis for RESUS dose, infusion rate, and max. dose
– Improved outcome...
173
Extensive HEM-0115 clinical data with < 6 units of
HBOC-201 predict reasonable risk (especially in
younger subject) an...
174
Limited HEM-0115 clinical data with infusion rate
> 25 ml/min predict reasonable risk and support
RESUS infusion rate
...
175
Interim HEM-0125 clinical data in trauma patients
with dose and infusion rate similar to RESUS
predict reasonable risk...
176
Extensive DCLHb clinical data in trauma patients in
HOST trial show similar SBP responses with dose
similar to RESUS (...
177
Preclinical and clinical data support
RESUS Dosing Guidelines
Maximum dose
1. Extensive preclinical data
2. Extensive ...
178
Non-serious AEs
179
Some non-serious safety signals reflect
characteristic side effects of HBOCs
(irrespective of trial type)
• Transient ...
180
Non-serious AE database has minimal relevance
to prediction of benefit:risk in RESUS
• Morbidity trial (HEM-0115)
– Im...
181
Non-serious safety signals such as oliguria do not
significantly affect RESUS benefit:risk prediction
• HEM-0115
– Oli...
182
Troponin elevation but not MI was more frequent
with HBOC-201 in HEM-0115
HBOC-201
%
RBC
%
Group
difference
%
P
> ROC ...
183
Definition of MI
(ESC/ACC consensus, Alpert, 2000)
“Either one of the following criteria satisfies the diagnosis for a...
184
Misdiagnosis of MI by troponin
(Khavandi A, Emerg Med J, 2005)
“…there has been widespread misinterpretation of the ne...
185
That most were low level troponin T elevations and
fewer met ESC/ACC definition in HEM-0115, predicts
lower risk in RE...
186
Low risk of troponin elevations in younger subjects
in HEM-0115 predicts low risk in RESUS
21.6
13.2
10.1
3.1
0
1.6
0....
187
Troponin elevation was an isolated lab abnormality
without significant effect on predicted benefit:risk
in RESUS
1. Le...
188
Semi-quantitative predictions of
benefit:risk in RESUS
189
Objective benefit:risk analysis (state-of-the-art)
• Holden WL, Drug Safety 2003
– “…benefit-risk analysis must be the...
190
A semi-quantitative analysis which partially accounts for
disparity in the clinical significance of death and SAE
occu...
191
The analysis predicts favorable benefit:risk over a
wide range of control mortality and effect size
estimate assumptio...
192
Conclusions
(RESUS target population)
1. HS is the most common potentially preventable cause of death
in trauma, most ...
193
Conclusions
(RESUS preclinical database)
3. The breadth and redundancy of improved outcome in
preclinical HS studies p...
194
Conclusions
(RESUS clinical database)
5. That there was only a mild adverse shift in the safety profile of
HBOC-201 de...
195
Conclusions
(overall RESUS benefit:risk prediction)
8. Qualitative analysis of preclinical and clinical studies predic...
196
Conclusions
(regulatory requirements)
11. All requirements of 21 CFR 50.24 have been met and the
RESUS IND Clinical Ho...
197
BIRMINGHAM REGIONAL
EMERGENCY MEDICAL
SERVICES SYSTEM
BREMSS/UAB
Joe Acker EMT-P, MPH
Executive Director
198
BREMSS
• Six Counties in
Alabama
• 1.2 + Million
• 80 + Cities
• 18 Hospitals
• 20, 000 EMS
responses a month
• 4,000 ...
199
Why do we need the RESUS
study ?
• A – airway
• B- ventilation
• C- circulation
200
We need interventions for
Circulation !
• Risk/benefit
• Civilian EMS Study
• We can do !
• We must do if trauma
patie...
201
IMPACT ON
TRAUMA CARE
Lewis J. Kaplan, MD, FACS, FCCM, FCCP
Associate Professor Of Surgery
Yale University School of M...
202
IMPACT ON TRAUMA CARE
• Pre-hospital trauma care
– No significant advances since 1970’s
– “Load and go” care
• Trauma ...
203
IMPACT ON TRAUMA CARE
• High-risk patient population
– Hospital course marked by AE’s and SAE’s as
part of the disease...
Upcoming SlideShare
Loading in …5
×

ppt

1,027 views
910 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,027
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
21
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • The RESUS study was designed to validate the hypothesis that HBOC-201 can be used to improve the survival of severely injured victims of hemorrhagic shock.
  • STAGES I-II DATA INTEGRATION AND SAMPLE SIZE OPTIMIZATION
    The decision about whether to integrate data from Stages I into II or to analyze and report separate phase IIb and III trials will default to integration. Only protocol QA issues, described below as integration prohibition criteria, would preclude integration of the data and necessitate separate trials. The process of determining integration will be as follows:
    Integration prohibition criteria will be reviewed by the RESUS Advisory Board.
    An integration disposition recommendation will be submitted in ~30 days in a written summary to the DMC, IRBs, and the FDA—an additional 30 day window for review will be planned.
    If the Advisory Board recommends against the default of integrating the data, Stage II will not be resumed until noted QA issues and necessary study modifications are addressed and approved by the DMC, IRBs, and FDA.
    In order to assure that a planned 50-patient Efficacy and Safety Review (ESR) will have no possibility of bias regarding the integration decision, the Advisory Board will submit the integration disposition recommendation prior to the ESR. Although ESR data will have no effect on the data-integration decision, the study could be halted if efficacy/safety stopping criteria are met. Aggregate mortality data (n=50) will be calculated and utilized to optimize control treatment mortality prediction and study sample size.
    In summary, “post-phase II-like” decision making will occur in the following order: (1) Integration disposition (2) ESR (3) sample size optimization.
    Data will not be integrated and phase IIb and III trials will be analyzed and reported separately only if any integration prohibition criteria, as below, are met. A deliberate attempt was made to find a balance between the need for relatively specific prospective criteria and the need to allow for logical deliberative flexibility.
    The integration prohibition criteria are:
    Feasibility—Despite the best of intentions and effort imputed into the design of this study, including evidence-based predictions, multidisciplinary expertise, and planned dry runs, numerous studies have failed due to design flaws. Thus, if execution of the study, as written, turns out to be logistically unfeasible and will not answer the primary efficacy and safety outcome questions, Stage I will be terminated and analyzed/reported separately. Minor study design optimizations would not satisfy requirements for integration prohibition criteria. Specific QA issues that could satisfy this feasibility criterion include but are not limited to:
    Recruitment/screening—Subjects cannot be recruited and screened adequately.
    Randomization—Subjects cannot be randomly allocated to the two study groups.
    Study drug administration—Study drug cannot be administered due to timing or other logistic reasons.
    Data collection—Data cannot be collected adequately.
    Inclusion/exclusion criteria—Subjects screened and enrolled do not represent the targeted study population (i.e., severe HS without severe TBI). For example, basing our prediction on prior experience (i.e., DCLHb trial [Sloan EP]), ~25% of subjects are expected to have significant TBI despite the exclusion criteria—if this percentage turns out to be significantly erroneous, the study would not answer the primary questions. QA issues that are significant enough to prompt significant changes in inclusion/exclusion criteria are likely to satisfy this criterion.
  • &amp;lt;number&amp;gt;
  • The enrollment criteria in RESUS have been designed to focus the enrolled subjects to maximize the potential for benefit and to minimize the potential for risk.
    Revised Trauma Score (RTS): The main objective of incorporating the RTS 1 to &amp;lt; 5 RESUS inclusion criterion is to maximize enrollment of a population most likely to benefit from the studied intervention. Recognizing that survival of all-comers in a HS population defined by hypotension alone may not be sufficiently high (&amp;lt; 20%) and may be excessively heterogeneous, we sought to target a population with higher and more homogeneous mortality. Specifically, we aimed to target a traumatic HS population with intermediate predicted risk of death, excluding patients at very low and high extremes (those likely to die or to live irrespective of a new treatment modality). Thus, the RTS was selected because it has been shown to predict survival in trauma patients (Riou, 2001), focuses the population to decrease heterogeneity, and can realistically be evaluated by EMS personnel in the field without significant delay in care. This approach was recommended by OBRR. The RTS range of 1 to &amp;lt; 5 was selected to target an intermediate predicted mortality in control subjects (~ 58%).
  • CTM re-infusion
    Repeat administration of CTM (500 ml) will occur similarly to general PHTLS/ATLS guidelines—i.e., persistent signs of class III or IV (and sometimes class II) HS. As summarized above, persistent severe hypotension (SBP &amp;lt; 90 mm Hg) will suffice as a sole criterion for re-infusion of CTM. In addition, moderate hypotension (SBP 90-99 mm Hg) in combination with tachycardia (HR &amp;gt; 100 bpm) will be a 2nd CTM re-infusion criterion. A maximum (total) of 6 units of HBOC-201 may be administered (HBOC-201: 250 ml = 32.5 g Hb/unit x 6 units = 195 g Hb in 1,500 ml). A maximum of 1,500 ml (three 500 ml units in two doses) of LR will be considered CTM. Because urban transportation times are usually short, it is expected that most subjects will receive only 2 units of HBOC-201 (and 1,000 ml of LR), a minority will receive 4 units of HBOC-201, and a smaller minority with prolonged transportation time and persistent hypotension, will receive 6 units of HBOC-201.
    LR control
    LR was chosen as the control fluid because it is commonly used for both prehospital and hospital resuscitation of trauma patients. LR is manufactured and distributed in the U.S. as either pure levo L-isomer (l-LR, Baxter Healthcare Corp.) or as a 50:50 racemic mixture of levo and dextro isomers (dl-LR, Abbott Laboratories and B. Braun Medical Inc.). There are theoretical reasons (i.e., toxicity, LA accumulation, and immune activation) to choose l-LR over racemic dl-LR. However, the current standard of care in the U.S. includes use of either dl-LR or l-LR. Moreover, dl-LR is used in HBOC-201. Thus, as directed by OBRR, dl-LR (Abbott Laboratories or B. Braun Medical Inc.) will be used as control prehospital resuscitative fluid CTM in this protocol.
    OTHER/STANDARD IV FLUIDS
    All other medical care and monitoring will follow standard procedures. This includes administration of standard IV resuscitative fluids (crystalloid and/or colloid solutions) if deemed clinically indicated where SBP and/or tachycardia criteria for re-administration of CTM are not met. Occult shock may occur in patients despite restoration of stable BP and HR. For example, if other medical conditions that can also cause shock are ruled out in a patient with SBP restored to &amp;gt; 100 mm hg but with persistent tachycardia, tachypnea, narrow pulse pressure, cool pale skin, and/or mental status changes, he/she is likely to have persistent HS and further IV fluid administration will be indicated. Similarly, if SBP is restored to &amp;gt; 90 mm Hg even without tachycardia, if other such signs of shock are present, he/she is likely to have persistent HS and further IV fluid administration will be indicated. EMS providers will be educated that further IV fluid resuscitation will be indicated in such cases (per standard of care). EMS providers will be reminded about potential for paradoxical bradycardia in HS patients.
    Some of the other signs of occult hypoperfusion are listed below (EMS personnel should recall that these signs are nonspecific and may reflect other physiological derangements [e.g., compromised airway, hypoxemia and hypoventilation due to pulmonary injuries, and TBI]):
    Weak and/or thready pulse; Narrow pulse pressure (&amp;lt; 40 BPM); Bradycardia (HR &amp;lt; 60 BPM); Tachypnea; Decreased oxygen saturation; Oximeter failure to obtain reading; Skin pallor; Cool and clammy skin; Decreased capillary refill; Mental status change (in absence of TBI)
    Non-CTM infusions will include all fluid infusions after 1,500 ml of CTM and for indications not meeting CTM administration criteria.
  • (Need to add something about TBI – since Dan included TBI in the in-hospital trauma care guidelines)
  • The requirements for research involving subjects enrolled under an EIC are set forth in the Code of Federal Regulation, 21 CFR 50.24. These requirements are listed below along with bulleted statements demonstrating how the RESUS study protocol has met and in many cases exceeded them. Details regarding EIC, CCD, and RESUS protocol details are provided in Appendix A (these appendices are subject to change in the December 14 briefing book).
    This RESUS trial will enroll subjects who, by virtue of the inclusion criteria, will be unable to provide IC prior to enrollment. IC will not be feasible in the majority of subjects due to the acuity of their medical condition and a therapeutic window of minutes before treatment must be initiated. Thus, the conduct of the RESUS trial requires a provision for EIC. Recognizing high ethical standards necessary for EIC trials, NMRC researchers went to extraordinary lengths to ensure a scientifically- and ethically-optimal trial design. Specifically, a comprehensive CCD process was developed to maximize informed decision making by affected communities; inclusion/exclusion criteria were selected to target subjects with severe HS, a high rate of mortality, and for whom blood transfusions were unavailable (i.e., those subjects predicted to benefit most from the proposed intervention); provisions were included to prevent any delay in providing standard care (especially blood transfusions); IC will be obtained or Pre-ED will be provided when feasible to maximize individual subject autonomy; multiple risk mitigation strategies were incorporated to minimize risk to subjects (especially exclusion of the elderly because safety data from prior trials showed that they appeared most sensitive to potentially adverse vasoactive effects of HBOC-201); and independent government direction, funding, and sponsorship of the trial were insisted upon to minimize potential bias. Moreover, despite OBRR’s concern that uncontrolled hemorrhage and concomitant TBI might not be adequately treatable with HBOC-201, in a complex OBRR-directed RESUS IND-enabling swine study, NMRC showed significantly improved outcome in that simulated clinical setting (Appendix B) (these appendices are subject to change in the December 14 briefing book)..
  • Example of the RESUS website.
  • Examples of how RESUS CCD presentation notifies the public about risks associated with the use of HBOC-201.
  • WHY WAS SUCH AN EXCEPTION GRANTED IN CONNECTION WITH THE RESUS STUDY?
    The Restore Effective Survival in Shock or RESUS study is designed to determine if a new, investigational product called HBOC-201 (bovine polymerized hemoglobin), also called Hemopure®, will decrease mortality of trauma victims with life-threatening blood loss (hemorrhagic shock) even before they reach the emergency room.
    Currently there are no U.S. Food &amp; Drug Administration (FDA) approved oxygen-carrying therapies to treat hemorrhagic shock in the field or pre-hospital setting.
    Today, injured individuals are given saline or Lactated Ringer’s solution (or colloids) until blood can be transfused upon arrival at the hospital. These volume-expanding solutions help the heart to keep pumping, but in severe blood loss the oxygen content of the diluted blood may be critically low.
    In RESUS, if a patient meets enrollment criteria and time allows, ambulance personnel will try to get consent (permission) from patients or their Legally Authorized Representative (LAR) before enrolling them in the study. When consent is not possible, they try to provide disclosure (information) to patients or their family members about the study. That provides an opportunity to refuse participation. But most patients with shock are sleepy, confused, and unable to judge the risks and benefits of being in the study. Often, family members and friends are not available, and treatment needs to start right away. So, most patients will be enrolled in the RESUS study without prior consent or disclosure. Once a subject reaches the hospital, patients and/or their family members will receive disclosure about the risks and benefits of participation at the earliest feasible time after enrollment and be given an option to withdraw.
    Participating in the RESUS study has the prospect of direct benefit to enrolled subjects receiving HBOC-201:
    The proposed intervention is believed to be at least equal to standard therapy;
    Previous studies of HBOC-201 demonstrate its potential to provide a direct benefit;
    Risks associated with the use of HBOC-201 are reasonable in relation to the patients’ injuries, the risks and benefits of standard therapy, the risks and benefits of the proposed intervention, and the absence of blood transfusions.
    WHAT ARE SOME ADDITIONAL PROTECTIONS PUT IN PLACE?
    Protections to patients’ rights and welfare required by the EIC regulation for an Exception from Informed Consent study, as well as additional protections included in the RESUS study are:
    Consultation with representatives of the communities in which the study will be conducted and from which the subjects will be drawn;
    Public disclosure to the communities prior to initiation of the study of plans for the investigation and its risks and expected benefits;
    Public disclosure of information following completion of the study to inform the community and researchers of the study, including the demographic characteristics of the research population, and its results;
    Establishment of an independent data monitoring committee to exercise oversight of the study;
    Community members may choose to pre-exclude themselves (e.g., by obtaining a RESUS study pre-exclusion ID bracelet and/or window decal); and
    The investigator is committed to the process of contacting the subject&amp;apos;s LAR or family member within the therapeutic window. In the RESUS study the therapeutic window is a matter of seconds to minutes and, therefore, there will usually be insufficient time to prospectively fully inform and disclose the risks and benefits of participating in the study. However, ambulance personnel will attempt to contact the subject&amp;apos;s LAR or family member, if available and if feasible, and try to get full informed consent from patients or their LAR before enrolling them in the study.
    When consent is not possible, ambulance personnel will try to disclose to patients or their family members about the study in order to provide an opportunity to refuse participation. But most patients with shock are sleepy, confused, and unable to judge the risks and benefits of being in the study. Often, family members and friends are not available, and treatment needs to start right away. So, most patients will be enrolled in the RESUS study without prior full informed consent or disclosure.
    Upon hospitalization, study personnel will discuss the study with the patient and provide them with an option to withdraw from the study.
    Additionally, the local hospital Institutional Review Board (IRB), also called a Research Subject Protection Board, approves the study
  • Three (3) papers provide data on the effect of HBOC-201 on organ function and histopathology. These papers looked at heart, lungs, kidney and liver.
    There was a slightly greater incidence of histopathological changes in liver and kidney, and mild, transient increases in hepatic enzymes and BUN and Cr with HBOC-201 in the study by Johnson et al.
    Greater elevations in liver function tests and greater histopathological changes in the liver were also noted in the study by York et al. That is inadvertently omitted from this slide, and I apologize.
  • This may be too much context….
  • &amp;lt;number&amp;gt;
    This slide summarizes the clinical trials performed with HBOC-201 from 1992 through 2005 organized according to the phase and type of study
    There were 4 Phase 1 studies involving a total of 93 normal volunteers that examined safety and tolerability, exercise tolerance with dose and rate of infusion escalation, as well as immunologic response to HBOC-201 infusions
    There were 13 Phase 1/2 studies involving a total of 296 general surgery subjects as well as non-surgical subjects with sickle cell anemia with or without vaso-occlusive crisis
    There were 4 Phase 2 studies involving a total of 266 subjects including cardiopulmonary bypass, abdominal aortic aneurysm reconstruction, percutaneous coronary intervention, and non cardiac surgery subjects
    Finally, there were 2 Phase 3 studies involving a total of 848 subjects, one in non cardiac subjects, and the second and largest study in orthopedic surgery subjects.
    -There were 160 subjects in study HEM-0114 and 688 subjects in study HEM-0115 with 83 and 350 subjects receiving treatment with HBOC-201, respectively.
    Of the total 1503 subjects in these 22 clinical studies, 826 received HBOC-201 and 677 received infusion of control solutions (LRS, saline, colloid, or RBCs)
  • &amp;lt;number&amp;gt;
    The 22 clinical trials are summarized here according to the nature of the controls used and study phase.
    There were 3 uncontrolled studies, 5 studies in which colloid control was administered, 10 involving crystalloid control, and the largest number of subjects studied received RBCs as the control infusion.
    These studies involved not only different control solutions but also involved different study designs, some controlled, uncontrolled, single blind or double blind, different doses of drug and dosing periods, and some with asymmetric study arm design. These differences contribute to the need for caution when attempting to interpret data combined from all these studies.
    Note: The following table summarizes the AE and SAE data for the colloid and crystalloid (non oxygen carrying solution) controlled studies:
    HBOC-201(n=131)
    Controls(n=108)
    P-value*
    Adverse Events
    109(83.2%)
    81(75.0%)
    0.147
    AEs/Patient
    6.46
    5.52
    0.225
    Serious Adverse
    Events
    20 (15.3%)
    12(11.1%)
    0.446
    SAEs/Patient
    0.27
    0.14
    0.138
  • &amp;lt;number&amp;gt;
    The overall experience with HBOC-201 is summarized in this slide in terms of the exposure to drug.
    87% of subjects were exposed to the HBOC in the dose range related to RESUS….
    Addresses an FDA issue and question….
    These data show that 87% of subjects (N =718) exposed to HBOC-201 received 6 or less units of HBOC-201. The vast majority of experience lies in this range of doses which contributed to the recommended change in the maximum dose of HBOC-201 (6 units) to be used in RESUS.
  • For the first few slides, after the presentation of credentials, we do start with a review of all previous experience. Here, it is N trials with NN patients, noting carefully the differences in models, controls, ratios of treated to controls, lack of homogeneity of populations  and accumulation of AE and SAE data that forms an initial impression of a safety profile.....note a wide range of observations were made but none clinically
    Rearranged some of the points…stress the waived consent…go to side effects and then look at ISS and here will have to dismiss it…
    Can question including point #3 here as the next slide takes it on in terms of dismissing it….
  • &amp;lt;number&amp;gt;
    The review of HBOC-201’s safety profile will focus on the adverse events observed in the phase 3 orthopedic surgery study for the following reasons:
    This was the largest single study performed with HBOC-201, representing 42 percent of all subjects treated with drug and 66% of subjects in the RBC-controlled trials.
    This study was powered to detect a 1% difference in the incidence of adverse events between treatment groups.
    All of the trends seen in earlier studies are reflected in the differences between groups in this one study, including non-significant trends, or “safety signals”.
  • &amp;lt;number&amp;gt;
    This table summarizes the differences in the incidence and the overall adverse events and serious adverse events per patient in the two treatment groups. It is clear that the incidence of overall AEs and SAEs is statistically significantly higher.
    The same trend in AEs and SAEs that was seen in the pooled studies analysis is reflected in the HEM-0115 study. The difference in adverse events is contributed primarily by the side effect profile of HBOC-201 that will be discussed in the following slides. The difference in SAEs is dictated by factors that were identified in the process of root cause analysis performed on the HEM-0115 study results and will be discussed in the next slides as well.
  • May not have to use this one….could be the outline for the back up slides…
  • &amp;lt;number&amp;gt;
    Analysis of the trends in adverse events showed that the incidence was a function of age. The most significant example of age dependence is seen in subjects above and below age 85 where all of the difference in mortality and 90% of the difference in cardiac serious adverse events between treatment groups was observed.
    Consistent with the age restriction suggested by NMRC for the RESUS protocol, this slide shows a side-by-side comparison of cardiac and nervous system SAEs and mortality are presented showing, in particular, the much higher incidence of cardiac SAEs in patients above age 70. Furthermore, there is a statistically significant difference between treatment groups in the &amp;gt;70 year old subjects. The nervous system SAEs are approaching significance in this older population. In the &amp;lt; 70 year old population there are no significant differences.
    In the next slides we will look more closely at the profile cardiac serious adverse events and distribution of these events according to age.
    Note regarding age dependence reflected in patients above and below age 85:
    A total of 16 deaths occurred during this study: 10 (2.9%) deaths in the HBOC-201 group and six (1.8 %) deaths in the RBC group (p = 0.450). The increase in the number of deaths in the HBOC-201 group was contributed by patients who were &amp;gt; 85 years. The data showed that the mortality rate for patients  85 years of age was 1.5% (N = 5) in both groups. Whereas, of the six deaths among the patients &amp;gt; 85 years, five were reported in the HBOC-201 and one in the RBC group. Of these five HBOC-201 patients, three were &amp;gt; 90 years of age.
    In addition, 90% of the disparity in cardiac serious adverse events is accounted for by subjects above age 85 (22 vs 9 cardiac SAEs in the total population and 11 vs 7 in the &amp;lt;85 years of age subjects). This is not surprising that there is a strong correspondence between mortality and serious cardiac adverse events in this case as cardiac SAEs were associated with the majority of the deaths in this population.
  • &amp;lt;number&amp;gt;
    There is no question that the incidence of cardiac serious adverse events is higher in the HBOC-201 group in this study. In particular, when one groups events such as cardiac failure, congestive heart failure, cardio-respiratory arrest and pulmonary edema these difference between groups becomes more evident with 11 subjects in the HBOC-201 group and 0 subjects in the RBC population. This also highlights the possibility that fluid volume management was an issue in this study.
    An independent review of all the cardiac adverse events was performed by Dr. Steve Schulman at John’s Hopkins and one of his conclusions was that a significant proportion of patients experienced volume overload and this volume overload was not managed adequately (proper use of diuretics, limiting crystalloid volume, etc.). Thus, these data clearly point to the possibility that the relative lack of experience with the colloidal solution that HBOC-201 represents, combined with administration of other colloid solutions and large volumes of crystalloid may have resulted in the observed increased incidence of these adverse events. These data argue that more comprehensive training with regard to proper volume management when HBOC-201 is used as a blood substitute to treat perioperative surgical anemia is needed.
    From Dr. Schulman’s Patient Review:
    “Many subjects received many liters of fluid in the intra/perioperative period and it was evident that in many patients whose adverse event was classified by the investigator as heart failure, the etiology was volume overload. Many of the patients with this event did not receive adequate diuresis in the postoperative period resulting in volume overload.”……“Although HBOC-201 and RBCs contributed to this volume overload, it appears on reviewing the medical records in these patients that diuretic therapy was often started late with inadequate doses.”
    “It is therefore suspected that the lack of experience in using a new transfusion agent compared to red blood cells contributed to the disproportionate total number of cardiovascular or CNS events in the HBOC-201 group, including inadequate use of product.”
  • &amp;lt;number&amp;gt;
    Comparing this same grouping of cardiac serious adverse events described above (heart failure, CHF, etc.) the difference between groups goes from 11 vs 0 to 3(1%) vs 0, (statistically insignificant) in subjects &amp;lt; 70 years of age. This is also true for the entire SOC with a p-value = 0.3834.
    Again, it is likely that the incidence of these volume-related events might be significantly reduced, particularly in the elderly subjects, with protocols in place to ensure proper volume management in the setting of orthopedic surgery and the treatment of perioperative anemia.
  • &amp;lt;number&amp;gt;
    Adverse events affecting renal function have been of historical concern in the field of HBOCs, particularly with the early generation products. Polymerization is one modification that has contributed to reducing such events. Although the overall renal SAE profile does not show evidence of any statistically significant trends, these data taken together with the fact that there were two subjects requiring dialysis in the group of subjects with acute renal failure (where there was no antecedent event or factors predisposing for renal failure) suggest the need for monitoring of creatinine clearance in this patient population to mitigate against the possibility of renal failure.
    On the average, mean serum creatinine levels were similar between the HBOC-201 (0.67 - 0.82 mg/dL) and the RBC (0.77 - 0.9 mg/dL) treatment groups with a trend for slightly higher mean concentrations in the RBC group. Analysis of the shifts from normal baseline concentrations to clinically significantly high (CSH) concentrations shows that the shift is relatively low (≤ 6%) in both study groups. The percent patients sampled at any particular time point tended to be higher in the HBOC-201-treatment group. The slightly higher incidence of shifts to CSH concentrations of serum creatinine were consistent with the higher incidence (five HBOC-201 vs. two RBC patients) of acute renal failure in the HBOC-201-treatment group.
  • &amp;lt;number&amp;gt;
    There was a no statistically significant increase in overall nervous system serious adverse events. However, there was a significant increase in the number of cerebrovascular accidents in the HBOC-201 group. However, the incidence of CVA was lower in the &amp;lt;70 year old subjects and the difference was non-significant in this group.
  • &amp;lt;number&amp;gt;
    Overall there is no significant difference between the treatment groups in terms of respiratory system adverse events. However, the difference in the incidence of respiratory failure is approaching statistical significance in the overall population. As discussed previously this may be related to excess volume infusion which could exacerbate pulmonary edema and respiratory dysfunction. There is no evidence of this imbalance in the subjects &amp;lt;70 years of age.
  • &amp;lt;number&amp;gt;
    The difference in the incidence of Hapatobiliary SAEs is significant with 5 versus 0 events in the two treatment arms. This is due , in large part, to serious events related to cholecystitis. These events are not seen in the younger population. There was one case of hepatomegaly and one case of hepatorenal failure as well, however, no trends are suggested by these data.
    As will be seen, in the discuss of the clinical laboratory data, there is a significant and transient increase in LFTs associated with the treatment with HBOC-201.
  • &amp;lt;number&amp;gt;
    Since blood pressures in both groups following the first infusion remained elevated compared to baseline, serial blood pressure data were analyzed to determine the duration of the elevated blood pressure when patients were treated according to this protocol. Specifically, systolic blood pressures were compared at seven time points during the observation period (baseline, immediately after completion of last CTM treatment, days 1 and 2 after completion of last CTM treatment, at day 6 after treatment start or discharge, and at 6 week follow-up). Compared to baseline, the average increase in systolic blood pressure after the last CTM treatment was 22 1 mm Hg (n=324) with HBOC-201 and was 10 1 mm Hg (n = 313) with pRBCs.
    Elevations of blood pressure occurred more frequently in the HBOC-201 treated patients compared to pRBC treated patients (85% vs. 63% for HBOC-201 and pRBC, respectively). The largest average increase in blood pressure occurred after the first exposure to HBOC-201 (500 mL, 2 units), resulting in increases (pre to post infusion) in systolic and diastolic blood pressures (meansem) of 23 1 mm Hg (n = 319) and 13 1 mm Hg (n=319), respectively. The first treatment with pRBCs (250 ml, 1 unit) resulted in increases in systolic and diastolic blood pressures of 4 1 mm Hg (n=246), (Figure 2.1) and 1 1 mm Hg (n=246), respectively. The second and subsequent infusions of CTM started at slightly higher blood pressures than baseline (~15-20 mm Hg for HBOC-201 and ~5-10 mm Hg for pRBC) and resulted in smaller increases in systolic blood pressure, averaging less than 7 mm Hg (where n &amp;gt;20) in both groups.
  • &amp;lt;number&amp;gt;
    Based on the results from preclinical studies and previous clinical trials changes in AST and ALT levels in the plasma are characteristic following administrations of HBOC-201. During Day 1 and Day 2 post-CTM, the mean AST and ALT activities were approximately two to three-fold greater in the HBOC-­201-treated patients than in the RBC-treated patients. The level of these enzymes in both treatment groups were slightly elevated at Day 6 or Discharge and returned to baseline by the 6-Week Follow-up visit assessment. The incidence of CSH elevations of enzyme activity was higher in the HBOC-201 (8-13%) group compared to the RBC (2-9%) group. However, the majority of patients with elevated AST and ALT values had transient elevations that did not require intervention, or discontinuation of CTM, and were not suggestive of hepatic dysfunction. These observations are likely related to the large protein (Hb) load that the liver is required to clear from the circulation following administration of HBOC-201.
  • &amp;lt;number&amp;gt;
    There was no difference in the mean value of lipase activities between the HBOC-201 and the RBC groups at follow-up periods except during the CTM infusion time period where lipase activities in the HBOC-201 group were increased by several fold compared to that of the RBC. However, this difference was transient with similar values for both treatment groups at the 6-Week Follow-up visit. Lipase laboratory measurements showed that 5-10% of patients in the HBOC-201 and 1-2% of patients in the RBC group had clinically significant elevations between Day 1 and Day 6 of Follow-up. At the 6-Week Follow-up period, 1% in the HBOC-201 and 2% of patients in the RBC group showed clinically significant elevations in this enzyme.
    These data are consistent with the reported lipase elevation AEs as 32 patients (9%) in the HBOC-201-treatment group and seven patients (2%) in the RBC-treatment group reported lipase elevation as an AE. In this study, any increase in lipase activity &amp;gt; 25% of the upper limit of normal was evaluated by a gastroenterologist. Of the 39 patients with lipase elevations reported as AEs, 25 were further evaluated (laboratory monitoring, ultrasound and barium swallows) and 24 of the 25 were found to be asymptomatic (without clinical evidence of pancreatitis). One patient (Patient 0716) had mild pancreatitis suspected to be associated with gastritis and peptic ulcer disease. A CT scan of the abdomen revealed an adrenal hematoma and the gastroenterologist determined that no further intervention was needed. The patient was administered Axid 150 mg PO BID for eight weeks and the patient recovered. Although there were significant increases in lipase activities in the HBOC-201-treatment group, increases were mild-moderate and transient. The increases appeared to be dose dependent. A majority of the patients with elevated lipase activities were asymptomatic and had no clinical features suggestive of pancreatitis. These data suggest that elevations of lipase activity are not uncommon following infusion of HBOC-201.
    The incidence of CSH elevations is &amp;lt; 10% and is unlikely to be associated with pancreatitis. Nonetheless, the incidence of lipase elevations following HBOC-201 infusion requires careful monitoring and consultation to ensure the absence of pancreatitis.
  • &amp;lt;number&amp;gt;
    On the average, mean serum creatinine levels were similar between the HBOC-201 (0.67 - 0.82 mg/dL) and the RBC (0.77 - 0.9 mg/dL) treatment groups with a trend for slightly higher mean concentrations in the RBC group. Analysis of the shift from normal baseline concentrations to clinically significantly high (CSH) concentrations shows that the shift is relatively low (≤ 6%) in both study groups. The percent patients sampled at any particular time point tended to be higher in the HBOC-201-treatment group. The slightly higher incidence of shifts to CSH concentrations of serum creatinine were consistent with the higher incidence (four HBOC-201 vs. two RBC patients) of acute renal failure in the HBOC-201-treatment group.
    BUN levels were slightly increased from baseline (2.4 - 4.3 mg/dL) in the HBOC-201 group compared to a slight decrease through Day 6 or discharge and 3.1 mg/dL increase from baseline at follow-up in the RBC group. The differences between groups was minimal at Day 6 or discharge and at follow-up.
  • &amp;lt;number&amp;gt;
    The clinical experience with HBOC-201 is important in identifying potential safety and efficacy in the RESUS Study.
    The HEM-0115 study conclusions identify the major outcomes for efficacy and safety in HBOC-201 use for elective Orthopedic patients in comparison to red cells
  • &amp;lt;number&amp;gt;
    HBOC-201 can be stored without refrigeration for at least three years.
    It is universally compatible (does not require blood banking) and can be infused easily without special training.
    It is also a low volume/weight resuscitative fluid.
    HBOC-201 is relatively pure, containing less than 3% tetrameric hemoglobin, the main culprit of vasoactivity side effects.
    HBOC-201, although bovine derived, has negligible BSE risk.
    Over 800 subjects have been evaluated with HBOC-201 in orthopedics and general surgery settings.
    Biopure, the manufacturer of HBOC-201, submitted a Biological License Application (BLA) to FDA for an orthopedic surgery indication, but the product has not been approved in the U.S.
    HBOC-201 is approved for human use in South Africa.
  • T ½ is 19 hrs
  • * OBRR/Biopure Combination 22 (June 2006)
    ** OBRR/Biopure Combination 20 (June 2006)
  • ^ OBRR/Biopure Combination 26 (June 2006)—MI, myocardial ischemia, angina pectoris, unstable angina pectoris.
    * OBRR/Biopure Combination 22 (June 2006).
    ** OBRR/Biopure Combination 20 (June 2006).
  • Reduction in power to detect group differences (relative to overall population):
    # Threshold to detect group differences increases 1.8-fold.
    * Threshold to detect group differences increases 1.2-fold.
    ^ Threshold to detect group differences increases 2.2-fold.
  • The same observations and trends were found in the overall Integrated Safety of Summary (all trials).
    Heart failure/fluid overload—combination 22.
    Cardiac arrest—combination 20.
  • * OBRR/Biopure Myocardial ischemia Combination 5 (June 2006)
  • OBRR/Biopure Combination 22 (June 2006)
  • Cardiac arrest data: Biopure/OBRR “Combination 20” (29 June 2006)
    Differences in incidences (delta) of key safety signals in &amp;gt; 70 vs. &amp;lt; 70 years old was consistently higher in HBOC-201 than RBC subjects.
    Data suggest that elderly patients may be particularly sensitive to even seemingly relatively mild to moderate vasoactive effects of HBOC-201.
    Awareness of potential vasoactivity risk in the elderly, exclusion of elderly, in-hospital trauma care guidelines, lower maximum doses, CTM stopping criteria, and comprehensive surveillance for adverse vasoactivity signals should diminish potential risk due to intrinsic vasoactivity in RESUS.
  • Target a population with severe HS and without access to blood transfusion
    Maximizes benefit by enrolling population with high mortality but without access to optimal resuscitation; this minimizes risk.
    Exclude elderly
    Minimizes risk by excluding the older sub-population which had the highest incidence of significant SAEs
    Hypotension and tachycardia CTM re-infusion criteria
    Maximizes benefit by inclusion of more consistent markers of HS
    Minimizes risk of inadequate fluid resuscitation and hypoperfusion
  • Thorough EMS and trauma center training
    Maximizes benefit, minimizes risk, and standardizes care by education about optimal practice guidelines
    Access to standard IV fluids during the prehospital phase
    Minimizes risk of inadequate fluid resuscitation and secondary hypoperfusion
    Standardization of prehospital care
    Maximizes benefit via optimal practice guidelines, minimizing risk of inadequate fluid resuscitation and secondary hypoperfusion
    Standardization of in-hospital care
    Minimizes risk of inadequate fluid resuscitation and secondary hypoperfusion
    Minimizes risk of inadequate blood transfusion resuscitation and secondary anemia
    Peak SBP (120 mm Hg) CTM stopping criterion
    Minimizes risk of uncommon idiosyncratic severe BP responses
  • “Increased BP” and “hypertension” coding definitions
    Minimizes risk by promoting efficient regulatory AE reporting
    Extensive secondary outcome measurements
    Minimizes risk by comprehensively following safety signals
    Lactic acid trial relative stopping criterion
    Minimizes risk by stopping the trial if there is evidence of hypoperfusion
    SBP stopping criterion SBP &amp;gt; 120 mm Hg
    Minimizes risk by decreasing risk of rare idiosyncratic severe BP responses
    Expedited AE reporting
    Minimizes risk by ensuring efficient regulatory AE reporting
    Hypoperfusion markers reports
    Minimizes risk by comprehensively following potentially “vasoactivity-related” hypoperfusion safety signals, and ensuring efficient regulatory reporting
    Early efficacy and safety reviews
    Minimizes risk by ensuring early interim analysis of safety data and regulatory reporting (after enrollment of only 25 HBOC-201 subjects)
  • (this is not a BLA)
  • Sauaia A, Arch Surg 1994
    Moore FA, Arch Surg 1997
    Claridge JA, Am Surg 2002
    Malone DL, J Trauma 2003
    Malone D, Crit Care Med 2003
    Hill GE, J Trauma 2003
    Dunne JR, Surg Infect 2004
  • Note: ESC/ACC consensus: only 5-11/18 met typical rise and gradual fall requirement (Alpert 2000). AHA Scientific Statement: only 1/18 met diagnostic biomarkers case-definition (Luepker RV, 2003).
    ^ “Isolated” troponin elevations have been reported to often be “spurious” (e.g., Ng SM, 2001).
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • &amp;lt;number&amp;gt;
  • ppt

    1. 1. 1 A pivotal, randomized, controlled, and single-blinded trial of the hemoglobin-based oxygen carrier (HBOC), bovine polymerized hemoglobin (HBOC-201), for the prehospital resuscitation of patients with severe hemorrhagic shock (HS) Daniel Freilich, MD, CDR, MC, USN RESUS Sponsor Lead Investigator Naval Medical Research Center, Silver Spring, MD Specialty: Internal Medicine, Infectious Diseases Research interests: hemorrhagic shock, malaria, bioterrorism agents
    2. 2. 2 Outline of NMRC/RESUS Advisory Board presentations 1. Introduction: Daniel Freilich, MD, CDR, MC, USN 2. Importance of RESUS to the Navy and Marines Corps: John Mateczun, MD, RADM, MC, USN 3. Hemorrhagic shock: pathophysiology, clinical presentation, and treatment: Lewis Kaplan, MD 4. Overview of RESUS study: Richard Dutton, MD 5. Preclinical HBOC-201 HS studies: Susan Stern, MD 6. Synopsis of HBOC-201 clinical studies: Gerson Greenburg, MD, PhD 7. RESUS IND Clinical Hold issues: Daniel Freilich, MD, CDR, MC, USN 8. Concluding remarks—importance of RESUS to civilian EMS community: Joseph Acker, EMT-P, MPH 9. Concluding remarks—importance of RESUS to civilian trauma community: Lewis Kaplan, MD
    3. 3. 3 Hemorrhagic Shock Lewis J. Kaplan, MD, FACS, FCCM, FCCP Associate Professor Of Surgery Yale University School of Medicine Section of Trauma, Surgical Critical Care and Emergency General Surgery Director, SICU and Surgical Critical Care Fellowship
    4. 4. 4 OBJECTIVES • Hemorrhagic shock (HS) – Pathophysiology – Clinically relevant indicators of HS – Acute therapeutic goals • Resuscitation paradigm construction – Outcome benefit
    5. 5. 5 HEMORRHAGIC SHOCK • Results from acute blood loss – Trauma (blunt and penetrating) – Emergency general surgery – Elective surgery + complications • Spine reconstruction • Cesarean section • Hepatic transplantation – Interventional Radiology procedures
    6. 6. 6 PATHOPHYSIOLOGY • Acute blood loss – Reduced red cell mass – Reduced plasma volume • Reduced tissue oxygen delivery • Impaired balance of tissue oxygen utilization and supply – Demand >>> supply
    7. 7. 7 PATHOPHYSIOLOGY • Unbalanced utilization and delivery – Anaerobic metabolism – Systemic lactic acidosis – Cellular hypoxia • Compounded by central shunting of effective circulating volume – protect cardio-pulmonary and cerebral oxygen delivery
    8. 8. 8 SHOCK CLASSES: ATLS 2004 Class I Class II Class III Class IV EBL (ml) < 750 750-1500 1500-2000 > 2000 EBL (%) < 15% 15-30% 30-40% > 40% Pulse < 100 > 100 > 120 > 140 BP normal normal decreased decreased Pulse P Norm. to inc. decreased decreased decreased Resp rate 14-20 20-30 30-40 > 35 Urine output > 30 20-30 5-15 minimal CNS / mental status Slightly anxious Mild anxiety Anxious, confused Confused, lethargic Fluid therapy Crystalloid Crystalloid IVF + PRBC IVF + PRBC
    9. 9. 9 CLINICAL CORRELATES: Standard Field Criteria PHTLS 2004 • Discoverable by all EMS providers – Tachycardia (HR > 100 bpm) – Hypotension (SBP < 90 mm Hg) – Cool extremities (central shunting and peripheral vasoconstriction) – Multiple manifestations (i.e. unobtainable SaO2) • As shock progresses . . . – Disordered mentation – Obtundation – Loss of consciousness
    10. 10. 10 INTERVENTION OPPORTUNITY • Intervene during the evolution of hemorrhagic shock to avoid severe sequelae • Survival directly related to rapidity of hemorrhage control – “Golden hour” – Time to definitive hemorrhage control • Difficult areas: military, rural civilian trauma
    11. 11. 11 UNIVERSAL THERAPY (HS): Trauma Bay • ABCDE – ATLS driven • Airway control + 100% O2 • Resuscitation (IVF + PRBC’s) • Laboratory investigation • Initial radiologic survey • Focused Assessment by Sonography for Trauma (FAST)
    12. 12. 12 SHOCK IDENTIFIERS • Vital signs • Core temperature • Peripheral temp • Urine output • ABG, arterial lactate • Derived indices – Anion gap – Corrected anion gap – Unmeasured ions • Response to PVE/PRBC – Vital signs – Cardiac performance • CVP/PA Catheter – Volume responsive cardiac output – ScvO2 / SvO2 • Trans-esophageal echocardiography – End systolic elastance
    13. 13. 13 INTERVENTION CHALLENGES: Field and Transport • Lack of definitive control, plasma, RBC • US standard of care = crystalloid solutions – Immune activating – Dilute clotting factors, RBC mass – Induce hyperchloremic acidosis • Compounds lactic acidosis – At best 1/3 remains intravascular • Large volume resuscitation • Potential hemorrhage acceleration
    14. 14. 14 FLUIDS FOR SMALL VOLUME RESUSCITATION • Hextend – 6% HES in balanced salt solution – Special Forces, US civilian centers • Hypertonic saline – Single dose due to electrolyte abnormalities – Potential benefit in TBI only • Neither augments oxygen carrying capacity nor RBC mass
    15. 15. 15 OPTIMAL FLUIDS FOR SMALL VOLUME RESUSCITATION • Ideal fluid – Small volume – Repeatedly doseable – Free of electrolyte abnormalities – Augments oxygen carrying capacity • Targets reversing the pathophysiology of hemorrhagic shock • Hemoglobin-based oxygen carrier
    16. 16. 16 SURVIVAL AND LACTATE CLEARANCE AFTER TRAUMA Abramson et al., J Trauma, 1993; 35:584-9
    17. 17. 17 RESUS: In-hospital Trauma Care Assumes resuscitation is ongoing . . . Hemorrhagic Shock Ongoing Bleeding Bleeding Controlled IVF + PRBC/FFP/Plt OR + IR Hemodynamic Assessment Persistent: Abnormal VS? Oliguria? High LA/acidosis? Dx Dilemma? Hemorrhage Control PA Catheter CVP Echocardiography Volume Depletion Volume Replete Volume Overload
    18. 18. 18 RESUS ALGORITHM: PVE and Component Therapy Volume Depletion Volume Replete Volume Overload IVF / Colloid PRBC/FFP Hemodynamic Reassessment Laboratory reevaluation Hgb 8-10 g/dl (acute) Adequate Cardiac Performance? YesNo Consider pressor Hemodynamic Reassessment Laboratory reevaluation Hgb 7-8 g/dl (stable) Consider Diuresis or Afterload Reduction Goals: Cardiac Performance Optimization (CO, SvO2,LA)
    19. 19. 19 HEMORRHAGIC SHOCK, MSOF, AND MORTALITY RISK 0 50 Mortality Injury MSOF I ncreasing time Injury MSOF Kaplan L, et al. Curr Op Crit Care, 1999; 5(6):458-463 Death from refractory shock
    20. 20. 20 CONCLUSION • Hemorrhagic shock – Known pathophysiology – Targeted intervention • Survival is enhanced with early hemorrhage control and resuscitation • HBOC-201 is a directed PREHOSPITAL intervention to ameliorate HS pathophysiology and offers a sound approach to enhancing survival and minimizing morbidity
    21. 21. 21 RESUS Richard P. Dutton, MD MBA Chief, Trauma Anesthesiology R Adams Cowley Shock Trauma Center University of Maryland Medical Center Restore Effective Survival in Shock
    22. 22. 22 Objective To compare HBOC-201 with lactated Ringers solution for prehospital resuscitation of patients with severe hemorrhagic shock.
    23. 23. 23 Trial Design • Part I (Phase 2b trial): 50 subjects • Part II (Phase 3 trial): 1,108 subjects
    24. 24. 24 Inclusion Criteria • Adults 18 to < 70 years old • Injury with suspected bleeding • SBP < 90 mmHg • Revised Trauma Score (RTS) 1 to < 5 • Planned transport to study hospital • IV access secured
    25. 25. 25 Revised Trauma Score • Blood pressure • Respiratory rate • Glasgow Coma Scale (GCS) score
    26. 26. 26 “Blood transfusion available” exclusion criterion • Intent – To exclude subjects with short transportation delay • Who have access to blood transfusions shortly • Who have insufficient time to potentially benefit from HBOC-201 • Guideline (majority of RESUS subjects) – Expected < 10-15 minutes to hospital arrival  “blood transfusion available” – Expected > 10-15 minutes to hospital arrival  “blood transfusion unavailable” • Exception for critical patients (minority of RESUS subjects) – May enroll critical patients with expected < 10-15 minutes to hospital arrival. • Patients with severely unstable vital signs • Patients not expected to survive to hospital arrival – Per EMS judgment
    27. 27. 27 Exclusions • Penetrating brain injury • Paralysis • Known pregnancy • Burns • Cardiac arrest • Allergy • Known opposition to prehospital research • Transport time to study hospital <10-15 min
    28. 28. 28 Pre-Hospital Procedures • Screening • Pre-enrollment disclosure or informed consent (when feasible) • Enrollment and randomization • Trial product infusion over 10 minutes – 500 ml HBOC-201 – 1,000 ml LR • Re-infusion if: – SBP < 90 mm Hg, or – SBP 90-99 mm Hg and HR > 100 bpm. • Infusion stopped if: – SBP > 120 mm Hg • Maximum HBOC-201 dosage: 6 units
    29. 29. 29 RESUS EMS interventions Inclusion/exclusion criteria not met DO NOT ENROLLDO NOT ENROLL If do NOT agree to participate DO NOT ENROLLDO NOT ENROLL Patient or LAR/family member agree to participate ENROLL PATIENT using PreED or ICENROLL PATIENT using PreED or IC MINORITY OF CASESMINORITY OF CASES Patient CONSCIOUS or LAR/family member AVAILABLE Provide IC or Pre-ED (if feasible) Be alert for side effects Repeat CTM re-infusion cycle Asses and re-infuse CTM PRN Until maximum dose CTM re-infusion criteria met SBP < 90 mm Hg Or SBP 91-99 mm Hg and HR >/= 100 bpm Complete CRF Admin standard IV fluids Re-evaluate Inadequate Resuscitation Persistent other signs of HS NO fluid therapy Re-evaluate Adequate Resuscitation No persistent other signs of HS CTM re-infusion criteria NOT met SBP >/= 100 mm Hg Or SBP 91-99 mm Hg and HR < 100 bpm ASSESS CTM RE-INFUSION CRITERIA ENROLL PATIENT using EICENROLL PATIENT using EIC Open pre-randomization envelope Infuse entire HBOC-201 or LR dose MAJORITY OF CASESMAJORITY OF CASES Patient UNCONSCIOUS, CONFUSED, OR DISORIENTED LAR/family member UNAVAILABLE Inclusion/exclusion criteria met CONTINUE ENROLLMENT/CONSENTCONTINUE ENROLLMENT/CONSENT ATLS ABCDEs: circulation (C) Diagnose HS requiring fluid resuscitation Screen pt Review inclusion criteria (including SPB < 90 mm Hg) and exclusion criteria Complete CRFComplete CRF
    30. 30. 30 In-Hospital Procedures • Finish incomplete trial product infusion • Routine initial care (ATLS) • “Best practice” continuing care • Ongoing informed consent / disclosure • Continued data collection • Surveillance for adverse events
    31. 31. 31 RESUS In-Hospital Trauma Care Guidelines • Fluid resuscitation – Prior to hemorrhage control target SBP of 90 mmHg, then – Following hemorrhage control target normal perfusion • Blood composition – Hgb 8-10 g/dL during early resuscitation (active bleeding) – Hgb 7-8 g/dL when hemodynamically stable – Platelets and clotting factors as indicated • Inotropic and vasoconstrictive medications – Guided by advanced monitoring (PA, TEE, SvO2) – Titrated to cardiac output • Traumatic brain injury: per Brain Trauma Foundation guidelines
    32. 32. 32 Primary Outcomes • Reduced 28 day mortality • Safe and tolerable
    33. 33. 33 Other Outcomes • Key Clinical Parameters: 1. Hemodynamics 11. Hemostasis 2. Tissue oxygenation (lactate) 12. Blood transfusions 3. Renal function 13. Fluid requirements 4. O2 content 14. Immune activation 5. Organ function 15. Neurocognitive function 6. Trauma scores 16. Neurophysiology 7. Infectious complications 17. Safety labs 8. Abdominal complications 18. Clinical safety 9. Length of stay (LOS) 19. Disposition 10. Ventilator support 20. Survival (prehospital) • Composite Surrogate Score (CSS)
    34. 34. 34 Consent • Exception from informed consent per 21CFR50.24 • Community consultation & disclosure: – media public service announcements – house mailing brochures – town hall discussions – church meetings – health fairs • Ongoing consent process: – Pre-enrollment disclosure – Post-enrollment discussion – Option to withdraw
    35. 35. 35
    36. 36. 36 Some potential serious side effects/risks of getting HBOC-201 (Each less than 6% in phase III orthopedics trial)  CardiovascularCardiovascular  Increased blood pressure (BP)Increased blood pressure (BP)  Heart attackHeart attack  Abnormal heart rhythmAbnormal heart rhythm  Heart failureHeart failure  LungsLungs  Respiratory failureRespiratory failure  Pulmonary edema (fluid overload)Pulmonary edema (fluid overload)  PneumoniaPneumonia  KidneysKidneys  Kidney failureKidney failure  BrainBrain  Stroke & transient ischemic attack (TIA) (preStroke & transient ischemic attack (TIA) (pre--stroke)stroke)  ConfusionConfusion Significance of prior HBOC-201 serious side effects for RESUS  Likelihood ofLikelihood of serious side effectsserious side effects  Phase III orthopedics trialPhase III orthopedics trial  24% HBOC24% HBOC--201 vs. 18% control subjects had at least 1201 vs. 18% control subjects had at least 1 (difference insignificant)(difference insignificant)  Each happened in less than 6% of HBOCEach happened in less than 6% of HBOC--201 subjects201 subjects  Some were less common in subjects with low blood pressureSome were less common in subjects with low blood pressure or traumaor trauma  RESUSRESUS trialtrial •• Difference expected to be lowerDifference expected to be lower •• Clinical benefit expected to be higher than potential forClinical benefit expected to be higher than potential for serious side effectsserious side effects  Clinical significance ofClinical significance of serious side effectsserious side effects  Could complicate and prolong hospitalizationCould complicate and prolong hospitalization  Could be lifeCould be life--threatening, cause disability, and even cause deaththreatening, cause disability, and even cause death Increased blood pressure (BP) from HBOC-201  Phase III orthopedics trialPhase III orthopedics trial  Mild to moderate increases were commonMild to moderate increases were common  11% had high BP11% had high BP ““adverse eventsadverse events””  Severe increases were rareSevere increases were rare  Less than 1% had high BPLess than 1% had high BP ““serious adverse eventsserious adverse events””  BP increases were less in subjects with low BP or traumaBP increases were less in subjects with low BP or trauma  LikeLike RESUSRESUS patientspatients  Expected significance forExpected significance for RESUSRESUS patientspatients  Insignificant in most patientsInsignificant in most patients  ““BP medicinesBP medicines”” may be required in some patientsmay be required in some patients  Potentially:Potentially:  Could make the heart pump less stronglyCould make the heart pump less strongly  Could confuse medical personnel, resulting in underCould confuse medical personnel, resulting in under--resuscitationresuscitation (inadequate treatment)(inadequate treatment)  Could increase bleedingCould increase bleeding  Could cause otherCould cause other serious side effectsserious side effects, complicate and prolong, complicate and prolong hospitalization, be lifehospitalization, be life--threatening, and cause disability or deaththreatening, and cause disability or death
    37. 37. 37 Pre-enrollment disclosure script 1. You appear to have severe bleeding, are in shock, and need treatment with fluids. 2. As part of a research study, we are testing a new fluid called HBOC-201 that study doctors believe may improve your chance of surviving. 3. This research study is approved by (hospital name)’s committee for the protection of human subjects. 4. There are risks and HBOC-201 could be harmful, but study doctors believe that the benefits outweigh the risks. 5. Unless you object, you will be included in the study and will get HBOC-201 or regular IV fluids. All other medical care will be standard. 6. If you do not want to be in the study, you will get standard medical care. 7. Because treatment needs to start right away, you must tell us immediately ifyou must tell us immediately if you do NOT want to be in the studyyou do NOT want to be in the study.
    38. 38. 38 Data Monitoring Committee • Will review the study for efficacy and safety • Planned interim analyses in accordance with 21CFR50.24 • Analysis after accrual of: • 50 patients (5%) • 222 patients (20%) • 554 patients (50%) • 1,108 patients (100%)
    39. 39. 39 Stopping Criteria: Efficacy • Absolute: Significantly decreased 28-day relative risk of mortality – Intent-to-treat [ITT] analysis – Appropriate boundary modification (O’Brien-Fleming)
    40. 40. 40 Stopping Criteria: Safety • Absolute: Increased risk of death, disability or birth defects in the HBOC-201 group • Relative: Increased serious adverse events, in the absence of a survival benefit • Relative: Worsening of key surrogate measurements, in the absence of a survival benefit
    41. 41. 41 RESUS Summary • A pivotal trial of HBOC-201 for prehospital resuscitation of severe hemorrhagic shock • Comparison to the current standard of care • Does not alter in-house trauma treatment • Requires exception from informed consent • Powered to demonstrate a 15% reduction in the relative risk of death
    42. 42. 42 Pre-Clinical Data: HBOC-201 Swine Hemorrhagic Shock Studies Susan A. Stern, MD Associate Professor Associate Chair for Education Department of Emergency Medicine University of Michigan Ann Arbor, Michigan
    43. 43. 43 Preclinical Hemorrhagic Shock (HS) Studies 22 Trauma Related HS Studies: – 12 Controlled Hemorrhage Models • Fixed volume model- – 40-50% blood volume removed – Concomitant soft tissue injury (muscle crush) – Moderate to severe hemorrhagic insult • Fixed pressure model- – Animal bled to a target MAP = 30-40 mmHg – Mild to moderate hemorrhagic insult – 6 Uncontrolled Hemorrhage Models • Liver crush/laceration • Arterial laceration – 4 Combined HS & Traumatic Brain Injury (TBI)
    44. 44. 44 Study Methodologies • Animal preparation – Swine were anesthetized and fasted – One study in which animals were dehydrated • Study design – Simulated prehospital phase - short (30 min) to long (8 hrs) – Simulated hospital phase - hours to days • Fluid resuscitation regimen – Bolus or continuous, target MAP and HR – HBOC-201 total dose: 4-313 ml/kg (7-522% of EBV ) – HBOC-201 infusion rate: 0.5-10 ml/kg/min • COMPARABILITY TO RESUS – RESUS individual dose: 7-21 ml/kg – RESUS infusion rate: 0.7 ml/kg/min (50 ml/min)
    45. 45. 45 Data • Survival • Hemodynamics • Tissue oxygenation (direct and indirect) • Blood loss • Organ function
    46. 46. 46 Survival
    47. 47. 47 HBOC-201 Control p = 0.004 Survival was Significantly Improved with HBOC-201 88 53 0 10 20 30 40 50 60 70 80 90 100 103/117 59/112
    48. 48. 48 Survival - All Models 0 10 20 30 40 50 60 70 80 90 100 Y ork Sam pson K nudson M cN eilPhilbin (2) R ice PhilbinFitzpatrick N M R C TBISD M anning K atz G urney M anning N M R C TBILD Less Severe More Severe *p < 0.01 * * * ** HBOC-201 Control Fluid
    49. 49. 49 Hemodynamics
    50. 50. 50 Mean Arterial Pressure was Significantly Improved with HBOC-201 HBOC-201 HEX/LR = simulated hospital arrival = baseline for HBOC-201 Uncontrolled HS/TBI - Long Delay 0 10 20 30 40 50 60 70 80 90 100 110 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Short delay 0 10 20 30 40 50 60 70 80 90 100 110 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 55% controlled HS 0 10 20 30 40 50 60 70 80 90 100 110 0 10 20 30 40 50 60 90 120 150 180 210 240 Uncontrolled HS 0 10 20 30 40 50 60 70 80 90 100 110 0 10 20 30 40 50 60 90 120 150 180 210 240 40% controlled HS 0 10 20 30 40 50 60 70 80 90 100 110 0 10 20 30 40 50 60 90 120 150 180 210 240
    51. 51. 51 Mean Pulmonary Artery Pressure was Significantly Greater with HBOC-201 HBOC-201 HEX/LR = simulated hospital arrival = baseline for HBOC-201 40% controlled HS 0 5 10 15 20 25 30 0 10 20 30 40 50 60 90 120 150 180 210 240 Uncontrolled HS/TBI - Long Delay 0 5 10 15 20 25 30 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Short Delay 0 5 10 15 20 25 30 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS 0 5 10 15 20 25 30 0 10 20 30 40 50 60 90 120 150 180 210 240 55% controlled HS 0 5 10 15 20 25 30 0 10 20 30 40 50 60 90 120 150 180 210 240
    52. 52. 52 Cardiac Index was NOT Different with HBOC-201 HBOC-201 HEX/LR = simulated hospital arrival = baseline for HBOC-201 40% controlled HS 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 0 15 30 45 60 90 120 150 180 210 240 Uncontrolled HS/TBI - Long Delay 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Short Delay 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 0 15 30 45 60 90 120 150 180 210 240 55% controlled HS 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 0 10 20 30 40 50 60 90 120 150 180 210 240
    53. 53. 53 Tissue Oxygenation
    54. 54. 54 Transcutaneous Tissue Oxygen Tension was Significantly Improved with HBOC-201 HBOC-201 HEX/LR = simulated hospital arrival = baseline for HBOC-201 40% controlled HS 0 5 10 15 20 25 30 35 40 45 50 0 10 20 30 40 50 60 90 120 150 180 210 240 55% controlled HS 0 5 10 15 20 25 30 35 40 45 50 0 10 20 30 40 50 60 90 120 150 180 210 240 Uncontrolled HS 0 5 10 15 20 25 30 35 40 45 50 0 10 20 30 40 50 60 90 120 150 180 210 240 Uncontrolled HS/TBI - Short Delay 0 5 10 15 20 25 30 35 40 45 50 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Long Delay 0 5 10 15 20 25 30 35 40 45 50 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360
    55. 55. 55 Invasively Measured Tissue Oxygen Tension Brain Deltoid Liver Jejunum Lee et al Knudson et al York et al. Stern et al. Direction of arrow represents effect of HBOC-201 on tissue oxygen tension vs control.
    56. 56. 56 Arterial Lactate was Improved with HBOC-201 in the Severe Hemorrhage Models HBOC-201 HEX/LR = simulated hospital arrival = baseline for HBOC-201 40% controlled HS 0 1 2 3 4 5 6 0 30 60 180 240 55% controlled HS 0 1 2 3 4 5 6 7 8 9 0 15 30 60 180 240 Uncontrolled HS 0 1 2 3 4 5 6 7 8 9 0 30 60 180 240 Uncontrolled HS/TBI - Short Delay 0 1 2 3 4 5 6 7 8 9 0 15 30 45 60 75 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Long Delay 0 1 2 3 4 5 6 7 8 9 0 15 30 45 60 75 90 120 150 180 210 240 270 300 330 360
    57. 57. 57 Blood Loss
    58. 58. 58 Total Blood Loss HBOC-201 HEX/LR Uncontrolled HS 0 10 20 30 40 50 60 70 80 90 100 ml/kg Uncontrolled HS/TBI - Short Delay 0 10 20 30 40 50 60 70 80 90 100 ml/kg Uncontrolled HS/TBI - Long Delay 0 10 20 30 40 50 60 70 80 90 100 ml/kg HBOC-201 Infusion Did Not Increase Hemorrhage Volume in the Uncontrolled Hemorrhage Models
    59. 59. 59 Organ Function and Histopathology
    60. 60. 60 Organ Function and Histopathology • Johnson et al. Crit Care Med. 2006. – 40% Controlled HS – 55% Controlled HS – Uncontrolled HS • York et al. J Trauma. 2003. – Controlled HS • Fitzpatrick et al. J Trauma. 2005. – Controlled HS Liver - mild increase in histopathological changes and transient increases in LFTs with HBOC-201 (Johnson et al. & York et al.) Kidney – Mild increase in histopathological changes with HBOC-201 (Johnson et al. only)
    61. 61. 61 HBOC-201: Effects in Animal Models of Combined Hemorrhagic Shock (HS) and Traumatic Brain Injury (TBI) Potential Advantages of HBOCs for Combined HS and TBI: • enhanced oxygen delivery to the injured brain → prevention of secondary ischemic insults. • small volume resuscitation → avoid the ↑ intracranial hypertension associated with large volume resuscitation
    62. 62. 62 HBOC-201: Effects in Animal Models of HS & TBI Potential Concerns with HBOCs for Combined HS and TBI: – Increased vasoactivity might increase hemorrhage from intracranial and extracranial injury sites – Cerebrovasoconstriction might reduce O2delivery to brain tissue and exacerbate any secondary ischemic insult.
    63. 63. 63 Studies of HBOC-201 in the Setting of Combined HS and TBI • UTHSCSA (Kerby et al. Shock, in press) – rat, moderate controlled hemorrhage & controlled cortical impact TBI • University of Miami (Patel et al. J Trauma, 2006) – swine, severe controlled hemorrhage & fluid-percussion TBI • UCSF (Rosenthal et al. submitted) – swine, moderate controlled hemorrhage & controlled cortical impact TBI • NMRC study (Stern et al. submitted) – swine, severe uncontrolled HS (liver injury) & fluid-percussion TBI
    64. 64. 64 Pre-hospital Resuscitation with HBOC-201 in a Swine Model of Severe Uncontrolled HS/TBI (Stern et al. submitted) • Uncontrolled hemorrhage via liver laceration • Fluid-percussion TBI • Short-delay cohort (30 min) – HBOC-201 - 1 infusion – LR - 1 infusion • Long-delay cohort (75 min) – HBOC-201 - 4 infusions – LR - 4 infusions • FDA-requested study
    65. 65. 65 Survival was Significantly Improved with HBOC-201 for the Long Delay Cohort (Stern et al: HBOC-201 in severe uncontrolled hemorrhage and TBI) HBOC-201 LR Mean Survival Time 0 1 2 3 4 5 6 30 minute delay 75 minute delay hours *p < 0.01 * Uncontrolled HS/TBI - Long Delay 0 20 40 60 80 100 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Time (minutes) % Uncontrolled HS/TBI - Short Delay 0 20 40 60 80 100 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Time (minutes) %
    66. 66. 66 Cerebral Perfusion Pressure (Stern et al: HBOC-201 in severe uncontrolled hemorrhage and TBI) Uncontrolled HS/TBI - Short Delay 0 10 20 30 40 50 60 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Long Delay 0 10 20 30 40 50 60 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 HBOC-201 LR Sagittal Sinus Oxygen Saturation Uncontrolled HS/TBI - Long Delay 0 10 20 30 40 50 60 70 80 90 100 0 15 30 45 60 75 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Short Delay 0 10 20 30 40 50 60 70 80 90 100 0 15 30 45 60 75 90 120 150 180 210 240 270 300 330 360 Markers of Cerebral Perfusion were Significantly Improved with HBOC-201
    67. 67. 67 Brain Tissue Oxygen Tension was Significantly Greater with HBOC-201 (Stern et al: HBOC-201 in severe uncontrolled hemorrhage and TBI) HBOC-201 LR Uncontrolled HS/TBI - Long Delay -5 0 5 10 15 20 25 30 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360 Uncontrolled HS/TBI - Short Delay -5 0 5 10 15 20 25 30 0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360
    68. 68. 68 Other Studies of Controlled HS and TBI Demonstrate Improvement in Multiple Parameters with HBOC-201 CPP Brain Tissue O2 Tension Neuronal Cellular Degeneration / Contusion Volume Rosenthal et al. submitted Patel et al. J Trauma; 2006 Kerby et al. Shock; In press Direction of arrow represents effect of HBOC-201 vs control.
    69. 69. 69 Summary • Adverse Effects – Mild to moderate vasoactivity – Transiently elevated LFTs – Minimal hepatobilliary and renal papillary histopathology • Improved clinical outcomes with HBOC-201 vs. controls – Survival – More rapid stabilization of hemodynamics – Improved tissue oxygenation – Decreased anaerobic metabolism • These improved clinical outcomes were observed across a wide range of HS models, including those with TBI.
    70. 70. 70 A Gerson Greenburg, MD PhD FACS VP, Medical Affairs Biopure Corporation MD University of Chicago PhD Northwestern Univ. Industrial Engineering/Management Science Trauma Fellowship, Cook County Hospital Professor of Surgery USCD, Chief SICU VAMC SD Research Funding VA, US Army, Industry Professor of Surgery, Brown Medical School Surgeon in Chief, Chief Clinical Quality Management, The Miriam Hospital Chair, American College of Surgeons Pre-Post Op Committee President, Xth International Symposium on Blood Substitutes, 2005 Chair, Workshop on Toxicity of Blood Substitutes, NIH 2006 Bibliography (260 publications) includes: Blood substitutes, HBOC chemistry, Transfusion Guidelines
    71. 71. 71 Overview of Clinical Trials: HBOC-201 *Includes two non-surgical studies in Sickle cell anemia subjects Trials Study Population Type of Study Studies N Subjects N Phase 1 Normal Volunteers Safety & tolerance, exercise tolerance, dose and rate escalation, immunologic response 4 93 Phase1/2 General Surgical, etc Prostatectomy, gynaecological, orthopaedic, obstetric, abdominal aortic, liver resection, sickle cell anaemia with and without vaso-occlusive spasm 13 296 Phase 2 Cardiac, General, PCI Cardio-pulmonary Bypass, abdominal aortic aneurysm reconstruction, PCI, non-cardiac 4 266 Phase 3 Surgical Non-cardiac surgical, orthopedic surgery 2 848 Totals 22 1503
    72. 72. 72 Overview of Clinical Trials: HBOC-201 Trials Type Studies N Subjects N Uncontrolled Phase 1 3 15 “Colloid Control” Phase 1 &1-2 5 167 “Crystalloid Control” Phase 1-2 & 2 10 303 “RBC Controlled” Phase 2 and 3 4 1018 Totals 22 1503
    73. 73. 73 The majority of experience with HBOC-201 is with doses of ≤ 6 units Dose HBOC-201 Units (g Hb) Low ≤ 2 U (≤ 60 g Hb) Mid > 2 U – 6 U (>60 –180 g Hb) High > 6 U (> 180 g Hb) No. Subjects (%) 383 (46.4%) 335 (40.6%) 108 (13.0%) 87%
    74. 74. 74 Quantitative assessment of safety data rather than subjective evaluation of safety signals is necessary •Detection of safety signals from pooled adverse event data from all studies (ISS) •Accurate and appropriate quantitative assessment of risk necessary (21 CFR 50.24) •HEM-0115 provides the only homogeneous and sufficiently powered subset (44% all subjects) for accurate and appropriate quantitative assessment of risk
    75. 75. 75 Phase 3 Orthopedic Surgery Study: HEM-0115 • Largest trial; 688 subjects (350 vs. 338) • Powered to detect 1-2% difference in AEs between treatment groups • Safety evaluated by signals as well as significant differences • Any safety signal seen in previous studies was also seen in HEM-0115
    76. 76. 76 The overall pattern of serious and non-serious adverse events is accurately reflected in study HEM-0115 HBOC-201 (n=350) Controls (n=338) P-value* Adverse Events 95% (93%) 91% (88%) 0.024 AEs/Patient 8.47 (7.78) 5.88 (5.48) <0.001 Serious Adverse Events 25% (23%) 18% (18%) 0.014 SAEs/Patient 0.34 (0.34) 0.25 (0.25) 0.062 *Fisher exact test used for incidence and t-Test for events per patient
    77. 77. 77 Randomization 100% The study design of HEM-0115 RBC Treatment No Further Treatment 40% 60% HBOC Treatment RBC Treatment No Further Treatment N= 338 N= 350
    78. 78. 78 • Total fluid crystalloid/colloid administration • Total RBC administered • Higher estimated blood loss • Longer anesthesia time • Longer operating time • Baseline Hb at first treatment (32% <8g/dL) • History of pre-existing disease Factors That Differentiate the HBOC-201 plus RBC from the HBOC-201 Only Group
    79. 79. 79 • First treatment before the end of anesthesia • More cell-saver blood • Time to first treatment shorter • More total AE and AEs/pt • More total SAEs and SAEs/pt Factors That Differentiate the HBOC-201 plus RBC from the Avoidance Group
    80. 80. 80 Major contributors to imbalances in adverse events between treatment arms concentrated in the HBOC-201 plus RBC group • Under-treatment/resuscitation • Delay of adequate treatment • Volume overload: chasing transfusion avoidance • Need exceeded limitations of protocol Driven by Protocol Design Focused on Blood Avoidance without Adequate Bridging---unlikely to be seen in RESUS
    81. 81. 81 Adverse Events: Age Dependence Patients > 70 years of age n (%) Patients < 70 years of age n (%) SAEs HBOC-201 (n=111) RBC (n=111) P value HBOC-201 (n=239) RBC (n=227) P value* Cardiac 14(13%) 5(5%) 0.0525 8(3%) 4(2%) 0.3834 Nervous 3(3%) 0(0%) 0.2466 2(0.8%) 2(0.8%) 1 Death 8(7.2%) 6(5.4%) 0.7836 2(0.8%) 0(0.0%) 0.4993 *Reduction of sample size did not effect significantly the ability to detect a difference between groups (approximately 1.2% vs originally designed 1%).
    82. 82. 82 *System organ class and preferred terms from MedDRA Cardiac Serious Adverse Events All Subjects < 70 Years of Age Cardiac Disorders* HBOC-201 22 (6%) RBC 9 (3%) P-value 0.0266 HBOC-201 8(3%) RBC 4 (2%) P-value 0.3834 Angina Pectoris 1 (0%) 0 1 1(0%) 0 1 Angina Unstable 0 1(0%) 0.4913 0 1(0%) 0.4871 Arrhythmia 1(0%) 0 1 0 0 1 Atrial Fibrillation 1(0%) 1(0%) 1 1(0%) 1(0%) 1 Cardiac Arrest 5(1%) 2(1%) 0.4512 1(0%) 0 1 Cardiac Failure Congestive 3(1%) 0 0.6241 0 0 1 Cardiac Failure 1(0%) 0 1 1(0%) 0 1 Cardiovascular Disorder NOS 0 1(0%) 0.4913 0 1(0%) 0.4871
    83. 83. 83 *System organ class and preferred terms from MedDRA Cardiac Serious Adverse Events All Subjects < 70 Years of Age Cardiac Disorders* HBOC-201 22 (6%) RBC 9(3%) P-value 0.0266 HBOC-201 8 (3%) RBC 4(2%) P-value 0.3834 Bradycardia 1(0%) 0 1 0 0 1 Cardiovascular Respiratory Arrest 3(1%) 0 0.2491 1(0%) 0 1 Myocardial Infarction 4(1%) 2(1%) 0.6864 0 0 1 Myocardial Ischemia 1(0%) 1(0%) 1 1(0%) 1(0%) 1 Pulmonary Oedema NOS 4(1%) 0 0.1241 1(0%) 0 1 Supraventricular Tachycardia 0 1(0%) 0.4913 0 1(0%) 0.4871 Ventricular Tachycardia 1(0%) 1(0%) 1 1(0%) 0 1
    84. 84. 84 *System organ class and preferred terms from MedDRA Renal Serious Adverse Events All Subjects <70 Years of Age Renal and Urinary* Disorders HBOC- 201 7(2%) RBC 4 (1%) P-value 0.5462 HBOC- 201 5(2%) RBC 2 (1%) P-value 0.4507 Anuria 1 (0%) 0 1 1(0%) 0 1 Obstructive Uropathy 0 1(0%) 0.4913 0 0 1 Renal Failure Acute 5(1%) 2(1%) 0.4512 3(1%) 2(1%) 1 Renal Failure Chronic 0 1(0%) 0.4913 0 0 1 Renal Impairment NOS 1(0%) 0 1 1(0%) 0 1
    85. 85. 85 *System organ class and preferred terms from MedDRA CNS Serious Adverse Events All Subjects <70 Years of Age Nervous System Disorders* HBOC-201 5(1%) RBC 2(1%) P-value 0.4512 HBOC-201 2(1%) RBC 2(1%) P-value 1 Cerebrovascular Accident NOS 5 (0%) 0 0.0618 2(1%) 0 0.4993 Reversible Ischemia Neurological Deficit 0 1(0%) 0.4913 0 1(0%) 0.4871 Transient cerebrovascular Events 0 1(0%) 0.4913 0 1(0%) 0.4871
    86. 86. 86 *System organ class and preferred terms from MedDRA Respiratory Serious Adverse Events All Subjects < 70 Years of Age Respiratory Disorders HBOC- 201 7 (2%) RBC 3 (1%) P-value 0.3409 HBOC- 201 5 (2%) RBC 3(1%) P-value 0.7249 Acute Respiratory Distress Syndrome 1(0%) 0 1 0 0 1 Atelectasis 0 1(0%) 0.4913 0 1(0%) 0.4871 Chronic Obstructive Airway Disease Exacerbated 0 1(0%) 0.4913 0 1(0%) 0.4871 Hypoxia 0 1(0%) 0.4913 0 1(0%) 0.4871 Pneumonia Aspiration 2(1%) 0 0.4994 1(0%) 0 1 Respiratory Failure 4(2%) 0 0.1241 0 1(0%) 0.1239
    87. 87. 87 *System organ class and preferred terms from MedDRA Hepatobiliary Serious Adverse Events All Subjects <70 Years of Age Hepatobiliary Disorders* HBOC- 201 5(1%) RBC 0 (0%) P-value 0.0618 HBOC- 201 2(1%) RBC 0(0%) P-value 0.4993 Cholecystitis Acute NOS 1(0%) 0 1 0 0 1 Cholecystitis NOS 2(1%) 0 0.4994 0 0 1 Hepatomegaly 1(0%) 0 1 1(0%) 0 1 Hepatorenal Failure 1(0%) 0 1 1(0%) 0 1
    88. 88. 88 Changes In Systolic Blood Pressure 0 5 10 15 20 25 Baseline Post CTM Day 1 Post Day 2 Post Day 6/Dischage 6 w eek Follow -up Timepoints ChangeinSBPComparedtoBaseline(mmHg) HBOC-201 RBCs
    89. 89. 89 LFT Activity Over Study Period 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 2 0 0 B a s e l i n e D u r i n g C T M D a y 1 P o s t L a s t C T M D a y 6 / D i s c h a r g e 6 W e e k s Sa mpl e P e r i od AST(Units) ASTHBOC ASTRBC Error bars = ± SE 0 10 20 30 40 50 60 70 80 Baseline During CTM Day 1 Post CTM Da6/Discharge 6 Weeks Sample Period ALT(Units) ALTHBOC ALTRBC
    90. 90. 90 Lipase Activity Over Study Period Error bars = ± SE 0 20 40 60 80 100 120 140 160 Baseline During CTM Day 1 Day 2 Day 6 or Discharge Follow-up Units/Liter HBOC-201 RBC
    91. 91. 91 Creatinine & BUN Levels Over Study Period 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Baseline During CTM Day 1 Day 2 Discharge 6-Weeks mg/dL HBOC-201 RBC Error bars = ± SE 0 2 4 6 8 10 12 14 16 18 20 Baseline During CTM Day 1 Day 2 Day 6 or Discharge 6 Weeks BUNmg/dL HBOC-201 RBC
    92. 92. 92 Conclusions • In 22 clinical trials 826 subjects have received HBOC-201 • 87% of the clinical experience with HBOC-201 is with 6 units or less infusions, the proposed dosing for the RESUS study • In the HEM-0115 clinical trial there was : – Reduced allogenic blood use vs red cell group:- 59.4% at day 42 and 96.3% at 24 hours after the first infusion – Greater incidence of AEs and SAEs with HBOC-201 than red cells – Greater incidence of cardiac and CNS SAEs with HBOC-201 than red cells – Age dependency reduction of SAE’s for cardiac, renal, resp & CNS and in mortality for subjects randomized to HBOC-201 • A recommendation for continued close monitoring of cardiac, CNS and renal systems with HBOC-201 infusion, to predict adverse trends, so that interventions can mitigate the safety risks
    93. 93. 93 Given there is reasonable risk associated with the use of HBOC-201 and the potential benefits to patients in hemorrhagic shock apparent there are compelling reasons to lift the clinical hold on HBOC-201 and permit this trial to go forward.
    94. 94. 94 RESUS IND and Clinical Hold Daniel Freilich, MD, CDR, MC, USN RESUS Sponsor Lead Investigator Naval Medical Research Center, Silver Spring, MD
    95. 95. 95 “FDA has placed the RESUS IND on Clinical Hold for three primary reasons” 1. Safety concerns based on i. AEs seen in previous clinical studies ii. Potential risks related to product dosing and patient monitoring limitations 2. Heterogeneity in the expected mortality of individual subjects meeting the inclusion criteria for RESUS 3. Insufficient basis for estimating the effect size of HBOC-201 for possible reduction in mortality
    96. 96. 96 Outline of discussion points 1. Traumatic HS: public health problem, unsatisfactory treatment 2. RESUS: program evolution, transformational impact on trauma care 3. Target population: high mortality (58%), reasonable homogeneity 4. Preclinical database: prospect for benefit, 75% mortality reduction 5. Mortality reduction effect size: 15% conservatively estimated
    97. 97. 97 Outline of discussion points—continued 6. Clinical database: benefit, reasonable safety in overall pop., especially in younger sub-pop. 7. Dosing Guidelines: extensive preclinical and clinical rationale 8. Non-serious AEs: insignificant effect on benefit:risk 9. Monitoring limitations: mild vasoactivity, inclusion criteria, training 10. Risk mitigation strategies: further optimize benefit:risk 11. Qualitative and semi-quantitative analyses: robustly predict highly favorable benefit:risk in RESUS
    98. 98. 98 Background
    99. 99. 99 Improved prehospital HS resuscitation is an urgent unmet medical need • Trauma is the leading cause of death in young adults – 110,000 in U.S., 4.7 million worldwide • HS accounts for 30% of trauma deaths – 36,000 in U.S., 1.6 million worldwide – Most common potentially preventable cause • HS accounts for 45-68% of 2,900 U.S. military deaths in Operation Iraqi Freedom (OIF) – 1,300-2,000 • Most trauma deaths occur prior to hospital arrival – Civilian urban 50%, civilian rural 80%, military 90%
    100. 100. 100 HBOC-201 may equilibrate prehospital and in- hospital resuscitation Current standard HS treatment: • Prehospital: resuscitation with crystalloid/colloid fluids – Restore intravascular volume but not oxygen carrying – Dilute oxygen content  fail to correct tissue hypoxia  anaerobic metabolism  decompensated HS • In-hospital: blood transfusions – Restore intravascular volume and oxygen content – Often live-saving but rarely available in prehospital setting • HBOC-201 – Restores intravascular volume, carries oxygen, available in prehospital setting
    101. 101. 101 HBOC-201 is one component of a comprehensive strategy to diminish morbidity/mortality from HS after 911 and in The War on Terrorism • Force Protection – Body armor • Field resuscitation – Hemostasis • Local (bandages, dressings, and tourniquets) • Systemic (rfVIIa) – Resuscitative fluids • Hemolink® • Hemopure® (HBOC-201) • PolyHeme®
    102. 102. 102 HBOC-201 (Hemopure® ) (bovine polymerized hemoglobin) • Modified bovine hemoglobin 32.5 g in 250 ml bag modified LR • U.S. source • Highly purified • > 97% gluteraldehyde-polymerized • Oxygen dissociation curve right-shifted (P50 40 mm Hg) • Universally compatible • Stable without refrigeration for 3 years
    103. 103. 103 Objective criteria were used to select HBOC-201 for development for a traumatic HS indication • Improved resuscitative fluid – Replenishes intravascular volume and transports oxygen • Highly polymerized and purified – < 2-3% tetrameric hemoglobin, low infection transmission risk • Improved logistical requirements – Low volume/weight – Stable without refrigeration (clinical data with non-refrigerated product) – Universally compatible and easy to administer • Substantial preclinical and clinical data – Survival and physiologic benefits in multiple preclinical studies – Efficacy and reasonable safety in > 800 subjects in “high bar” comparisons • Independent Navy-sponsored/directed trial – Comprehensive community disclosure of potential benefits/risks – No withholding of standard care
    104. 104. 104 RESUS protocol under review is product of 5 years of comprehensive deliberation 2001 Sep Program conceived 2003 Apr RESUS Advisory Board established May Protocol submitted to NMRC IRB 2004 Feb NMRC assumes responsibility as regulatory sponsor Apr Pre-IND meeting with OBRR 2005 Apr NMRC completes OBRR-directed swine HS/TBI study Apr Protocol provisionally approved by NMRC IRB June IND application submitted to OBRR July IND placed on Clinical Hold Sep NMRC submits Complete Response to OBRR Oct NMRC submits Complete Response to OBRR 2006 Jan NMRC submits Complete Response to OBRR July BPAC meeting scheduled, cancelled Aug NMRC submits Complete Response to OBRR Dec BPAC rescheduled
    105. 105. 105 RESUS may have a transformational effect on trauma care Potential lives saved annually if RESUS is successful (15% mortality reduction): • RESUS inclusion criteria (efficacy) – RESUS trial 48 (total) – U.S 3,600 – Worldwide 156,000 • General HS population (effectiveness) – OIF 200-300 – U.S. 5,400 – Worldwide 234,000
    106. 106. 106 HBOC-201 clinical database Pivotal Phase 3 Orthopedic Trial (HEM-0115)
    107. 107. 107 The HEM-0115 trial enrolled mostly older adults undergoing orthopedic surgery • Trial design – Randomized, controlled, single-blinded • Setting/population – Perioperative anemia in orthopedic surgery subjects • Mean age – 61 years old • Intervention – HBOC-201 (n = 350, max 10 units, up to 6 days) vs. RBC (n = 338) • Primary aims – Efficacy—blood transfusion avoidance, safety, tolerability
    108. 108. 108 High blood transfusion avoidance confirmed efficacy in HEM-0115 > 95% in first 24 hours, 59% overall  Predicts transfusion avoidance in RESUS  Predicts “research holds out prospect of direct benefit” (21 CFR 50.24)  But prolonged CTM exposure and transfusion avoidance increased risk of AEs (high bar)
    109. 109. 109 There were a number of key adverse safety signals in HEM-0115 Overall • AEs • SAEs Cardiac • Cardiac SAEs • MI AEs • Troponin elevation • Heart failure/fluid overload AEs* • Cardiac arrest AEs** Neurologic • CVA (stroke) • Cerebral ischemic High blood pressure Mortality
    110. 110. 110 Overall safety signals were more frequent with HBOC-201 than RBC in HEM-0115 (overall population) HBOC-201 % RBC % Group difference % P Overall AEs 95.4 91.1 4.3 0.03 Overall SAEs 25.1 17.4 7.7 0.02
    111. 111. 111 Some cardiac safety signals were more frequent with HBOC-201 than RBC in HEM-0115 (overall population) HBOC-201 % RBC % Group difference % P Cardiac SAEs 6.3 2.7 3.6 0.03 MI AEs 1.1 0.6 0.6 0.7 Myocardial ischemia AEs^ 2.3 1.8 0.5 0.8 Troponin elevation 13.2 1.6 11.6 0.0003 HF/fluid overload AEs* 2.3 0.3 2.0 0.002 Cardiac arrest AEs** 2.3 0.6 1.7 0.1
    112. 112. 112 Cerebral ischemic AEs were more frequent with HBOC-201 than RBC in HEM-0115 (overall population) HBOC-201 % RBC % Group difference % P CVA AEs 1.7 0 1.7 0.03 All cerebral ischemic AEs 2.0 0.6 1.4 0.07
    113. 113. 113 Elevated BP safety signals were more frequent with HBOC-201 than RBC in HEM-0115 (overall population) HBOC-201 % RBC % Group difference % P Hypertension AEs 12.3 5.3 7.0 0.002 Hypertension SAEs 0.6 0 0.6 0.5 Peak SBP response > 140 mm Hg 56 28 28 0.0001
    114. 114. 114 Mortality was not significantly different in HEM-0115 (overall population) HBOC-201 % RBC % Group difference % P Mortality 2.9 1.8 1.1 0.2
    115. 115. 115 NMRC conclusions from HEM-0115 trial “…in a relatively older population undergoing orthopedic surgery, overall clinical outcome is better with RBC than HBOC-201…but remarkably, minimally so, and where safe and expeditious transfusions are available (i.e., in-hospital setting in developed countries). Thus, HBOC-201 is likely to have significant clinical utility where safe and rapidly available transfusions do not exist (e.g., prehospital, military, disaster stockpiling, and under-developed country settings).” “Risks…are reasonable in relation to what is known about the medical condition…and risks and benefits of standard therapy”
    116. 116. 116 HEM-0115 clinical database Pivotal Phase 3 Orthopedic Trial (younger sub-populations)
    117. 117. 117 Sub-populations stratified by age Population Mean age (yrs) N HBOC-201 N RBC > 70 years old# 77.0 111 111 Overall population 60.8 350 338 < 70 years old* 53.1 239 227 < 50 years old^ 39.9 84 65
    118. 118. 118 Key adverse safety signal group differences were decreased or absent in younger subjects 0 5 10 15 20 25 O verallSA EsC ardiac SA Es M IA EsTroponin elev H F/fluid overload*C ardiac arrest C erebralisch A Es C V A A Es M ortality % > 70 years old Overall pop < 70 years old < 50 years old
    119. 119. 119 No unreasonable overall SAE risk in younger subjects HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.005 35.1 25.1 20.5 20.6 23.4 17.5 14.5 14.5 11.7 7.6 6.0 6.1 0 5 10 15 20 25 30 35 40 > 70 y/o General < 70 y/o < 50 y/o OverallSAEincidence(%) HBOC RBC Delta
    120. 120. 120 No unreasonable cardiac SAE risk in younger subjects HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.002 12.6 6.3 3.3 2.1 4.5 2.7 1.8 0 8.1 3.6 1.5 2.1 0 2 4 6 8 10 12 14 > 70 y/o General < 70 y/o < 50 y/o CardiacSAEincidence(%) HBOC RBC Delta
    121. 121. 121 No unreasonable MI AE risk in younger subjects MI in HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.01 3.6 1.1 0.0 0.0 1.8 0.6 0.0 0.0 1.8 0.6 0.0 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 > 70 y/o General < 70 y/o < 50 y/o MIAEincidence(%) HBOC RBC Delta
    122. 122. 122 No unreasonable heart failure/fluid overload risk in younger subjects HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.01 5.4 2.3 0.8 0.0 0.9 0.3 0.0 0.0 4.5 2.0 0.8 0.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 > 70 y/o General < 70 y/o < 50 y/o Heartfailure/fluidoverload(%) HBOC RBC Delta
    123. 123. 123 No unreasonable cerebral ischemic risk in younger subjects 3.6 1.7 0.8 00 0 0 0 3.6 1.7 0.8 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 > 70 y/o General < 70 y/o < 50 y/o CVAAEincidence(%) HBOC RBC Delta CVA (stroke) AEs in HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.08 Cerebral isch AEs in HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.04 Mean age in HBOC-201 subjects: 75.6 + 3.3 years old 4.5 2 0.8 00 0.6 0.9 1.4 4.5 1.4 0.0 -1.4 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 > 70 y/o General < 70 y/o < 50 y/o CerebralischemicAEincidence(%) HBOC RBC Delta
    124. 124. 124 No unreasonable cardiac arrest or mortality risk in younger subjects 7.2 2.9 0.8 0.0 5.4 1.8 0.0 0.0 1.8 1.1 0.8 0.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 > 70 y/o General < 70 y/o < 50 y/o Mortality(%) HBOC RBC Delta Mortality in HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.002 5.4 2.3 0.8 1.0 1.8 0.6 0.0 0.0 3.6 1.7 0.8 1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 > 70 y/o General < 70 y/o < 50 y/o CardiAcarrestAE(%) HBOC RBC Delta Cardiac arrest in HBOC-201 subjects: > 70 years old vs. < 70 year old, p = 0.01
    125. 125. 125 NMRC conclusions from HEM-0115 trial “Our finding of an improved safety profile in sub- populations of subjects more closely resembling younger subjects who would be enrolled in acute trauma trials, predicts that the relative safety of HBOC- 201 will be improved in such trials.” “Risks…are reasonable in relation to what is known about the medical condition…and risks and benefits of standard therapy”
    126. 126. 126 Assumptions used to assess 21 CFR 50.24 benefit:risk requirements for RESUS
    127. 127. 127 Benefit:risk requirements of 21 CFR 50.24 1. “human subjects are facing a life-threatening situation” 2. “available treatments are unproven or unsatisfactory” 3. “research holds out the prospect of direct benefit” 4. “preclinical studies…support…potential…to provide…benefit” 5. “Risks associated with the intervention are reasonable in relation to what is known about the medical condition…and risks and benefits of standard therapy”
    128. 128. 128 1. Predicted mortality is 58.1% in the RESUS target population receiving standard care Two redundant and confirmatory sources: U. of Alabama/U. of Maryland (UAB/UMD) (prehospital) – N 497 – Mortality 58.1% – 95% CI 51.8-64.3 National Trauma Data Bank (NTDB) (in-hospital) – N 4,568 – Mortality 55.8% – 95% CI 53.8-57.8% • “subjects are facing a life-threatening situation” • “available treatments are…unsatisfactory”
    129. 129. 129 2. & 3. Preclinical HS studies with HBOC-201 show improved outcome and predict potential for benefit, including decreased mortality, in humans in RESUS • Survival benefit • Consistent physiologic benefits • Mild adverse events • Critical mass of data is in swine • Veterinary product, HBOC-301, is FDA-approved and marketed for 8 years for canine anemia • “preclinical studies…support…potential…to provide…benefit” • “research holds out…prospect of direct benefit”
    130. 130. 130 4. As efficacy data from preclinical and prior clinical trials show that HBOC-201 effectively transports oxygen, similar effects are predicted in RESUS • In vitro, HBOC-201 transports oxygen efficiently • In animals, HBOC-201 increases tissue oxygenation, and decreases anaerobic metabolism, blood lactate, and base deficit • In a Phase 1 trial, HBOC-201 maintained exercise performance and decreased blood lactic acid • In the Phase 3 HEM-0115 trial, HBOC-201 led to > 95% transfusion avoidance acutely • “preclinical studies…support…potential…to provide…benefit” • “research holds out…prospect of direct benefit”
    131. 131. 131 5. In the prior Phase 3 HEM-0115 trial, the AE profile of HBOC-201 was inferior to RBC in the overall mainly older population • Incidences of a number of key adverse safety signals were higher in HBOC-201 than RBC subjects
    132. 132. 132 6. Safety data in overall populations in prior HBOC-201 surgery/orthopedics trials are unlikely to accurately predict benefit:risk in RESUS HEM-0115 RESUS Potential benefit Transfusion avoidance Survival Clinical setting Elective surgery/orthopedics (inhospital) Acute HS (prehospital) Population Mainly elderly Mainly younger adults Exposure Prolonged blood transfusion substitution Brief oxygen bridge Physiologic state Mostly hemodynamically stable Hemodynamically unstable Comparator Gold standard RBC transfusion Crystalloid fluid Study design Asymmetric Symmetric
    133. 133. 133 6a. Even if one assumes prior trials accurately predict benefit:risk in RESUS, safety data in overall populations predict reasonable risk in RESUS • Group differences in key safety signals were relatively low when considered in context of: – high mortality in RESUS – potential for survival benefit in RESUS • “risks…are reasonable in relation to…the medical condition”
    134. 134. 134 6b. Even if one assumes prior trials accurately predict benefit:risk in RESUS, key safety signal group differences were narrowed in younger subjects a. Group differences were reduced in < 70 and < 50 year olds b. Improved safety in subjects without cardiovascular disease c. Trauma patients are a younger and healthier group • Lower incidence of co-morbid cardiovascular disease • HEM-0115 71% vs. NTDB 7% (Millham F, J Trauma 2004)  Lower risk for cardiovascular and cerebral ischemic SAEs • “risks…are reasonable in relation to…the medical condition”
    135. 135. 135 7. Favorable interim data from HEM-0125 S. Africa traumatic HS ER trial further predict reasonable risk in RESUS • Population similar to RESUS (but standard care comparator-- RBC)  deno benefit • Equivalent mortality • Improved safety profile in HBOC-201 subjects (trends) – Decreased AEs/subject and SAEs/subject – Decreased fluid and blood transfusion requirements • DSMB (U.S.) recommendation to continue trial • “risks…are reasonable in relation to…the medical condition”
    136. 136. 136 8. Safety data from prior Diaspirin Cross-linked Hemoglobin (DCLHb) trauma trials are unlikely to accurately predict benefit:risk in RESUS • HBOC-201 is less vasoactive than DCLHb • Different study designs – Increased mortality in in-hospital DCLHb trial (Sloan 1999) – Equivalent mortality in prehospital DCLHb trial (Kerner 2003) • Improved understanding of vasoactivity prompted incorporation of multiple risk mitigation strategies in RESUS • “risks…are reasonable in relation to…the medical condition”
    137. 137. 137 9. Preclinical and clinical data support RESUS Dosing Guidelines • Multiple HS preclinical studies: improved outcome with doses and rates of infusions similar to or higher than RESUS • HEM-0115 Phase 3 orthopedics trial: safety was reasonable (especially in younger subjects) in large database with doses similar to RESUS • HEM-0125 traumatic HS trial: equivalent mortality and favorable safety profile with doses and rates of infusions similar to or higher than RESUS (interim data) • “risks…are reasonable in relation to…the medical condition”
    138. 138. 138 10. Multiple protocol risk mitigation strategies further diminish risk in RESUS I. Optimization of target population selection II. Standardization and optimization of care with practice guidelines and training III. Allowance for concomitant standard care IV. Inclusion of comprehensive surveillance methods • “risks…are reasonable in relation to…the medical condition”
    139. 139. 139 I. Target population selection maximizes benefit and minimizes risk 1. Targeting a population with severe HS without access to blood transfusions – “exsanguinating hemorrhage” – “delay in emergency care” 2. Exclusion of elderly subjects 3. Hypotension and tachycardia criteria for re-infusion of HBOC-201 • “research holds out…prospect of…benefit…” • “risks…are reasonable in relation to…the medical condition”
    140. 140. 140 II. Standardization and optimization of care, training, and allowance for standard care minimize risk 4. Thorough EMS and trauma center training 5. Access to standard IV fluids during the prehospital period 6. Improved standardization of prehospital care 7. Access to standard blood transfusions immediately upon availability 8. Standardization of in-hospital care • “risks…are reasonable in relation to…the medical condition”
    141. 141. 141 III & IV. Comprehensive surveillance methods allow early detection and action and minimize risk 9. Prospective “increased BP” and “hypertension” coding definitions 10. Extensive secondary outcome measurements 11. “Elevated blood lactate” relative stopping criterion 12. HBOC-201 infusion stopping criterion (SBP > 120 mm Hg) 13. Expedited AE reporting to DMC and FDA 14. Hypoperfusion markers reports 15. Early interim analyses
    142. 142. 142 RESUS IND Clinical Hold* * Note: all consultant reports included in FDA’s BPAC Issue Summary were completed prior to incorporation of significant RESUS IND and protocol modifications made Jul-Oct 2006 (one included updated comments)
    143. 143. 143 FDA: “There is inadequate information to assess whether risks and benefits are reasonable…”
    144. 144. 144 There is more information than usual for an IND • Substantial preclinical database – 41 trauma-related studies (mainly swine) – 22 HS studies (+ TBI) • Substantial clinical database – 22 Phase 1-3 clinical trials, 1,503 subjects (826 HBOC-201) – Mainly surgical patients – 62 with stable trauma – 20 with traumatic HS • Post-marketing experience in S. Africa* – 336 HBOC-201 patients – 14 acute trauma * Levien L, ISBT Science Series, 2006
    145. 145. 145 FDA: “The toxicity profile of HBOC-201 precludes study in field trauma…unless the target population is projected to have an extremely high mortality risk…with exsanguinating hemorrhage …or…rapid bleeding with prolonged delay to emergency care”
    146. 146. 146 RESUS targets a population meeting OBRR’s criteria • “Exsanguinating hemorrhage” – Severe HS with projected mortality > 1 in 2 • “Rapid bleeding with prolonged delay to emergency care” – Inclusion criteria include “delay to emergency care” – Excludes some urban trauma (with short transportation time) • “risks…are reasonable in relation to…the medical condition”
    147. 147. 147 FDA: “Entry criteria for RESUS suggests that the patient population likely to be heterogeneous”
    148. 148. 148 • Mortality high in all RTS stratifications (reasonably homogeneous pop.) (left) • Target pop. has normalized (bell-shaped) distribution (right) • Typical trauma trial U-shaped distribution excluded (right) Mortality (%) N Stratification of RESUS target population based on RTS ranges reveals reasonably homogeneous mortality and normalized distribution (UAB/UMD)
    149. 149. 149 Stratification of RESUS target population based on RTS ranges reveals reasonable mortality homogeneity and distribution (NTDB) • Mortality high in all RTS stratifications (reasonably homogeneous pop.) (left) • Target pop. reasonably distributed (right) • Contrast with FDA RTS ranges from www.trauma.org (page 15) Mortality (%) N
    150. 150. 150 FDA: “For crystalloid/colloid controlled surgery studies…, the imbalances…persisted”
    151. 151. 151 “Crystalloid/colloid” studies have minimal impact on prediction of benefit:risk in RESUS • Key adverse signal: MI: HBOC-201 5/177 (2.8%) (three > 70 y/o) vs. control 1/131 (0.8%), p > 0.05 • Potential confounders related to prediction of benefit:risk in RESUS – High Hb trigger (10-12 g/dL): excludes benefit – Minimal blood loss: excludes benefit – Top load: increases vasoactivity risk – Blood avoidance endpoint: comparator includes RBC, prolonged exposure to CTM, delay in standard care  increases risk – 2:1 enrollment: increases expected observations – Heterogeneous studies: confound combined analysis – Early in HBOC-201 development: learning, risk mitigation  Setting of risk with minimal or no benefit  Demonstrates risk of MI in some clinical settings  No significant effect on overall benefit:risk in RESUS
    152. 152. 152 FDA: “…preclinical studies do not support… potential…to provide… direct benefit…”
    153. 153. 153 Preclinical data predict reduced mortality in RESUS • Mortality: reduced in all models combined – HBOC-201 12% vs. control 47%, p < 0.0001 – Group difference 35% – Reduction 75% (effect size) • Mortality: dramatically reduced in severe HS models – HBOC-201 17% vs. control 93%, p < 0.0001 – Group difference 76% – Reduction 82% (effect size)
    154. 154. 154 Preclinical data predict improved hemodynamic stabilization without unreasonable risk in RESUS • More rapid stabilization • Mild to moderate vasoactivity without increased hemorrhage – Mildly higher MAP, MPAP, and vascular resistance • CI returns to baseline in all models – Lower than control in less severe HS, not different in severe HS • PCWP/CVP equivalent • “risks…are reasonable in relation to…the medical condition”
    155. 155. 155 Preclinical data predict tissue oxygenation benefit in RESUS • Improved direct measures – Increased transcutaneous*, brain, and sagittal sinus oxygenation • Improved indirect measures (anaerobic metabolism) – Decreased lactic acid and base deficit in severe HS (blood and sagittal sinus) * Associated with improved outcome: Shoemaker WC, Chest 2001; Martin M, J Ped Surg 2005
    156. 156. 156 Preclinical data predict equivalent or improved myocardial effects in RESUS • No evidence of heart failure/fluid overload in HS – Mildly lower cardiac output – Equivalent LV filling pressure (PCWP and CVP) • No evidence of cardiac injury in HS – Equivalent troponin-I – Equivalent to improved histopathology • Decreased MI size in acute coronary stenosis models
    157. 157. 157 Preclinical data predict equivalent or improved respiratory effects in RESUS • No evidence of hypoxemia – Mildly decreased oxygen saturation with equivalent PO2 – Improved ventilator weaning • No evidence of pulmonary edema – Equivalent interstitial and alveolar edema • No evidence of pneumonitis
    158. 158. 158 Preclinical data predict mild GI/hepatic side effects without unreasonable risk in RESUS • No evidence of jejunal injury • Mild hepatic and pancreas side effects – Transiently elevated LFTs and lipase* – Mild hepatobiliary pathology in 3 of 4 studies – Mild hepatonecrosis in 1 of 4 studies – Equivalent pancreas pathology * In HEM-0115, incidence of lipase elevation was significantly lower in < 70 year old subjects
    159. 159. 159 Preclinical data predict mild renal side effects without unreasonable risk in RESUS • Mildly decreased urine output – Mainly with less severe HS – No oliguria • Slightly increased BUN and creatinine • Mild renal pathology – No cortical or medullary injury – Mild papillary pathology in 1 of 3 studies
    160. 160. 160 Preclinical data predict neurologic benefit without unreasonable risk in RESUS • No neurotoxicity in vitro • Improved brain oxygenation • Improved CPP* • Improved autoreactivity • Decreased contusion volume • Improved histopathology * Associated with improved outcome: Pietropaoli JA J Trauma 1992; Rosner MJ, J Neurosurg 1995
    161. 161. 161 Preclinical data predict hematologic benefits in RESUS • Hematology – Improved blood oxygen content – Decreased transfusion requirements (incidence, dose, delay)* – Mild methemoglobinemia – Equivalent effects on hemostasis • Equivalent innate immune responses – Immunophenotype, adhesion markers, cytokines, apoptosis • Equivalent effects on oxidative potential – Tissue 3-nitrotyrosine * Independently predict adverse outcome in trauma (mortality, MOF, SIRS, infection, ICU admission and LOS)
    162. 162. 162 Preclinical data predict significant benefit without unreasonable risk in RESUS • Overall results – Beneficial survival and physiologic effects, with mild AEs • Strengths – Numerous HS studies in a variety of species (mainly swine) – Multiple institutions, many independently funded – Variety of HS models (controlled/uncontrolled hemorrhage, TBI) – Model specific (soft tissue injury, anesthesia/sedation, follow-up) – Blinded – Redundant and highly significant results • Limitations – Simulation of RESUS conditions – Young animals without co-morbid conditions – Confounders (anesthesia, ketorolac)
    163. 163. 163 FDA: “…our concerns that when a vasoactive HBOC (DCLHb or HBOC-201) is infused…, the two endpoints typically used by EMT providers to estimate whether to give additional product—BP and HR—are insensitive surrogates of volume status”
    164. 164. 164 Vasoactivity is characteristic of all HBOCs Mechanism – Nitric oxide binding by tetrameric Hb – Mean mw effects on distribution within blood vessels – Response to increased tissue oxygenation – Endothelin activation – Arachidonic acid inhibition – Adrenergic receptor activation 1 3 31 32 100 0 10 20 30 40 50 60 70 80 90 100 PolyHeme HBOC-201 Hemolink HBOC-301 DCLHb TetramericHb(%)
    165. 165. 165 As HBOC-201 elicits mainly mild to moderate BP responses, risk of adverse effects on prehospital monitoring of fluid status is low – Preclinical HS studies* • Most MAP responses mild to moderate (94%) • Lower MAP ∆ responses with increasing HS severity – Clinical studies (HEM-0115) • Most SBP responses mild to moderate (94%) • No severe SBP responses related to CTM • SBP responses lower in younger and hypotensive subjects * Rice J, J Trauma 2006
    166. 166. 166 RESUS fluid re-infusion criteria (hypotension and tachycardia): – Preclinical HS studies* • Hypotension is sensitive in severe HS • Tachycardia is sensitive in moderate and severe HS – Clinical studies (prehospital DCLHb HOST trial**) • HR equivalent with DCLHb and NS * Rice J, J Trauma 2006, ** Kerner T, Intensive Care Med 2003 As preclinical HBOC-201 HS studies show that RESUS fluid re-infusion criteria are sensitive, risk of adverse effects on prehospital monitoring of fluid status is low
    167. 167. 167 Summary: HBOC-201 is unlikely to significantly adversely affect prehospital monitoring in RESUS • Low a priori risk due to mild to moderate vasoactivity – Low tetrameric Hb content – Mild to moderate BP responses without increased hemorrhage – Highly sensitive RESUS fluid re-infusion criteria • Standard EMS training includes use of multiple clinical parameters to evaluate fluid status • Risk mitigation strategies further reduce risk – Target population with severe HS – Exclusion of elderly – SBP > 120 mm Hg stopping criterion – Allowance for standard fluids if indicated – Comprehensive training and surveillance
    168. 168. 168 FDA: “…increases in SBP to 220 mm Hg have been noted with HBOC-201” 4 out of 826 subjects (< 0.5%)
    169. 169. 169 Rare hypertension SAEs in euvolemic and hypertensive subjects do not affect benefit:risk in hypovolemic/hypotensive subjects in RESUS 1. HEM-0115 (61 y/o) (“uncontrolled HTN, “tachycardia”) – Unrelated, euvolemic & hypertensive when CTM started, post-10th dose and 5 days of exposure, resolved 2. HEM-0115 (39 y/o) (“persistent HTN”) – Unrelated (43 days post-CTM), euvolemic when CTM started, resolved 3. COR-0001 (54 y/o) (“severe HTN not responding to meds”) – Related, euvolemic & hypertensive when CTM started, resolved 4. COR-0001 (60 y/o) (“severe HTN, EMD, MI, CVA”) – HTN related, complications unrelated, euvolemic & hypertensive when CTM started, resolved
    170. 170. 170 FDA: “There are very limited clinical data on dose and rate of administration using HBOC-201 to support the RESUS dosing guidelines”
    171. 171. 171 RESUS Dosing Guidelines – Dose 500 ml (2 units) (7 ml/kg) – Default* infusion duration 10 min – Default* infusion rate 50 ml/min (0.7 ml/kg/min) – Maximum number of doses 3 – Maximum dose 1,500 ml (6 units) (21 ml/kg) * Default recommendation is for most subjects in RESUS; duration/rate in individual subjects is based on clinical acuity
    172. 172. 172 Extensive preclinical HS data establish evidence basis for RESUS dose, infusion rate, and max. dose – Improved outcome with similar or higher doses and higher infusion rates than in RESUS Reference Model Dose (ml/kg) vs.RESUS Infusion rate (ml/kg/min) vs. RESUS Total dose (ml/kg) vs. RESUS Philbin,Rice, Gurney Cont/uncont HS 5-10 0.7-1.4X 0.5-1 0.7-1.4X 30 1.4X Katz UncontHS 45-90 6.4-12.8X 3-6 4.2-8.4X 135 6.4X Stern Uncont HS/TBI 10 1.4X 1 1.4X 10-40 0.5-1.9X Manning UncontHS 10-45 1.4-6.4X 2.6-10 3.7-14X 313 15X Patel ContHS/TBI 6 0.85X notreported - 6 0.85X Rosenthal ContHS/TBI 6 0.85X 0.6 0.85X 6 0.85X
    173. 173. 173 Extensive HEM-0115 clinical data with < 6 units of HBOC-201 predict reasonable risk (especially in younger subject) and support RESUS max. dose SAE and mortality incidence in HEM-0115 stratified by dose 34 2.1 21 0.8 17 0.5 0 5 10 15 20 25 30 35 40 Overall SAEs Mortality Groupdifferenceinincidence(%) > 6 units All < 6 units * Limitation: possible confounding by patient condition • 81% (285/350) received < 6 units (HEM-0115)  reasonable risk • Key safety signal group differences lower with < 6 units, especially in < 70 year olds*
    174. 174. 174 Limited HEM-0115 clinical data with infusion rate > 25 ml/min predict reasonable risk and support RESUS infusion rate * Limitation: small N: first infusion HBOC 17 vs. RBC 14, any infusion HBOC 30 vs. 17 – SBP responses similar to overall pop.* – First infusion: 10 vs. 17 mm Hg – Any infusion: 18 vs. 9 mm Hg – Key safety signal group differences similar to overall pop.*
    175. 175. 175 Interim HEM-0125 clinical data in trauma patients with dose and infusion rate similar to RESUS predict reasonable risk and support RESUS dosing Dosing HEM-0125 RESUS • Volume (ml) 305 + 55 500 • Duration (min) 18 + 4 10 • Rate (ml/min) 73 + 15 50 Results HBOC-201 Control • Mortality 4/10 (40%) 4/10 (40%) • AEs/subject 9.1 17 • SAEs/subject 1.0 1.4 • Asang fluid vol/subject 15,716 + 2,570 30,242 + 8,088 • RBC transf/subject 5.4 + 1.2 16.8 + 5.7 (p=0.08)
    176. 176. 176 Extensive DCLHb clinical data in trauma patients in HOST trial show similar SBP responses with dose similar to RESUS (1,000 ml), predict reasonable risk and support RESUS maximum dose
    177. 177. 177 Preclinical and clinical data support RESUS Dosing Guidelines Maximum dose 1. Extensive preclinical data 2. Extensive clinical data with reasonable safety, especially in younger subjects (HEM-0115) 3. Limited clinical trauma data with favorable safety (HEM-0125) 4. Similar SBP responses in DCLHb prehospital trauma trial Infusion rate 1. Extensive preclinical data 2. Limited clinical data with reasonable safety (HEM-0115) 3. Limited clinical trauma data with favorable safety (HEM-0125)
    178. 178. 178 Non-serious AEs
    179. 179. 179 Some non-serious safety signals reflect characteristic side effects of HBOCs (irrespective of trial type) • Transient elevation of LFTs and lipase • Jaundice and skin discoloration • Gastrointestinal symptoms • Higher BP responses • Mild methemoglobinemia • Mild oxygen desaturation [with normal oxygen tension] • Oliguria ?
    180. 180. 180 Non-serious AE database has minimal relevance to prediction of benefit:risk in RESUS • Morbidity trial (HEM-0115) – Important in overall benefit:risk analysis • Mortality trial (RESUS) – Background noise (akin to nausea AEs in chemotherapy trials) – Require risk mitigation strategies to reduce risk • Survival and SAEs should be key safety parameters for prediction of benefit:risk in RESUS
    181. 181. 181 Non-serious safety signals such as oliguria do not significantly affect RESUS benefit:risk prediction • HEM-0115 – Oliguria AEs more frequent • HBOC-201 39/350 (11%) vs. RBC 16/338 (5%), p = 0.002 – Acute renal failure AEs equivalent • 5/350 (1.4%) vs. 4/338 (1.2%), p = 1.0 • RESUS – Preclinical HS studies show low risk – Extrapolation from prior surgical clinical trials may be inaccurate – Awareness led to mitigation strategies to minimize fluid under- resuscitation – Insignificant risk in context of high mortality RESUS trial
    182. 182. 182 Troponin elevation but not MI was more frequent with HBOC-201 in HEM-0115 HBOC-201 % RBC % Group difference % P > ROC (%) 13.2 1.6 11.6 0.0003 Mean age (yrs) 65 MI AEs 1.1 0.9 0.2 0.7 ROC = Receiver Operator Curve
    183. 183. 183 Definition of MI (ESC/ACC consensus, Alpert, 2000) “Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: 1) Typical rise and gradual fall (troponin)…of biochemical markers of myocardial necrosis with at least one of the following: a) Ischemic symptoms b) development of pathologic Q waves on the ECG; c) ECG changes indicative of ischemia (ST segment elevation or depression); or d) coronary artery intervention (e.g., coronary angioplasty). 2) Pathologic findings of an acute MI”
    184. 184. 184 Misdiagnosis of MI by troponin (Khavandi A, Emerg Med J, 2005) “…there has been widespread misinterpretation of the new definition, and troponin concentrations are frequently assumed to reflect myocardial infarction without corroborative evidence from the patient’s history or ECG”
    185. 185. 185 That most were low level troponin T elevations and fewer met ESC/ACC definition in HEM-0115, predicts lower risk in RESUS Subject ng/L AHA Scientific Statement Criteria (Luepker RV, Circulation 2003) 1 0.10 Isolated 2 0.12 Isolated then detectable < ROC 3 0.12 Isolated then detectable < ROC 4 0.12 Isolated then detectable < ROC 5 0.12 Isolated then detectable < ROC 6 0.12 Isolated 7 0.13 Isolated then detectable < ROC 8 0.16 ↑ Pre-CTM 9 0.17 ↑ Pre-CTM 10 0.17 Serial 11 0.18 Isolated 12 0.24 Isolated 13 0.26 Isolated then detectable < ROC 14 0.26 Serial 15 0.31 Serial 16 0.58 Serial (MI) 17 0.89 Serial 18 5.6 ↑ Pre-CTM*  Low level elevations akin to PCI ‘troponin leaks’ (Cavallini C, Europ Heart J 2005)  Lower group difference * Troponin I
    186. 186. 186 Low risk of troponin elevations in younger subjects in HEM-0115 predicts low risk in RESUS 21.6 13.2 10.1 3.1 0 1.6 0.2 0 21.6 11.6 9.9 3.1 0.0 5.0 10.0 15.0 20.0 25.0 > 70 y/o General < 70 y/o < 50 y/o Troponinelevationincidence(%) HBOC RBC Delta > ROC data
    187. 187. 187 Troponin elevation was an isolated lab abnormality without significant effect on predicted benefit:risk in RESUS 1. Less a priori significance (Alpert 2000, Luepker 2003) – CK-MB equivalent 2. Questionable clinical significance – Only 1/18 associated with MI – Low level elevations 3. Lower group differences in younger subjects 4. No adverse signal in preclinical studies – Equivalent or improved myonecrosis and troponins in HS – Decreased infarct size in acute coronary stenosis models 5. RESUS risk mitigation strategies
    188. 188. 188 Semi-quantitative predictions of benefit:risk in RESUS
    189. 189. 189 Objective benefit:risk analysis (state-of-the-art) • Holden WL, Drug Safety 2003 – “…benefit-risk analysis must be the scientific underpinning of risk management, as risk in and of itself cannot be…the sole criterion on which regulatory (and clinical) decisions are made; benefit must be accounted for as well” • Committee for Proprietary Medicinal Products (CPMP) – “…both benefits and risks should be considered…The degree of risk that may be considered acceptable is dependent on the seriousness of the disease being treated” • Council for International Organizations of Medical Sciences (CIOMS [WHO, UNESCO]) – “there are no standard, widely acknowledged definitions of the terms benefit and risk as applied…to medicinal products…” • WHO programme: global monitoring – “Benefit-risk analysis is…in its infancy for drug therapy”
    190. 190. 190 A semi-quantitative analysis which partially accounts for disparity in the clinical significance of death and SAE occurrence, predicts highly favorable benefit:risk in RESUS • Assessment assumptions – For benefit: control mortality = 58.1%, effect size = 15% – For risk: HEM-0115 overall SAEs from overall pop and < 70 year old sub-pop • Read out: Excess SAE Score (ESS) – No. excess subjects expected to experience > 1 SAE for every life saved – NNT/NNH = 11.5/13 (overall pop), 11.5/17 (< 70 year old sub-pop) – ESS < 1 highly favorable…ESS > 4 possibly unfavorable • Limitation: overly conservative estimation of overall SAE tolerability (subjective, not validated) • Results: ESS = 0.71-0.92 (highly favorable benefit:risk) – For every life saved, 0.71-0.92 excess SAEs may be predicted – “risks…are reasonable” (amphotericin example)
    191. 191. 191 The analysis predicts favorable benefit:risk over a wide range of control mortality and effect size estimate assumptions • Revised assumptions – Mortality 45%  ESS < 1 in < 70 year old sub-pop – Effect size 10%  ESS 1-1.3 in < 70 year old sub-pop • Even if assumptions are inaccurate, favorable benefit:risk is predicted for RESUS • “risks…are reasonable” (21 CFR 50.24)
    192. 192. 192 Conclusions (RESUS target population) 1. HS is the most common potentially preventable cause of death in trauma, most occurring during the prehospital phase 2. As trauma registry queries demonstrate ~ 58% mortality in the subset of the hypotensive HS population with severe HS targeted by RESUS, current treatment is unsatisfactory in these patients
    193. 193. 193 Conclusions (RESUS preclinical database) 3. The breadth and redundancy of improved outcome in preclinical HS studies predict prospect for benefit in humans in RESUS 4. As preclinical HS studies demonstrate a mortality reduction effect size of 75%, the RESUS mortality reduction effect size of 15% provides a conservative 5-fold margin of error
    194. 194. 194 Conclusions (RESUS clinical database) 5. That there was only a mild adverse shift in the safety profile of HBOC-201 despite comparison with gold standard RBC transfusions and prolonged exposure in the older overall population in prior surgical trials, predicts reasonable risk in comparison with LR and with brief exposure in RESUS 6. That group differences in key adverse safety signals were narrowed or nonexistent in younger and trauma sub-populations in prior surgical trials, further predicts reasonable risk in RESUS 7. That interim data from the S. Africa ER trauma trial reveal trends to an improved safety profile with HBOC-201 vs. controls, further predicts reasonable risk in RESUS
    195. 195. 195 Conclusions (overall RESUS benefit:risk prediction) 8. Qualitative analysis of preclinical and clinical studies predicts highly favorable benefit:risk in RESUS 9. Semi-quantitative analyses of preclinical and clinical HBOC- 201 studies robustly demonstrate Excess SAE Score (ESS) < 1, predicting highly favorable benefit:risk in RESUS 10. Extensive protocol risk mitigation strategies further minimize risk in RESUS, strengthening prediction of highly favorable benefit:risk in RESUS
    196. 196. 196 Conclusions (regulatory requirements) 11. All requirements of 21 CFR 50.24 have been met and the RESUS IND Clinical Hold should be lifted
    197. 197. 197 BIRMINGHAM REGIONAL EMERGENCY MEDICAL SERVICES SYSTEM BREMSS/UAB Joe Acker EMT-P, MPH Executive Director
    198. 198. 198 BREMSS • Six Counties in Alabama • 1.2 + Million • 80 + Cities • 18 Hospitals • 20, 000 EMS responses a month • 4,000 Trauma System patients routed each year • Many trauma’s with long transport times • Mitertek-Harvard 2006 Homeland Security Innovation Award
    199. 199. 199 Why do we need the RESUS study ? • A – airway • B- ventilation • C- circulation
    200. 200. 200 We need interventions for Circulation ! • Risk/benefit • Civilian EMS Study • We can do ! • We must do if trauma patients in extreme shock are to survive ! • EMS can do the study with the current protocol !
    201. 201. 201 IMPACT ON TRAUMA CARE Lewis J. Kaplan, MD, FACS, FCCM, FCCP Associate Professor Of Surgery Yale University School of Medicine Section of Trauma, Surgical Critical Care and Emergency General Surgery Director, SICU and Surgical Critical Care Fellowship
    202. 202. 202 IMPACT ON TRAUMA CARE • Pre-hospital trauma care – No significant advances since 1970’s – “Load and go” care • Trauma and critical care advances – In-hospital – Depends on receiving a sustainable patient – Paradigm changes over the last 20 years • HBOC-201 – Addresses pre-hospital needs • blood is not available
    203. 203. 203 IMPACT ON TRAUMA CARE • High-risk patient population – Hospital course marked by AE’s and SAE’s as part of the disease process • Benefits >> Risks • Military and civilian arenas – Trial design – HBOC implementation – Mass and single casualty survival

    ×