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
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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
Outline of NMRC/RESUS Advisory Board presentations
1. Introduction: Daniel Freilich, MD, CDR, MC, USN2. Importance of RESUS to the Navy and Marines Corps: John
treatment: Lewis Kaplan, MD4. Overview of RESUS study: Richard Dutton, MD5. Preclinical HBOC-201 HS studies: Susan Stern, MD6. Synopsis of HBOC-201 clinical studies: Gerson Greenburg, MD, PhD 7. RESUS IND Clinical Hold issues: Daniel Freilich, MD, CDR, MC,
USN8. Concluding remarks—importance of RESUS to civilian EMS
community: Joseph Acker, EMT-P, MPH9. Concluding remarks—importance of RESUS to civilian trauma
community: Lewis Kaplan, MD
3
Hemorrhagic Shock Lewis J. Kaplan, MD, FACS, FCCM, FCCP
Associate Professor Of SurgeryYale University School of Medicine
Section of Trauma, Surgical Critical Care and Emergency General Surgery
Director, SICU and Surgical Critical Care Fellowship
Kaplan L, et al. Curr Op Crit Care, 1999; 5(6):458-463
Death from refractory shock
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
RESUS
Richard P. Dutton, MD MBAChief, Trauma Anesthesiology
R Adams Cowley Shock Trauma CenterUniversity of Maryland Medical Center
Restore Effective Survival in Shock
22
Objective
To compare HBOC-201 with lactated Ringers solution for prehospital resuscitation of patients with severe hemorrhagic shock.
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 Score (RTS) 1 to < 5• Planned transport to study hospital• IV access secured
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 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
• 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
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
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
RESUS EMS interventions
Inclusion/exclusion criteria not met DO NOT ENROLLDO NOT ENROLL
If do NOT agree to participateDO NOT ENROLLDO NOT ENROLL
Patient or LAR/family member agree to participateENROLL PATIENT using PreED or ICENROLL PATIENT using PreED or IC
MINORITY OF CASESMINORITY OF CASESPatient CONSCIOUS or LAR/family member AVAILABLE
Provide IC or Pre-ED (if feasible)
Be alert for side effects
Repeat CTM re-infusion cycleAsses and re-infuse CTM PRN
Until maximum dose
CTM re-infusion criteria metSBP < 90 mm Hg
OrSBP 91-99 mm Hg and HR >/= 100
bpm
Complete CRF
Admin standard IV fluidsRe-evaluate
Inadequate ResuscitationPersistent other signs of HS
NO fluid therapyRe-evaluate
Adequate ResuscitationNo persistent other signs of HS
CTM re-infusion criteria NOT metSBP >/= 100 mm Hg
OrSBP 91-99 mm Hg and HR < 100 bpm
ASSESS CTM RE-INFUSION CRITERIA
ENROLL PATIENT using EICENROLL PATIENT using EIC
Open pre-randomization envelopeInfuse entire HBOC-201 or LR
dose
MAJORITY OF CASESMAJORITY OF CASESPatient UNCONSCIOUS, CONFUSED, OR DISORIENTED
LAR/family member UNAVAILABLE
Inclusion/exclusion criteria met CONTINUE ENROLLMENT/CONSENTCONTINUE ENROLLMENT/CONSENT
Screen ptReview inclusion criteria (including SPB < 90 mm Hg) and exclusion criteria
Complete CRFComplete CRF
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
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
Significance of prior HBOC-201 serious side effects for RESUS
Likelihood of Likelihood of serious side effectsserious side effects Phase III orthopedics trialPhase III orthopedics trial
24% HBOC24% HBOC--201 vs. 18% control subjects had at least 1 201 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 pressure Some 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 for Clinical benefit expected to be higher than potential for
serious side effectsserious side effects
Clinical significance of Clinical 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 BP 11% had high BP ““adverse eventsadverse events”” Severe increases were rareSevere increases were rare
Less than 1% had high BP Less 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
Like Like RESUSRESUS patientspatients
Expected significance for Expected 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--resuscitation resuscitation
(inadequate treatment)(inadequate treatment) Could increase bleedingCould increase bleeding Could cause other Could 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
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 if you must tell us immediately if you do NOT want to be in the studyyou do NOT want to be in the study.
38
Data Monitoring Committee
• Will review the study for efficacy and safety• Planned interim analyses in accordance with
HBOC-201 Infusion Did Not Increase Hemorrhage Volume in the Uncontrolled Hemorrhage Models
59
Organ Function and Histopathology
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
HBOC-201: Effects in Animal Models of Combined Hemorrhagic Shock (HS) andTraumatic 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
HBOC-201: Effects in Animal Models ofHS & TBI
Potential Concerns with HBOCs for Combined HS and TBI:
– Increased vasoactivity might increase hemorrhage from intracranial and extracranial injury sites
– Cerebrovasoconstriction might reduce O2 delivery to brain tissue and exacerbate any secondary ischemic insult.
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
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
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
A Gerson Greenburg, MD PhD FACS
VP, Medical Affairs Biopure CorporationMD University of ChicagoPhD Northwestern Univ. Industrial Engineering/Management Science
Trauma Fellowship, Cook County HospitalProfessor of Surgery USCD, Chief SICU VAMC SD Research Funding VA, US Army, Industry Professor of Surgery, Brown Medical SchoolSurgeon in Chief, Chief Clinical Quality Management, The Miriam HospitalChair, American College of Surgeons Pre-Post Op CommitteePresident, Xth International Symposium on Blood Substitutes, 2005Chair, Workshop on Toxicity of Blood Substitutes, NIH 2006Bibliography (260 publications) includes:
*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
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
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
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
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
Events25% (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
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
• 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
• 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
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
Adverse Events: Age Dependence
Patients > 70 years of age
n (%)
Patients < 70 years of age
n (%)
SAEsHBOC-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
*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*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
*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
*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
*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
*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
Changes In Systolic Blood Pressure
0
5
10
15
20
25
Baseline Post CTM Day 1 Post Day 2 Post Day6/Dischage
6 w eekFollow -up
Timepoints
Ch
ang
e in
SB
P C
om
par
ed t
o B
asel
ine
(mm
Hg
)
HBOC-201
RBCs
89
LFT Activity Over Study Period
0
20
40
60
80
100
120
140
160
180
200
B as el i ne Dur i ng C T M Day 1 P os t Las t C T M Day 6/ D i s c har ge 6 Weeks
Sample Per iod
AS
T (
Uni
ts)
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
AL
T (
Un
its
)
ALTHBOC
ALTRBC
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 orDischarge
Follow-up
Un
its/L
iter
HBOC-201
RBC
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 orDischarge
6 Weeks
BU
N m
g/d
L
HBOC-201
RBC
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
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
RESUS IND and Clinical Hold
Daniel Freilich, MD, CDR, MC, USN
RESUS Sponsor Lead Investigator
Naval Medical Research Center, Silver Spring, MD
95
“FDA has placed the RESUS IND on Clinical Hold for three primary reasons”
1. Safety concerns based oni. AEs seen in previous clinical studiesii. 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
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
• 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
Objective criteria were used to select HBOC-201 for development for a traumatic HS indication
• Improved resuscitative fluid– Replenishes intravascular volume and transports oxygen
• 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
RESUS protocol under review is product of 5 years of comprehensive deliberation
2001 Sep Program conceived
2003Apr RESUS Advisory Board established
May Protocol submitted to NMRC IRB
2004Feb 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
RESUS may have a transformational effect on trauma care
Potential lives saved annually if RESUS is successful (15% mortality reduction):
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
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
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
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
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
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
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
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”
Key adverse safety signal group differences were decreased or absent in younger subjects
0
5
10
15
20
25
%
> 70 years old Overall pop < 70 years old < 50 years old
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 20.623.4
17.514.5 14.5
11.7
7.66.0 6.1
0
5
10
15
20
25
30
35
40
> 70 y/o General < 70 y/o < 50 y/o
Ov
era
ll S
AE
in
cid
ence
(%
)
HBOC RBC Delta
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
2.71.8
0
8.1
3.6
1.52.1
0
2
4
6
8
10
12
14
> 70 y/o General < 70 y/o < 50 y/o
Car
dia
c S
AE
in
cid
ence
(%
)
HBOC RBC Delta
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 0.00.0
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
MI
AE
inci
den
ce (
%)
HBOC RBC Delta
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
0.30.0 0.0
4.5
2.0
0.8
0.00.0
1.0
2.0
3.0
4.0
5.0
6.0
> 70 y/o General < 70 y/o < 50 y/o
Hea
rt f
ail
ure
/flu
id o
ver
loa
d (
%)
HBOC RBC Delta
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
00.0
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
CV
A A
E i
nci
den
ce (
%)
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
0.60.9
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
Cer
ebra
l is
chem
ic A
E i
nci
den
ce (
%)
HBOC RBC Delta
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
1.10.8
0.00.0
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
Mor
tali
ty (
%)
HBOC RBC Delta
Mortality in HBOC-201 subjects:> 70 years old vs. < 70 year old, p = 0.002
5.4
2.3
0.81.0
1.8
0.6
0.0 0.0
3.6
1.7
0.81.0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
> 70 y/o General < 70 y/o < 50 y/o
Car
diA
c ar
rest
AE
(%
)
HBOC RBC Delta
Cardiac arrest in HBOC-201 subjects:> 70 years old vs. < 70 year old, p = 0.01
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
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 treatments are unproven or unsatisfactory”
3. “research holds out the prospect of direct 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
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
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
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
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
6. Safety data in overall populations in prior HBOC-201 surgery/orthopedics trials are unlikely to accurately
Comparator Gold standard RBC transfusion Crystalloid fluid
Study design Asymmetric Symmetric
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
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
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
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
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
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
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
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
III & IV. Comprehensive surveillance methods allow early detection and action and minimize risk
9. Prospective “increased BP” and “hypertension” coding definitions
• Post-marketing experience in S. Africa*– 336 HBOC-201 patients– 14 acute trauma * Levien L, ISBT Science Series, 2006
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
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
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-shaped) distribution (right)• Typical trauma trial U-shaped distribution excluded (right)
Mortality (%) N UAB/UMD mortality, RTS stratified, SBP < 90 mm Hg, no GCS exclusion, 18-
69 y/o, all
96.0
88.6
57.9
45.542.5
14.1
5.7 5.0
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
0-1 1.1 to 2 2.1 to 3 3.1 to 4 4.1 to 5 5.1 to 6 6.1 to 6.5 >6.5
RTS range
Mor
talit
y (%
)
Mort 58.1%
UAB/UMD N RTS stratified, SBP < 90 mm Hg, no GCS exclusion, 18-69 y/o, ALL w/o and w/ TBI)
144
3955
25 17 10 11 19
150
44
95
5540
71
192
378
0
50
100
150
200
250
300
350
400
0-1 1.1 to 2 2.1 to 3 3.1 to 4 4.1 to 5 5.1 to 6 6.1 to6.5
>6.5
RTS range
N
Dead N
Total N
Stratification of RESUS target population based on RTS ranges reveals reasonably homogeneous
mortality and normalized distribution (UAB/UMD)
149
Stratification of RESUS target population based on RTS ranges reveals reasonable mortality homogeneity and distribution (NTDB)
NTDB mort RTS stratified, SBP < 90 mm Hg, no GCS exclusion, 18-69 y/o, all
67.6
56.8
44.1
29.7
16.610.3
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
1 to < 2 2 to < 3 3 to < 4 4 to < 5 5 to < 6 6 to 6.5
RTS range
Mor
talit
y (%
)
Mort 55.8%N 406
• 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)
NTDB N RTS stratified, SBP < 90 mm Hg, no GCS exclusion, 18-69 y/o, all
789
293172
109 96159
1168
516
390 367
577
1550
0
200
400
600
800
1000
1200
1400
1600
1800
1 to < 2 2 to < 3 3 to < 4 4 to < 5 5 to < 6 6 to 6.5
“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: 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
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. 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
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
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
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
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
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
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
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
Preclinical data predict hematologic benefits in RESUS
• Equivalent effects on oxidative potential– Tissue 3-nitrotyrosine
* Independently predict adverse outcome in trauma (mortality, MOF, SIRS, infection, ICU admission and LOS)
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
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
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
0102030405060708090
100
PolyHeme HBOC-201 Hemolink HBOC-301 DCLHb
Tet
ram
eric
Hb (%
)
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
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
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
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
* Default recommendation is for most subjects in RESUS; duration/rate in individual subjects is based on clinical acuity
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 - 1.4 X 0.5 - 1 0.7-1.4 X 30 1.4 X
Katz Uncont HS 45 - 90 6.4 - 12.8 X 3 - 6 4.2-8.4 X 135 6.4 X
Stern Uncont HS/TBI
10 1.4 X 1 1.4 X 10 - 40 0.5 - 1.9 X
Manning Uncont HS 10 - 45 1.4 - 6.4 X 2.6 - 10 3.7-14 X 313 15 X Patel Cont HS/TBI 6 0.85 X not reported - 6 0.85 X Rosenthal Cont HS/TBI 6 0.85 X 0.6 0.85 X 6 0.85 X
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
0.50
5
10
15
20
25
30
35
40
Overall SAEs Mortality
Gro
up
dif
fere
nce
in
in
cid
ence
(%
)
> 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
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
Interim HEM-0125 clinical data in trauma patients with dose and infusion rate similar to RESUS
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
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
Non-serious AEs
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
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
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
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
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 symptomsb) development of pathologic Q waves on the ECG;c) ECG changes indicative of ischemia (ST segment elevation
or depression); ord) coronary artery intervention (e.g., coronary angioplasty).
2) Pathologic findings of an acute MI”
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
That most were low level troponin T elevations and fewer met ESC/ACC definition in HEM-0115, predicts
Low risk of troponin elevations in younger subjects in HEM-0115 predicts low risk in RESUS
21.6
13.2
10.1
3.1
01.6
0.2 0
21.6
11.69.9
3.1
0.0
5.0
10.0
15.0
20.0
25.0
> 70 y/o General < 70 y/o < 50 y/o
Tro
po
nin
ele
va
tio
n i
ncid
en
ce (
%)
HBOC RBC Delta
> ROC data
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
Semi-quantitative predictions of benefit:risk in RESUS
• 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
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
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
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
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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
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