ppt

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

Mateczun, MD, RADM, MC, USN3. Hemorrhagic shock: pathophysiology, clinical presentation, and

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

4

OBJECTIVES

• Hemorrhagic shock (HS)– Pathophysiology– Clinically relevant indicators of HS– Acute therapeutic goals

• Resuscitation paradigm construction– Outcome benefit

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

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

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

SHOCK CLASSES: ATLS 2004

Class I Class II Class III Class IVEBL (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

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

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

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)

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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

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

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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

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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

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SURVIVAL AND LACTATE CLEARANCE AFTER TRAUMA

Abramson et al., J Trauma, 1993; 35:584-9

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RESUS: In-hospital Trauma CareAssumes resuscitation is ongoing . . .

Hemorrhagic Shock

Ongoing BleedingBleeding 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

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RESUS ALGORITHM:PVE and Component Therapy

Volume Depletion Volume Replete Volume Overload

IVF / Colloid PRBC/FFP

Hemodynamic ReassessmentLaboratory reevaluation

Hgb 8-10 g/dl (acute)

AdequateCardiac Performance?

YesNo

Consider pressorHemodynamic Reassessment

Laboratory reevaluationHgb 7-8 g/dl (stable)

Consider Diuresisor Afterload Reduction

Goals: Cardiac Performance Optimization (CO, SvO2,LA)

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HEMORRHAGIC SHOCK, MSOF, AND MORTALITY RISK

0

50

Mortality

Inju

ryM

SOF

Increasing time

Injury

MSOF

Kaplan L, et al. Curr Op Crit Care, 1999; 5(6):458-463

Death from refractory shock

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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

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RESUS

Richard P. Dutton, MD MBAChief, Trauma Anesthesiology

R Adams Cowley Shock Trauma CenterUniversity of Maryland Medical Center

Restore Effective Survival in Shock

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Objective

To compare HBOC-201 with lactated Ringers solution for prehospital resuscitation of patients with severe hemorrhagic shock.

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Trial Design

• Part I (Phase 2b trial): 50 subjects

• Part II (Phase 3 trial): 1,108 subjects

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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

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Revised Trauma Score

• Blood pressure

• Respiratory rate

• Glasgow Coma Scale (GCS) score

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“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

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Exclusions• Penetrating brain injury• Paralysis• Known pregnancy• Burns• Cardiac arrest• Allergy• Known opposition to prehospital research• Transport time to study hospital <10-15

min

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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

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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

ATLS ABCDEs: circulation (C)Diagnose HS requiring fluid resuscitation

Screen ptReview inclusion criteria (including SPB < 90 mm Hg) and exclusion criteria

Complete CRFComplete CRF

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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

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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

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Primary Outcomes

• Reduced 28 day mortality

• Safe and tolerable

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Other Outcomes• Key Clinical Parameters:1. Hemodynamics 11. Hemostasis 2. Tissue oxygenation (lactate) 12. Blood transfusions 3. Renal function 13. Fluid requirements4. O2 content 14. Immune activation

5. Organ function 15. Neurocognitive function6. Trauma scores 16. Neurophysiology7. Infectious complications 17. Safety labs8. Abdominal complications 18. Clinical safety 9. Length of stay (LOS) 19. Disposition 10. Ventilator support 20. Survival (prehospital)

• Composite Surrogate Score (CSS)

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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

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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 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

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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.

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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%)

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Stopping Criteria: Efficacy

• Absolute: Significantly decreased 28-day relative risk of mortality – Intent-to-treat [ITT] analysis– Appropriate boundary modification (O’Brien-Fleming)

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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

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

Pre-Clinical Data: HBOC-201 Swine

Hemorrhagic Shock Studies

Susan A. Stern, MDAssociate Professor

Associate Chair for EducationDepartment of Emergency Medicine

University of MichiganAnn Arbor, Michigan

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

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

Data

• Survival

• Hemodynamics

• Tissue oxygenation (direct and indirect)

• Blood loss

• Organ function

46

Survival

47HBOC-201Control

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

Survival - All Models

0

10

20

30

40

50

60

70

80

90

100

York

Sampso

n

Knudson

McN

eil

Philbin

(2)

Rice

Philbin

Fitzpat

rick

NMRC T

BI SD

Man

ning

Katz

Gurney

Man

ning

NMRC T

BI LD

Less Severe More Severe

*p < 0.01

* *

*

**

HBOC-201Control Fluid

49

Hemodynamics

50

Mean Arterial Pressure was Significantly Improved with HBOC-201

HBOC-201HEX/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

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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

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Mean Pulmonary Artery Pressure was Significantly Greater with HBOC-201

HBOC-201HEX/LR



40% controlled HS

0

5

10

15

20

25

30

0 10 20 30 40 50 60 90 120 150 180 210 240


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

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Cardiac Index was NOT Different with HBOC-201

HBOC-201HEX/LR



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


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


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

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Tissue Oxygenation

54

Transcutaneous Tissue Oxygen Tension was Significantly Improved with HBOC-201

HBOC-201HEX/LR



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


0

5

10

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50

0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360


0

5

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50

0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360

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Invasively Measured Tissue Oxygen Tension

Brain Deltoid Liver JejunumLee et alKnudson et alYork et al.Stern et al.

Direction of arrow represents effect of HBOC-201 on tissue oxygen tension vs control.

56

Arterial Lactate was Improved with HBOC-201 in the Severe Hemorrhage Models

HBOC-201HEX/LR



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


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


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

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Blood Loss

58

Total Blood Loss

HBOC-201HEX/LR

Uncontrolled HS

0

10

20

30

40

50

60

70

80

90

100

ml/k

g


0

10

20

30

40

50

60

70

80

90

100

ml/

kg


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

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

• 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

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

Survival was Significantly Improved with HBOC-201 for the Long Delay Cohort

(Stern et al: HBOC-201 in severe uncontrolled hemorrhage and TBI)

HBOC-201LR

Mean Survival Time

0

1

2

3

4

5

6

30 minute delay 75 minute delay

hou

rs

*p < 0.01

*


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)

%


0

20

40

60

80

100

0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360Time (minutes)

%

66

Cerebral Perfusion Pressure



0

10

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60

0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360


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-201LR

Sagittal Sinus Oxygen SaturationUncontrolled 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


0

10

20

30

40

50

60

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80

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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

Brain Tissue Oxygen Tension was Significantly Greater with HBOC-201


HBOC-201LR


-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


-5

0

5

10

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0 10 20 30 40 50 60 90 120 150 180 210 240 270 300 330 360

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

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:

Blood substitutes, HBOC chemistry, Transfusion Guidelines

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

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

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


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


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


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


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

5. Mortality reduction effect size: 15% conservatively estimated

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

Background

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

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

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

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

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

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):

• 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

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, 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

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


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


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


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


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”

116

HEM-0115 clinical database

Pivotal Phase 3 Orthopedic Trial(younger sub-populations)

117

Sub-populations stratified by age

PopulationMean 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

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


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


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”

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

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

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

ExposureProlonged blood transfusion

substitutionBrief oxygen bridge

Physiologic state

Mostly hemodynamically stable Hemodynamically unstable

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


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


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


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)


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


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


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

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

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 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

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)


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

RTS range

N

Dead N

Total N

Mortality (%) N

http://www.trauma.org/

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: 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


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

• 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

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

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

FDA:

“There are very limited clinical data on dose and rate of administration using HBOC-201 to

support the RESUS dosing guidelines”

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

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

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

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

lower risk in RESUS

Subject ng/LAHA Scientific Statement Criteria (Luepker RV, Circulation 2003)

1 0.10 Isolated2 0.12 Isolated then detectable < ROC3 0.12 Isolated then detectable < ROC4 0.12 Isolated then detectable < ROC5 0.12 Isolated then detectable < ROC6 0.12 Isolated7 0.13 Isolated then detectable < ROC8 0.16 Pre-CTM 9 0.17 Pre-CTM 10 0.17 Serial11 0.18 Isolated12 0.24 Isolated13 0.26 Isolated then detectable < ROC14 0.26 Serial15 0.31 Serial16 0.58 Serial (MI)17 0.89 Serial18 5.6 Pre-CTM*

Low level elevations akin to PCI ‘troponin leaks’ (Cavallini C, Europ Heart J 2005)

Lower group difference

* Troponin I

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

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

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

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

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

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

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

Conclusions(regulatory requirements)

11. All requirements of 21 CFR 50.24 have been met and the RESUS IND Clinical Hold should be lifted

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 Trauma System patients routed each year

• Many trauma’s with long transport times

• Mitertek-Harvard 2006 Homeland Security Innovation Award

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

patients in extreme shock are to survive !

• EMS can do the study with the current protocol !

201

IMPACT ON TRAUMA CARE

Lewis J. Kaplan, MD, FACS, FCCM, FCCPAssociate 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


• 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


• 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

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