# Presentation: 935869

## 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

## Outline of NMRC/RESUS Advisory Board presentations

**Introduction:** Daniel Freilich, MD, CDR, MC, USN
**Importance of *****RESUS***** to the Navy and Marines Corps:** John Mateczun, MD, RADM, MC, USN
**Hemorrhagic shock: pathophysiology, clinical presentation, and treatment:** Lewis Kaplan, MD
**Overview of *****RESUS***** study:** Richard Dutton, MD
**Preclinical HBOC-201 HS studies:** Susan Stern, MD
**Synopsis of HBOC-201 clinical studies:** Gerson Greenburg, MD, PhD*** ***
***RESUS***** IND Clinical Hold issues:** Daniel Freilich, MD, CDR, MC, USN
**Concluding remarks—importance of *****RESUS***** to civilian EMS community:** Joseph Acker, EMT-P, MPH
**Concluding remarks—importance of *****RESUS***** to civilian trauma community:** Lewis Kaplan, MD

## Hemorrhagic Shock 

- Lewis J. Kaplan, MD, FACS, FCCM, FCCP
- Associate Professor Of Surgery
- Yale University School of Medicine
- Section of Trauma, Surgical Critical Care and Emergency General Surgery
- Director, SICU and Surgical Critical Care Fellowship

## OBJECTIVES

- Hemorrhagic shock (HS)
- Pathophysiology
- Clinically relevant indicators of HS
- Acute therapeutic goals
- Resuscitation paradigm construction
- Outcome benefit

## 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

## 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

## 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

## SHOCK CLASSES: ATLS 2004

|  | Class I | Class II | Class III | Class IV |
| --- | --- | --- | --- | --- |
| EBL (ml) | < 750 | 750-1500 | 1500-2000 | > 2000 |
| EBL (%) | < 15% | 15-30% | 30-40% | > 40% |
| Pulse | < 100 | > 100 | > 120 | > 140 |
| BP | normal | normal | decreased | decreased |
| Pulse P | Norm. to inc. | decreased | decreased | decreased |
| Resp rate | 14-20 | 20-30 | 30-40 | > 35 |
| Urine output | > 30 | 20-30 | 5-15 | minimal |
| CNS / mental status | Slightly anxious | Mild anxiety | Anxious, confused | Confused, lethargic |
| Fluid therapy | Crystalloid | Crystalloid | IVF + PRBC | IVF + PRBC |

## 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

## 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

## 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)

## 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

## 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

## 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

## 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

## SURVIVAL AND LACTATE CLEARANCE AFTER TRAUMA

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

## RESUS: In-hospital Trauma CareAssumes resuscitation is ongoing . . .

**Hemorrhagic Shock**

**Ongoing Bleeding**

**Bleeding** **Controlled**

**IVF +** **PRBC/FFP/Plt**

**OR **_**+**_** IR**

**Hemodynamic Assessment**

**Persistent:**
**Abnormal VS?**
**Oliguria?**
**High LA/acidosis?**
**Dx Dilemma**?

**Hemorrhage Control**

**PA Catheter**

**CVP**

**Echocardiography**

**Volume Depletion**

**Volume Replete**

**Volume Overload**

## RESUS ALGORITHM:PVE and Component Therapy

**Volume** **Depletion**

**Volume Replete**

**Volume Overload**

**IVF / Colloid**

**PRBC/FFP**

**Hemodynamic Reassessment**
**Laboratory reevaluation**
**Hgb 8-10 g/dl (acute)**

**Adequate**
**Cardiac Performance?**

**Yes**

**No**

**Consider pressor**

**Hemodynamic Reassessment**
**Laboratory reevaluation**
**Hgb 7-8 g/dl (stable)**

**Consider Diuresis**
**or Afterload Reduction**

**Goals: ****Cardiac Performance Optimization (CO, SvO****2****,LA)**

## HEMORRHAGIC SHOCK, MSOF, AND MORTALITY RISK

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

- Death from refractory shock

## 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

## RESUS 

**Richard P. Dutton, MD MBA**
- Chief, Trauma Anesthesiology
- R Adams Cowley Shock Trauma Center
- University of Maryland Medical Center

**R**estore **E**ffective **Su**rvival in **S**hock

**Notes:**
The RESUS study was designed to validate the hypothesis that HBOC-201 can be used to improve the survival of severely injured victims of hemorrhagic shock. 

## Objective

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

## Trial Design

- Part I (**Phase 2b** trial):  	50 subjects
- Part II (**Phase 3** trial):	1,108 subjects

**Notes:**
STAGES I-II DATA INTEGRATION AND SAMPLE SIZE OPTIMIZATION
The decision about whether to integrate data from Stages I into II or to analyze and report separate phase IIb and III trials will default to integration. Only protocol QA issues, described below as integration prohibition criteria, would preclude integration of the data and necessitate separate trials. The process of determining integration will be as follows: 
Integration prohibition criteria will be reviewed by the RESUS Advisory Board. 
An integration disposition recommendation will be submitted in ~30 days in a written summary to the DMC, IRBs, and the FDA—an additional 30 day window for review will be planned. 
If the Advisory Board recommends against the default of integrating the data, Stage II will not be resumed until noted QA issues and necessary study modifications are addressed and approved by the DMC, IRBs, and FDA. 
In order to assure that a planned 50-patient Efficacy and Safety Review (ESR) will have no possibility of bias regarding the integration decision, the Advisory Board will submit the integration disposition recommendation prior to the ESR. Although ESR data will have no effect on the data-integration decision, the study could be halted if efficacy/safety stopping criteria are met. Aggregate mortality data (n=50) will be calculated and utilized to optimize control treatment mortality prediction and study sample size. 
In summary, “post-phase II-like” decision making will occur in the following order: (1) Integration disposition (2) ESR (3) sample size optimization.
Data will not be integrated and phase IIb and III trials will be analyzed and reported separately only if any integration prohibition criteria, as below, are met. A deliberate attempt was made to find a balance between the need for relatively specific prospective criteria and the need to allow for logical deliberative flexibility.
The integration prohibition criteria are:
Feasibility—Despite the best of intentions and effort imputed into the design of this study, including evidence-based predictions, multidisciplinary expertise, and planned dry runs, numerous studies have failed due to design flaws. Thus, if execution of the study, as written, turns out to be logistically unfeasible and will not answer the primary efficacy and safety outcome questions, Stage I will be terminated and analyzed/reported separately. Minor study design optimizations would not satisfy requirements for integration prohibition criteria. Specific QA issues that could satisfy this feasibility criterion include but are not limited to:
Recruitment/screening—Subjects cannot be recruited and screened adequately.
Randomization—Subjects cannot be randomly allocated to the two study groups.
Study drug administration—Study drug cannot be administered due to timing or other logistic reasons.
Data collection—Data cannot be collected adequately.
Inclusion/exclusion criteria—Subjects screened and enrolled do not represent the targeted study population (i.e., severe HS without severe TBI). For example, basing our prediction on prior experience (i.e., DCLHb trial [Sloan EP]), ~25% of subjects are expected to have significant TBI despite the exclusion criteria—if this percentage turns out to be significantly erroneous, the study would not answer the primary questions. QA issues that are significant enough to prompt significant changes in inclusion/exclusion criteria are likely to satisfy this criterion.

## 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

## Revised Trauma Score

- Blood pressure
- Respiratory rate
- Glasgow Coma Scale (GCS) score

## “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**

## Exclusions

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

**Notes:**
The enrollment criteria in RESUS have been designed to focus the enrolled subjects to maximize the potential for benefit and to minimize the potential for risk. 

Revised Trauma Score (RTS): The main objective of incorporating the RTS 1 to < 5 RESUS inclusion criterion is to maximize enrollment of a population most likely to benefit from the studied intervention. Recognizing that survival of all-comers in a HS population defined by hypotension alone may not be sufficiently high (< 20%) and may be excessively heterogeneous, we sought to target a population with higher and more homogeneous mortality. Specifically, we aimed to target a traumatic HS population with intermediate predicted risk of death, excluding patients at very low and high extremes (those likely to die or to live irrespective of a new treatment modality). Thus, the RTS was selected because it has been shown to predict survival in trauma patients (Riou, 2001), focuses the population to decrease heterogeneity, and can realistically be evaluated by EMS personnel in the field without significant delay in care. This approach was recommended by OBRR. The RTS range of 1 to < 5 was selected to target an intermediate predicted mortality in control subjects (~ 58%).

## 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

**Notes:**

CTM re-infusion 
Repeat administration of CTM (500 ml) will occur similarly to general PHTLS/ATLS guidelines—i.e., persistent signs of class III or IV (and sometimes class II) HS. As summarized above, persistent severe hypotension (SBP < 90 mm Hg) will suffice as a sole criterion for re-infusion of CTM. In addition, moderate hypotension (SBP 90-99 mm Hg) in combination with tachycardia (HR > 100 bpm) will be a 2nd CTM re-infusion criterion. A maximum (total) of 6 units of HBOC-201 may be administered (HBOC-201: 250 ml = 32.5 g Hb/unit x 6 units = 195 g Hb in 1,500 ml). A maximum of 1,500 ml (three 500 ml units in two doses) of LR will be considered CTM. Because urban transportation times are usually short, it is expected that most subjects will receive only 2 units of HBOC-201 (and 1,000 ml of LR), a minority will receive 4 units of HBOC-201, and a smaller minority with prolonged transportation time and persistent hypotension, will receive 6 units of HBOC-201. 

LR control
LR was chosen as the control fluid because it is commonly used for both prehospital and hospital resuscitation of trauma patients. LR is manufactured and distributed in the U.S. as either pure levo L-isomer (l-LR, Baxter Healthcare Corp.) or as a 50:50 racemic mixture of levo and dextro isomers (dl-LR, Abbott Laboratories and B. Braun Medical Inc.). There are theoretical reasons (i.e., toxicity, LA accumulation, and immune activation) to choose l-LR over racemic dl-LR. However, the current standard of care in the U.S. includes use of either dl-LR or l-LR. Moreover, dl-LR is used in HBOC-201. Thus, as directed by OBRR, dl-LR (Abbott Laboratories or B. Braun Medical Inc.) will be used as control prehospital resuscitative fluid CTM in this protocol. 

OTHER/STANDARD IV FLUIDS
All other medical care and monitoring will follow standard procedures. This includes administration of standard IV resuscitative fluids (crystalloid and/or colloid solutions) if deemed clinically indicated where SBP and/or tachycardia criteria for re-administration of CTM are not met. Occult shock may occur in patients despite restoration of stable BP and HR. For example, if other medical conditions that can also cause shock are ruled out in a patient with SBP restored to > 100 mm hg but with persistent tachycardia, tachypnea, narrow pulse pressure, cool pale skin, and/or mental status changes, he/she is likely to have persistent HS and further IV fluid administration will be indicated. Similarly, if SBP is restored to > 90 mm Hg even without tachycardia, if other such signs of shock are present, he/she is likely to have persistent HS and further IV fluid administration will be indicated. EMS providers will be educated that further IV fluid resuscitation will be indicated in such cases (per standard of care). EMS providers will be reminded about potential for paradoxical bradycardia in HS patients. 
Some of the other signs of occult hypoperfusion are listed below (EMS personnel should recall that these signs are nonspecific and may reflect other physiological derangements [e.g., compromised airway, hypoxemia and hypoventilation due to pulmonary injuries, and TBI]):

Weak and/or thready pulse; Narrow pulse pressure (< 40 BPM); Bradycardia (HR < 60 BPM); Tachypnea; Decreased oxygen saturation; Oximeter failure to obtain reading; Skin pallor; Cool and clammy skin; Decreased capillary refill; Mental status change (in absence of TBI)

Non-CTM infusions will include all fluid infusions after 1,500 ml of CTM and for indications not meeting CTM administration criteria.

##  RESUS EMS interventions

** *****RESUS***** ****EMS interventions**

** ****Inclusion/exclusion criteria not met **
**DO NOT ENROLL**

**If do NOT agree to participate**
**DO NOT ENROLL**

**Patient  or LAR/family member agree to participate**
**ENROLL PATIENT using PreED or IC**

**MINORITY OF CASES**
**Patient CONSCIOUS or LAR/family member AVAILABLE**
**Provide IC or Pre-ED (if feasible)**

**Be alert for side effects**

**Repeat CTM re-infusion cycle**
**Asses and re-infuse CTM PRN**
**Until maximum dose**

**CTM re-infusion criteria met**
**SBP < 90 mm Hg**
**Or**
**SBP 91-99 mm Hg and HR >/= 100 bpm**

**Complete CRF**

**Admin standard IV fluids**
**Re-evaluate**

**Inadequate Resuscitation**
**Persistent other signs of HS**

**NO fluid therapy**
**Re-evaluate**

**Adequate Resuscitation**
**No persistent other signs of HS**

**CTM re-infusion criteria NOT met**
**SBP >/= 100 mm Hg**
**Or**
**SBP 91-99 mm Hg and HR < 100 bpm**

**ASSESS CTM RE-INFUSION CRITERIA**

**ENROLL PATIENT using EIC**

**Open pre-randomization envelope**
**Infuse entire HBOC-201 or LR dose**

**MAJORITY OF CASES**
**Patient UNCONSCIOUS, CONFUSED, OR DISORIENTED**
**LAR/family member UNAVAILABLE**

** ****Inclusion/exclusion criteria met **
**CONTINUE ENROLLMENT/CONSENT**

**ATLS ABCDEs: circulation (C)**
**Diagnose HS requiring fluid resuscitation**
**Screen pt**
**Review inclusion criteria (including SPB < 90 mm Hg) and exclusion criteria**

**Complete CRF**

**Complete CRF**

## 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

## 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

**Notes:**
(Need to add something about TBI – since Dan included TBI in the in-hospital trauma care guidelines)

## Primary Outcomes

- Reduced 28 day mortality
- Safe and tolerable

## Other Outcomes

- Key Clinical Parameters:
- 1.	Hemodynamics  			11. Hemostasis
- 2. 	Tissue oxygenation (lactate)		12. Blood transfusions
- 3. 	Renal function  			13. Fluid requirements
- 4. 	O2 content   				14. Immune activation
- 5. 	Organ function   			15. Neurocognitive function
- 6. 	Trauma scores  			16. Neurophysiology
- 7. 	Infectious complications 		17. Safety labs
- 8. 	Abdominal complications 		18. Clinical safety
- 9. 	Length of stay (LOS) 		19. Disposition
- 10. Ventilator support			20. Survival (prehospital)
- Composite Surrogate Score (CSS)

## 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

**Notes:**
The requirements for research involving subjects enrolled under an EIC are set forth in the Code of Federal Regulation, 21 CFR 50.24. These requirements are listed below along with bulleted statements demonstrating how the RESUS study protocol has met and in many cases exceeded them. Details regarding EIC, CCD, and RESUS protocol details are provided in Appendix A (these appendices are subject to change in the December 14 briefing book). 

This RESUS trial will enroll subjects who, by virtue of the inclusion criteria, will be unable to provide IC prior to enrollment. IC will not be feasible in the majority of subjects due to the acuity of their medical condition and a therapeutic window of minutes before treatment must be initiated. Thus, the conduct of the RESUS trial requires a provision for EIC. Recognizing high ethical standards necessary for EIC trials, NMRC researchers went to extraordinary lengths to ensure a scientifically- and ethically-optimal trial design. Specifically, a comprehensive CCD process was developed to maximize informed decision making by affected communities; inclusion/exclusion criteria were selected to target subjects with severe HS, a high rate of mortality, and for whom blood transfusions were unavailable (i.e., those subjects predicted to benefit most from the proposed intervention); provisions were included to prevent any delay in providing standard care (especially blood transfusions); IC will be obtained or Pre-ED will be provided when feasible to maximize individual subject autonomy; multiple risk mitigation strategies were incorporated to minimize risk to subjects (especially exclusion of the elderly because safety data from prior trials showed that they appeared most sensitive to potentially adverse vasoactive effects of HBOC-201); and independent government direction, funding, and sponsorship of the trial were insisted upon to minimize potential bias. Moreover, despite OBRR’s concern that uncontrolled hemorrhage and concomitant TBI might not be adequately treatable with HBOC-201, in a complex OBRR-directed RESUS IND-enabling swine study, NMRC showed significantly improved outcome in that simulated clinical setting (Appendix B) (these appendices are subject to change in the December 14 briefing book).. 

## Slide 35

**Notes:**
Example of the RESUS website.

## Slide 36

**Notes:**
Examples of how RESUS CCD presentation notifies the public about risks associated with the use of HBOC-201.

## Pre-enrollment disclosure script

***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 do NOT want to be in the study**_**.**

**Notes:**
WHY WAS SUCH AN EXCEPTION GRANTED IN CONNECTION WITH THE RESUS STUDY?
The Restore Effective Survival in Shock or RESUS study is designed to determine if a new, investigational product called HBOC-201 (bovine polymerized hemoglobin), also called Hemopure®, will decrease mortality of trauma victims with life-threatening blood loss (hemorrhagic shock) even before they reach the emergency room.  
Currently there are no U.S. Food & Drug Administration (FDA) approved oxygen-carrying therapies to treat hemorrhagic shock in the field or pre-hospital setting.
Today, injured individuals are given saline or Lactated Ringer’s solution (or colloids) until blood can be transfused upon arrival at the hospital.  These volume-expanding solutions help the heart to keep pumping, but in severe blood loss the oxygen content of the diluted blood may be critically low.
In RESUS, if a patient meets enrollment criteria and time allows, ambulance personnel will try to get consent (permission) from patients or their Legally Authorized Representative (LAR) before enrolling them in the study.  When consent is not possible, they try to provide disclosure (information) to patients or their family members about the study.  That provides an opportunity to refuse participation.  But most patients with shock are sleepy, confused, and unable to judge the risks and benefits of being in the study.  Often, family members and friends are not available, and treatment needs to start right away.  So, most patients will be enrolled in the RESUS study without prior consent or disclosure.  Once a subject reaches the hospital, patients and/or their family members will receive disclosure about the risks and benefits of participation at the earliest feasible time after enrollment and be given an option to withdraw.   
Participating in the RESUS study has the prospect of direct benefit to enrolled subjects receiving HBOC-201:
The proposed intervention is believed to be at least equal to standard therapy;
Previous studies of HBOC-201 demonstrate its potential to provide a direct benefit;
Risks associated with the use of HBOC-201 are reasonable in relation to the patients’ injuries, the risks and benefits of standard therapy, the risks and benefits of the proposed intervention, and the absence of blood transfusions.

WHAT ARE SOME ADDITIONAL PROTECTIONS PUT IN PLACE?
Protections to patients’ rights and welfare required by the EIC regulation for an Exception from Informed Consent study, as well as additional protections included in the RESUS study are: 
Consultation with representatives of the communities in which the study will be conducted and from which the subjects will be drawn;
Public disclosure to the communities prior to initiation of the study of plans for the investigation and its risks and expected benefits;
Public disclosure of information following completion of the study to inform the community and researchers of the study, including the demographic characteristics of the research population, and its results;
Establishment of an independent data monitoring committee to exercise oversight of the study; 
Community members may choose to pre-exclude themselves (e.g., by obtaining a RESUS study pre-exclusion ID bracelet and/or window decal); and
The investigator is committed to the process of contacting the subject's LAR or family member within the therapeutic window.  In the RESUS study the therapeutic window is a matter of seconds to minutes and, therefore, there will usually be insufficient time to prospectively fully inform and disclose the risks and benefits of participating in the study.  However, ambulance personnel will attempt to contact the subject's LAR or family member, if available and if feasible, and try to get full informed consent from patients or their LAR before enrolling them in the study. 
When consent is not possible, ambulance personnel will try to disclose to patients or their family members about the study in order to provide an opportunity to refuse participation.  But most patients with shock are sleepy, confused, and unable to judge the risks and benefits of being in the study.  Often, family members and friends are not available, and treatment needs to start right away.  So, most patients will be enrolled in the RESUS study without prior full informed consent or disclosure.
Upon hospitalization, study personnel will discuss the study with the patient and provide them with an option to withdraw from the study.
Additionally, the local hospital Institutional Review Board (IRB), also called a Research Subject Protection Board, approves the study 

## 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%)

## Stopping Criteria: Efficacy 

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

## 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

## 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

## Pre-Clinical Data: HBOC-201 Swine Hemorrhagic Shock Studies

**Susan A. Stern, MD**
**Associate Professor**
**Associate Chair for Education**
**Department of Emergency Medicine**
**University of Michigan**
**Ann Arbor, Michigan**

## 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)_

## 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)

## Data

- Survival
- Hemodynamics
- Tissue oxygenation (direct and indirect)
- Blood loss
- Organ function

## Survival

## Survival was Significantly Improved with HBOC-201

**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

## *p < 0.01

*******p < 0.01**

*****

*****

*****

*****

*****

## Hemodynamics

## Mean Arterial Pressure was Significantly Improved with HBOC-201 

## Mean Pulmonary Artery Pressure was Significantly Greater with HBOC-201 

## Cardiac Index was NOT Different with HBOC-201 

## Tissue Oxygenation

## Transcutaneous Tissue Oxygen Tension was Significantly Improved with HBOC-201

## Invasively Measured Tissue Oxygen Tension

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

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

## Blood Loss

## Total Blood Loss

**HBOC-201 Infusion Did Not Increase Hemorrhage Volume in the Uncontrolled Hemorrhage Models**

## Organ Function and Histopathology

## 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)*

**Notes:**
Three (3) papers provide data on the effect of  HBOC-201 on organ function and histopathology.   These papers looked at heart, lungs, kidney and liver.  

There was a slightly greater incidence of histopathological changes in liver and kidney, and mild, transient increases in hepatic enzymes and BUN and Cr with HBOC-201 in the study by Johnson et al.
Greater elevations in liver function tests and greater histopathological changes in the liver were also noted in the study by York et al.  That is inadvertently omitted from this slide, and I apologize.   

## HBOC-201: Effects in Animal Models of Combined Hemorrhagic Shock (HS) andTraumatic Brain Injury (TBI)

- _Potential Advantages of HBOCs for Combined HS and TBI_:
- enhanced oxygen delivery to the injured brain **→** prevention of secondary ischemic insults.
- small volume resuscitation **→** avoid the **↑** intracranial hypertension associated with large volume resuscitation

## HBOC-201: Effects in Animal Models ofHS & TBI

- _Potential Concerns with HBOCs for Combined HS and TBI_:
- Increased vasoactivity might increase hemorrhage from intracranial and extracranial injury sites
- Cerebrovasoconstriction  might reduce O2 delivery to brain tissue and exacerbate any secondary ischemic insult.

## 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

## 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

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

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

## Sagittal Sinus Oxygen Saturation

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

**Sagittal Sinus Oxygen Saturation**

_***Markers of Cerebral Perfusion***_** were Significantly Improved with HBOC-201**

## Brain Tissue Oxygen Tension was Significantly Greater with HBOC-201

- (Stern et al: HBOC-201 in severe uncontrolled hemorrhage and 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.**

## 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.****  **

## A Gerson Greenburg, MD PhD FACS 

- 	VP, Medical Affairs Biopure Corporation
*	*MD *  *University of Chicago
- 	PhD  Northwestern Univ. Industrial Engineering/Management Science
- 	Trauma Fellowship, Cook County Hospital
- 	Professor of Surgery USCD, Chief SICU VAMC SD
- 	 	Research Funding VA, US Army, Industry
- 	Professor of Surgery, Brown Medical School
- 	Surgeon in Chief, Chief Clinical Quality Management, The Miriam Hospital
- 	Chair, American College of Surgeons Pre-Post Op Committee
- 	President, Xth International Symposium on Blood Substitutes, 2005
- 	Chair, Workshop on Toxicity of Blood Substitutes, NIH 2006
- 	Bibliography (260 publications) includes:
- 		 Blood substitutes, HBOC chemistry, Transfusion Guidelines

**Notes:**
This may be too much context....

## 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 |

**Notes:**
This slide summarizes the clinical trials performed with HBOC-201 from 1992 through 2005 organized according to the phase and type of study
There were 4 Phase 1 studies involving a total of 93 normal volunteers that examined safety and tolerability, exercise tolerance with dose and rate of infusion escalation, as well as immunologic response to HBOC-201 infusions
There were 13 Phase 1/2 studies involving a total of 296 general surgery subjects as well as non-surgical subjects with sickle cell anemia with or without vaso-occlusive crisis
There were 4 Phase 2 studies involving a total of 266 subjects including cardiopulmonary bypass, abdominal aortic aneurysm reconstruction, percutaneous coronary intervention, and non cardiac surgery subjects
Finally, there were 2 Phase 3 studies involving a total of 848 subjects, one in non cardiac subjects, and the second and largest study in orthopedic surgery subjects.
	-There were 160 subjects in study HEM-0114 and 688 subjects in study HEM-0115 with 83 and 350 subjects receiving treatment with HBOC-201, respectively.

Of the total 1503 subjects in these 22 clinical studies, 826 received HBOC-201 and 677 received infusion of control solutions (LRS, saline, colloid, or RBCs)

## 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 |

**Notes:**
The 22 clinical trials are summarized here according to the nature of the controls used and study phase. 
There were 3 uncontrolled studies, 5 studies in which colloid control was administered, 10 involving crystalloid control, and the largest number of subjects studied received RBCs as the control infusion.
These studies involved not only different control solutions but also involved different study designs, some controlled, uncontrolled, single blind or double blind, different doses of drug and dosing periods, and some with asymmetric study arm design. These differences contribute to the need for caution when attempting to interpret data combined from all these studies. 

Note: The following table summarizes the AE and SAE data for the colloid and crystalloid (non oxygen carrying solution) controlled studies: 

## 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%**

**Notes:**
The overall experience with HBOC-201 is summarized in this slide in terms of the exposure to drug.
87% of subjects were exposed to the HBOC in the dose range related to RESUS....
Addresses an FDA issue and question....

These data show that 87% of subjects (N =718) exposed to HBOC-201 received 6 or less units of HBOC-201. The vast majority of experience lies in this range of doses which contributed to the recommended change in the maximum dose of HBOC-201 (6 units) to be used in RESUS.

## 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_

**Notes:**
For the first few slides, after the presentation of credentials, we do start with a review of all previous experience. Here, it is N trials with NN patients, noting carefully the differences in models, controls, ratios of treated to controls, lack of homogeneity of populations  and accumulation of AE and SAE data that forms an initial impression of a safety profile.....note a wide range of observations were made but none clinically 
Rearranged some of the points...stress the waived consent...go to side effects and then look at ISS and here will have to dismiss it...
Can question including point #3 here as the next slide takes it on in terms of dismissing it....

## 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

**Notes:**
The review of HBOC-201’s safety profile will focus on the adverse events observed in the phase 3 orthopedic surgery study for the following reasons:
This was the largest single study performed with HBOC-201, representing 42 percent of all subjects treated with drug and 66% of subjects in the RBC-controlled trials. 
This study was powered to detect a 1% difference in the incidence of adverse events between treatment groups.
All of the trends seen in earlier studies are reflected in the differences between groups in this one study, including non-significant trends, or “safety signals”.

## The overall pattern of serious and non-serious adverse events is accurately reflected in study HEM-0115

|  | HBOC-201(n=350) | Controls(n=338) | P-value* |
| --- | --- | --- | --- |
|    Adverse Events | 95%  (93%) | 91%  (88%) | 0.024 |
|    AEs/Patient | 8.47  (7.78) | 5.88  (5.48) | <0.001 |
|    Serious Adverse  
   Events | 25%  (23%) | 18%  (18%) | 0.014 |
|    SAEs/Patient | 0.34  (0.34) | 0.25  (0.25) | 0.062 |

- *Fisher exact test used for incidence and t-Test for events per patient

**Notes:**
This table summarizes the differences in the incidence and the overall adverse events and serious adverse events per patient in the two treatment groups. It is clear that the incidence of overall AEs and SAEs is statistically significantly higher.

The same trend in AEs and SAEs that was seen in the pooled studies analysis is reflected in the HEM-0115 study.  The difference in adverse events is contributed primarily by the side effect profile of HBOC-201 that will be discussed in the following slides.  The difference in SAEs is dictated by factors that were identified in the process of root cause analysis performed on the HEM-0115 study results and will be discussed in the next slides as well.

## The study design of HEM-0115

**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***

## 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

- 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**

## 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

- 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**

## 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*

**Notes:**
May not have to use this one....could be the outline for the back up slides...

## Adverse Events: Age Dependence

|  | Patients > 70 years of age
n (%) |  |  | Patients < 70 years of age
n (%) |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| SAEs | HBOC-201
(n=111) | RBC
(n=111) | P value | HBOC-201
(n=239) | RBC
(n=227) | P value* |
| Cardiac | 14(13%) | 5(5%) | 0.0525 | 
8(3%)
 | 4(2%) | 0.3834 |
| Nervous | 3(3%) | 0(0%) | 0.2466 | 2(0.8%) | 2(0.8%) | 1 |
| Death | 8(7.2%) | 6(5.4%) | 0.7836 | 2(0.8%) | 0(0.0%) | 0.4993 |

- *Reduction of sample size did not effect significantly the ability to detect a difference between groups
- (approximately 1.2% vs originally designed 1%).

**Notes:**
Analysis of the trends in adverse events showed that the incidence was a function of age. The most significant example of age dependence is seen in subjects above and below age 85 where all of the difference in mortality and 90% of the difference in cardiac serious adverse events between treatment groups was observed.
Consistent with the age restriction suggested by NMRC for the RESUS protocol, this slide shows a side-by-side comparison of cardiac and nervous system SAEs and mortality are presented showing, in particular, the much higher incidence of cardiac SAEs in patients above age 70.  Furthermore, there is a statistically significant difference between treatment groups in the >70 year old subjects.  The nervous system SAEs are approaching significance in this older population. In the < 70 year old population there are no significant differences.

In the next slides we will look more closely at the profile cardiac serious adverse events and distribution of these events according to age.

Note regarding age dependence reflected in patients above and below age 85:
A total of 16 deaths occurred during this study: 10 (2.9%) deaths in the HBOC-201 group and six (1.8 %) deaths in the RBC group (p = 0.450).  The increase in the number of deaths in the HBOC-201 group was contributed by patients who were > 85 years.  The data showed that the mortality rate for patients  85 years of age was 1.5% (N = 5) in both groups. Whereas, of the six deaths among the patients > 85 years, five were reported in the HBOC-201 and one in the RBC group.  Of these five HBOC-201 patients, three were > 90 years of age. 

In addition, 90% of the disparity in cardiac serious adverse events is accounted for by subjects above age 85 (22 vs 9 cardiac SAEs in the total population and 11 vs 7 in the <85 years of age subjects). This is not surprising that there is a strong correspondence between mortality and serious cardiac adverse events in this case as cardiac SAEs were associated with the majority of the deaths in this population.

## Cardiac Serious Adverse Events

**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 |

**Notes:**
There is no question that the incidence of cardiac serious adverse events is higher in the HBOC-201 group in this study. In particular, when one groups events such as cardiac failure, congestive heart failure, cardio-respiratory arrest and pulmonary edema these difference between groups becomes more evident with 11 subjects in the HBOC-201 group and 0 subjects in the RBC population.  This also highlights the possibility that fluid volume management was an issue in this study. 

An independent review of all the cardiac adverse events was performed by Dr. Steve Schulman at John’s Hopkins and one of his conclusions was that a significant proportion of patients experienced volume overload and this volume overload was not managed adequately (proper use of diuretics, limiting crystalloid volume, etc.).   Thus, these data clearly point to the possibility that the relative lack of experience with the colloidal solution that HBOC-201 represents, combined with administration of other colloid solutions and large volumes of crystalloid may have resulted in the observed increased incidence of these adverse events. These data argue that more comprehensive training with regard to proper volume management when HBOC-201 is used as a blood substitute to treat perioperative surgical anemia is needed.

From Dr. Schulman’s Patient Review:

“Many subjects received many liters of fluid in the intra/perioperative period and it was evident that in many patients whose adverse event was classified by the investigator as heart failure, the etiology was volume overload.  Many of the patients with this event did not receive adequate diuresis in the postoperative period resulting in volume overload.”......“Although HBOC-201 and RBCs contributed to this volume overload, it appears on reviewing the medical records in these patients that diuretic therapy was often started late with inadequate doses.”

“It is therefore suspected that the lack of experience in using a new transfusion agent compared to red blood cells contributed to the disproportionate total number of cardiovascular or CNS events in the HBOC-201 group, including inadequate use of product.” 

## Cardiac Serious Adverse Events

**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 |

**Notes:**
Comparing this same grouping of cardiac serious adverse events described above (heart failure, CHF, etc.) the difference between groups goes from 11 vs 0 to 3(1%) vs 0, (statistically insignificant) in subjects < 70 years of age.   This is also true for the entire SOC with a p-value = 0.3834.

Again, it is likely that the incidence of these volume-related events might be significantly reduced, particularly in the elderly subjects, with protocols in place to ensure proper volume management in the setting of orthopedic surgery and the treatment of perioperative anemia.

## Renal Serious Adverse Events

**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 |

**Notes:**
Adverse events affecting renal function have been of historical concern in the field of HBOCs, particularly with the early generation products.  Polymerization is one modification that has contributed to reducing such events.   Although the overall renal SAE profile does not show evidence of any statistically significant trends, these data taken together with the fact that there were two subjects requiring dialysis in the group of subjects with acute renal failure (where there was no antecedent event or factors predisposing for renal failure) suggest the need for monitoring of creatinine clearance in this patient population to mitigate against the possibility of renal failure.

On the average, mean serum creatinine levels were similar between the HBOC-201 (0.67 - 0.82 mg/dL) and the RBC (0.77 - 0.9 mg/dL) treatment groups with a trend for slightly higher mean concentrations in the RBC group. Analysis of the shifts from normal baseline concentrations to clinically significantly high (CSH) concentrations shows that the shift is relatively low (≤ 6%) in both study groups. The percent patients sampled at any particular time point tended to be higher in the HBOC-201-treatment group. The slightly higher incidence of shifts to CSH concentrations of serum creatinine were consistent with the higher incidence (five HBOC-201 vs. two RBC patients) of acute renal failure in the HBOC-201-treatment group. 

## CNS Serious Adverse Events

**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 |

**Notes:**
There was a no statistically significant increase in overall nervous system serious adverse events. However, there was a significant increase in the number of cerebrovascular accidents in the HBOC-201 group. However, the incidence of CVA was lower in the <70 year old subjects and  the difference was non-significant in this group. 

## Respiratory Serious Adverse Events

**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 |

**Notes:**
Overall there is no significant difference between the treatment groups in terms of respiratory system adverse events. However, the difference in the incidence of respiratory failure is approaching statistical significance in the overall population. As discussed previously this may be related to excess volume infusion which could exacerbate pulmonary edema and respiratory dysfunction.  There is no evidence of this imbalance in the subjects <70 years of age. 

## Hepatobiliary Serious Adverse Events

**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 |

**Notes:**
The difference in the incidence of Hapatobiliary SAEs is significant with 5 versus 0 events in the two treatment arms. This is due , in large part, to serious events related to cholecystitis.  These events are not seen in the younger population.  There was one case of hepatomegaly and one case of hepatorenal failure as well, however, no trends are suggested by these data. 

As will be seen, in the discuss of the clinical laboratory data, there is a significant and transient increase in LFTs associated with the treatment with HBOC-201. 

## Changes In Systolic Blood Pressure

**Notes:**
Since blood pressures in both groups following the first infusion remained elevated compared to baseline, serial blood pressure data were analyzed to determine the duration of the elevated blood pressure when patients were treated according to this protocol. Specifically, systolic blood pressures were compared at seven time points during the observation period (baseline, immediately after completion of last CTM treatment, days 1 and 2 after completion of last CTM treatment, at day 6 after treatment start or discharge, and at 6 week follow-up).  Compared to baseline, the average increase in systolic blood pressure after the last CTM treatment was 22 1 mm Hg (n=324) with HBOC-201 and was 10 1 mm Hg (n = 313) with pRBCs. 

Elevations of blood pressure occurred more frequently in the HBOC-201 treated patients compared to pRBC treated patients (85% vs. 63% for HBOC-201 and pRBC, respectively).  The largest average increase in blood pressure occurred after the first exposure to HBOC-201 (500 mL, 2 units), resulting in increases (pre to post infusion) in systolic and diastolic blood pressures (meansem) of 23 1 mm Hg (n = 319) and 13 1 mm Hg (n=319), respectively. The first treatment with pRBCs (250 ml, 1 unit) resulted in increases in systolic and diastolic blood pressures of 4 1 mm Hg (n=246), (Figure 2.1) and 1 1 mm Hg (n=246), respectively. The second and subsequent infusions of CTM started at slightly higher blood pressures than baseline (~15-20 mm Hg for HBOC-201 and ~5-10 mm Hg for pRBC) and resulted in smaller increases in systolic blood pressure, averaging less than 7  mm Hg (where n >20) in both groups. 

## LFT Activity Over Study Period

- Error bars = ± SE

**Notes:**
Based on the results from preclinical studies and previous clinical trials changes in AST and ALT levels in the plasma are characteristic following administrations of HBOC-201. During Day 1 and Day 2 post-CTM, the mean AST and ALT activities were approximately two to three-fold greater in the HBOC-­201-treated patients than in the RBC-treated patients.  The level of these enzymes in both treatment groups were slightly elevated at Day 6 or Discharge and returned to baseline by the 6-Week Follow-up visit assessment.  The incidence of CSH elevations of enzyme activity was higher in the HBOC-201 (8-13%) group compared to the RBC (2-9%) group. However, the majority of patients with elevated AST and ALT values had transient elevations that did not require intervention, or discontinuation of CTM, and were not suggestive of hepatic dysfunction. These observations are likely related to the large protein (Hb) load that the liver is required to clear from the circulation following administration of HBOC-201. 

## Lipase Activity Over Study Period

- Error bars = ± SE

**Notes:**
There was no difference in the mean value of lipase activities between the HBOC-201 and the RBC groups at follow-up periods except during the CTM infusion time period where lipase activities in the HBOC-201 group were increased by several fold compared to that of the RBC.  However, this difference was transient with similar values for both treatment groups at the 6-Week Follow-up visit.   Lipase laboratory measurements showed that 5-10% of patients in the HBOC-201 and 1-2% of patients in the RBC group had clinically significant elevations between Day 1 and Day 6 of Follow-up. At the 6-Week Follow-up period, 1% in the HBOC-201 and 2% of patients in the RBC group showed clinically significant elevations in this enzyme.
These data are consistent with the reported lipase elevation AEs as 32 patients (9%) in the HBOC-201-treatment group and seven patients (2%) in the RBC-treatment group reported lipase elevation as an AE.  In this study, any increase in lipase activity > 25% of the upper limit of normal was evaluated by a gastroenterologist. Of the 39 patients with lipase elevations reported as AEs, 25 were further evaluated (laboratory monitoring, ultrasound and barium swallows) and 24 of the 25 were found to be asymptomatic (without clinical evidence of pancreatitis).  One patient (Patient 0716) had mild pancreatitis suspected to be associated with gastritis and peptic ulcer disease. A CT scan of the abdomen revealed an adrenal hematoma and the gastroenterologist determined that no further intervention was needed.  The patient was administered Axid 150 mg PO BID for eight weeks and the patient recovered.  Although there were significant increases in lipase activities in the HBOC-201-treatment group, increases were mild-moderate and transient. The increases appeared to be dose dependent. A majority of the patients with elevated lipase activities were asymptomatic and had no clinical features suggestive of pancreatitis.  These data suggest that elevations of lipase activity are not uncommon following infusion of HBOC-201.  
The incidence of CSH elevations is < 10% and is unlikely to be associated with pancreatitis. Nonetheless, the incidence of lipase elevations following HBOC-201 infusion requires careful monitoring and consultation to ensure the absence of pancreatitis. 

## Creatinine & BUN Levels Over Study Period

- Error bars = ± SE

**Notes:**
On the average, mean serum creatinine levels were similar between the HBOC-201 (0.67 - 0.82 mg/dL) and the RBC (0.77 - 0.9 mg/dL) treatment groups with a trend for slightly higher mean concentrations in the RBC group. Analysis of the shift from normal baseline concentrations to clinically significantly high (CSH) concentrations shows that the shift is relatively low (≤ 6%) in both study groups. The percent patients sampled at any particular time point tended to be higher in the HBOC-201-treatment group. The slightly higher incidence of shifts to CSH concentrations of serum creatinine were consistent with the higher incidence (four HBOC-201 vs. two RBC patients) of acute renal failure in the HBOC-201-treatment group. 
BUN levels were slightly increased from baseline (2.4 - 4.3 mg/dL) in the HBOC-201 group compared to a slight decrease through Day 6 or discharge and 3.1 mg/dL increase from baseline at follow-up in the RBC group. The differences between groups was minimal at Day 6 or discharge and at follow-up. 

## 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

**Notes:**
The clinical experience with HBOC-201 is important in identifying potential safety and efficacy in the RESUS Study.
The HEM-0115 study conclusions identify the major outcomes for efficacy and safety in HBOC-201 use for elective Orthopedic patients in comparison to red cells

## 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.

- 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.

## RESUS IND and Clinical Hold

- Daniel Freilich, MD, CDR, MC, USN
*RESUS* Sponsor Lead Investigator
- Naval Medical Research Center, Silver Spring, MD

## “FDA has placed the RESUS IND on Clinical Hold for three primary reasons”

_*Safety concerns*_* based on*
_*AEs seen in previous clinical studies*_
*Potential risks related to *_*product dosing*_* and patient*_* monitoring limitations*_
_*Heterogeneity in the expected mortality*_* of individual subjects meeting the inclusion criteria for RESUS*
*Insufficient *_*basis for estimating the effect size*_* of HBOC-201 for possible reduction in mortality*

## Outline of discussion points

**Traumatic HS:** public health problem, unsatisfactory treatment
***RESUS*****:** program evolution, transformational impact on trauma care
**Target population:** high mortality (58%), reasonable homogeneity
**Preclinical database**: *prospect* for benefit, 75% mortality reduction
**Mortality reduction effect size:** 15% conservatively estimated

## Outline of discussion points—continued

**Clinical database:** benefit, *reasonable* safety in overall pop., especially in younger sub-pop.
**Dosing Guidelines:** extensive preclinical and clinical rationale
**Non-serious AEs**: insignificant effect on benefit:risk
**Monitoring limitations: **mild vasoactivity, inclusion criteria, training
**Risk mitigation strategies:** further optimize benefit:risk
**Qualitative and semi-quantitative analyses:** robustly predict *highly favorable* benefit:risk in *RESUS*

## Background

## 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%

## 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

## 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®

## 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

**Notes:**
HBOC-201 can be stored without refrigeration for at least three years. 
It is universally compatible (does not require blood banking) and can be infused easily without special training. 
It is also a low volume/weight resuscitative fluid. 
HBOC-201 is relatively pure, containing less than 3% tetrameric hemoglobin, the main culprit of vasoactivity side effects. 
HBOC-201, although bovine derived, has negligible BSE risk. 
Over 800 subjects have been evaluated with HBOC-201 in orthopedics and general surgery settings. 
Biopure, the manufacturer of HBOC-201, submitted a Biological License Application (BLA) to FDA for an orthopedic surgery indication, but the product has not been approved in the U.S. 
HBOC-201 is approved for human use in South Africa.

## 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

## RESUS protocol under review is product of 5 years of comprehensive deliberation

| 2001 | Sep | Program conceived |
| --- | --- | --- |
| 2003 | Apr | RESUS Advisory Board established |
|  | May | Protocol submitted to NMRC IRB |
| 2004 | Feb | NMRC assumes responsibility as regulatory sponsor |
|  | Apr | Pre-IND meeting with OBRR |
| 2005 | Apr | NMRC completes OBRR-directed swine HS/TBI study |
|  | Apr | Protocol provisionally approved by NMRC IRB |
|  | June | IND application submitted to OBRR |
|  | July | IND placed on Clinical Hold |
|  | Sep | NMRC submits Complete Response to OBRR |
|  | Oct | NMRC submits Complete Response to OBRR |
| 2006 | Jan | NMRC submits Complete Response to OBRR |
|  | July | BPAC meeting scheduled, cancelled |
|  | Aug | NMRC submits Complete Response to OBRR |
|  | Dec | BPAC rescheduled |

## 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

## HBOC-201 clinical databasePivotal Phase 3 Orthopedic Trial (HEM-0115)

## 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

## 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)

**Notes:**
T 1⁄2 is 19 hrs

## 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**

**Notes:**
*   OBRR/Biopure Combination 22 (June 2006)
** OBRR/Biopure Combination 20 (June 2006)

## 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 |

## 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 |

**Notes:**
^ OBRR/Biopure Combination 26 (June 2006)—MI, myocardial ischemia, angina pectoris, unstable angina pectoris.
* OBRR/Biopure Combination 22 (June 2006).
** OBRR/Biopure Combination 20 (June 2006).

## 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 |

## 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 |

## 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 |

## 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*_*”*

## HEM-0115 clinical databasePivotal Phase 3 Orthopedic Trial(younger sub-populations)

## Sub-populations stratified by age

| Population | Mean age 
(yrs) | N
HBOC-201 | N
RBC |
| --- | --- | --- | --- |
| > 70 years old# | 77.0 | 111 | 111 |
| Overall population | 60.8 | 350 | 338 |
| < 70 years old* | 53.1 | 239 | 227 |
| < 50 years old^ | 39.9 | 84 | 65 |

**Notes:**
Reduction in power to detect group differences (relative to overall population):

# Threshold to detect group differences increases 1.8-fold.
* Threshold to detect group differences increases 1.2-fold.
^ Threshold to detect group differences increases 2.2-fold.

## Key adverse safety signal group differences were decreased or absent in younger subjects

**Notes:**
The same observations and trends were found in the overall Integrated Safety of Summary (all trials).

Heart failure/fluid overload—combination 22.

Cardiac arrest—combination 20.

## No unreasonable overall SAE risk in younger subjects

**HBOC-201 subjects: **_**>**_** 70 years old vs. < 70 year old, p = 0.005**

## No unreasonable cardiac SAE risk in younger subjects

**HBOC-201 subjects: **_**>**_** 70 years old vs. < 70 year old, p = 0.002**

## No unreasonable MI AE risk in younger subjects

**MI in HBOC-201 subjects: **_**>**_** 70 years old vs. < 70 year old, p = 0.01 **

**Notes:**
* OBRR/Biopure Myocardial ischemia Combination 5 (June 2006)

## No unreasonable heart failure/fluid overload risk in younger subjects

**HBOC-201 subjects: **_**>**_** 70 years old vs. < 70 year old, p = 0.01**

**Notes:**
OBRR/Biopure Combination 22 (June 2006)

## No unreasonable cerebral ischemic risk in younger subjects

**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**

## No unreasonable cardiac arrest or mortality risk in younger subjects

**Mortality in HBOC-201 subjects:**
_**>**_** 70 years old vs. < 70 year old, p = 0.002 **

**Cardiac arrest in HBOC-201 subjects:**
_**>**_** 70 years old vs. < 70 year old, p = 0.01 **

**Notes:**
Cardiac arrest data: Biopure/OBRR “Combination 20” (29 June 2006)

Differences in incidences (delta) of key safety signals in > 70 vs. < 70 years old was consistently higher in HBOC-201 than RBC subjects. 

Data suggest that elderly patients may be particularly sensitive to even seemingly relatively mild to moderate vasoactive effects of HBOC-201. 

Awareness of potential vasoactivity risk in the elderly, exclusion of elderly, in-hospital trauma care guidelines, lower maximum doses, CTM stopping criteria, and comprehensive surveillance for adverse vasoactivity signals should diminish potential risk due to intrinsic vasoactivity in RESUS. 

## 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*_*”*

## Assumptions used to assess 21 CFR 50.24 benefit:risk requirements for RESUS

## Benefit:risk requirements of 21 CFR 50.24

- “*human* *subjects are facing a *_*life-threatening situation*__”_
- “_*available treatments are*_* unproven or *_*unsatisfactory*_”
- “_*research*_* holds out the *_*prospect of direct benefit*_”
- “_*preclinical studies...support...potential*_*...to provide...*_*benefit*_”
- “_*Risks*_* associated with the intervention *_*are reasonable in relation to what is known about the medical condition*_*...and risks and benefits of standard therapy”*

## 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*_”

## 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*_”

## 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*_”

## 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

## 6. Safety data in overall populations in prior HBOC-201 surgery/orthopedics trials are unlikely to accurately predict benefit:risk in RESUS

|  | HEM-0115 | RESUS |
| --- | --- | --- |
| Potential benefit | Transfusion avoidance | Survival |
| Clinical setting | Elective surgery/orthopedics
(inhospital) | Acute HS
(prehospital) |
| Population | Mainly elderly | Mainly younger adults |
| Exposure | Prolonged blood transfusion substitution | Brief oxygen bridge |
| Physiologic state | Mostly hemodynamically stable | Hemodynamically unstable |
| Comparator | Gold standard RBC transfusion | Crystalloid fluid |
| Study design | Asymmetric | Symmetric |

## 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*_*”*

## 6b. Even if one assumes prior trials accurately predict benefit:risk in RESUS, key safety signal group differences were narrowed in younger subjects

- Group differences were reduced in < 70 and < 50 year olds
- Improved safety in subjects without cardiovascular disease
- 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*_*”*

## 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*_*”*

## 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*_*”*

## 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*_*”*

## 10. Multiple protocol risk mitigation strategies further diminish risk in RESUS

- Optimization of target population selection
- Standardization and optimization of care with practice guidelines and training
- Allowance for concomitant standard care
- Inclusion of comprehensive surveillance methods
- “_*risks*_*...are *_*reasonable*_* in relation to...the *_*medical condition*_*”*

## I. Target population selection maximizes benefit and minimizes risk

- Targeting a population with severe HS without access to blood transfusions
- “*exsanguinating hemorrhage*”
- “*delay in emergency care*”
- Exclusion of elderly subjects
- 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*_*”*

**Notes:**
 Target a population with severe HS and without access to blood transfusion
 Maximizes benefit by enrolling population with high mortality but without access to optimal resuscitation; this minimizes risk.

 Exclude elderly
 Minimizes risk by excluding the older sub-population which had the highest incidence of significant SAEs

 Hypotension and tachycardia CTM re-infusion criteria
 Maximizes benefit by inclusion of more consistent markers of HS
 Minimizes risk of inadequate fluid resuscitation and hypoperfusion

## II. Standardization and optimization of care, training, and allowance for standard care minimize risk

- Thorough EMS and trauma center training
- Access to standard IV fluids during the prehospital period
- Improved standardization of prehospital care
- Access to standard blood transfusions immediately upon availability
- Standardization of in-hospital care
- “_*risks*_*...are *_*reasonable*_* in relation to...the *_*medical condition*_*”*

**Notes:**
 Thorough EMS and trauma center training
 Maximizes benefit, minimizes risk, and standardizes care by education about optimal practice guidelines

 Access to standard IV fluids during the prehospital phase
 Minimizes risk of inadequate fluid resuscitation and secondary hypoperfusion

 Standardization of prehospital care
 Maximizes benefit via optimal practice guidelines, minimizing risk of inadequate fluid resuscitation and secondary hypoperfusion

 Standardization of in-hospital care
 Minimizes risk of inadequate fluid resuscitation and secondary hypoperfusion
 Minimizes risk of inadequate blood transfusion resuscitation and secondary anemia

 Peak SBP (120 mm Hg) CTM stopping criterion
 Minimizes risk of uncommon idiosyncratic severe BP responses

## III & IV. Comprehensive surveillance methods allow early detection and action and minimize risk

- Prospective “*increased BP*” and “*hypertension*” coding definitions
- Extensive secondary outcome measurements
- “*Elevated blood lactate*” relative stopping criterion
- HBOC-201 infusion stopping criterion (SBP _>_ 120 mm Hg)
- Expedited AE reporting to DMC and FDA
- Hypoperfusion markers reports
- Early interim analyses
- “_*risks*_*...are *_*reasonable*_* in relation to...the *_*medical condition*_*”*

**Notes:**
 “Increased BP” and “hypertension” coding definitions
 Minimizes risk by promoting efficient regulatory AE reporting

 Extensive secondary outcome measurements
 Minimizes risk by comprehensively following safety signals

 Lactic acid trial relative stopping criterion
 Minimizes risk by stopping the trial if there is evidence of hypoperfusion

SBP stopping criterion SBP > 120 mm Hg
Minimizes risk by decreasing risk of rare idiosyncratic severe BP responses

 Expedited AE reporting
 Minimizes risk by ensuring efficient regulatory AE reporting

 Hypoperfusion markers reports
 Minimizes risk by comprehensively following potentially “vasoactivity-related” hypoperfusion safety signals, and ensuring efficient regulatory reporting

 Early efficacy and safety reviews
 Minimizes risk by ensuring early interim analysis of safety data and regulatory reporting (after enrollment  of only 25 HBOC-201 subjects)

## 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)

## FDA: “There is inadequate information to assess whether risks and benefits are reasonable...”

## 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

**Notes:**
(this is not a BLA)

## 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”

## 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*_*”*

## FDA:“Entry criteria for RESUS suggests that the patient population likely to be heterogeneous”

## Stratification of RESUS target population based on RTS ranges reveals reasonably homogeneous mortality and normalized distribution (UAB/UMD) 

-  Target pop. has normalized (bell-shaped) distribution (right)
-  Typical trauma trial U-shaped distribution excluded (right)

- Mortality (%)

- N

**Stratification of *****RESUS***** target population based on RTS ranges reveals reasonably homogeneous mortality and normalized distribution (**_**UAB/UMD**_**)**

## Stratification of RESUS target population based on RTS ranges reveals reasonable mortality homogeneity and distribution (NTDB) 

-  Mortality high in _all_ RTS stratifications (reasonably homogeneous pop.) (left)
-  Target pop. reasonably distributed (right)
-  Contrast with FDA RTS ranges from _[www.trauma.org](http://www.trauma.org/)_ (page 15)

- Mortality (%)

- N

## FDA:“For crystalloid/colloid controlled surgery studies..., the imbalances...persisted”

## “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*

## FDA:“...preclinical studies do not support... potential...to provide... direct benefit...”

## 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)

## 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*_*”*

## 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

## 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**

## 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**

## 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

## 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

## 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

## 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)

**Notes:**
Sauaia A, Arch Surg 1994
Moore FA, Arch Surg 1997
Claridge JA, Am Surg 2002
Malone DL, J Trauma 2003
Malone D, Crit Care Med 2003
Hill GE, J Trauma 2003
Dunne JR, Surg Infect 2004

## 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)

## 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”

## 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

## 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

***	******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**

## 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

## FDA:

“...increases in SBP to 220 mm Hg have been noted with HBOC-201”

**“*****...******increases in SBP to 220 mm Hg have been noted with HBOC-201*****”**

- 4 out of 826 subjects (< 0.5%)

## Rare hypertension SAEs in euvolemic and hypertensive subjects do not affect benefit:risk in hypovolemic/hypotensive subjects in RESUS 

**HEM-0115 **(61 y/o) (“*uncontrolled HTN*, “*tachycardia*”)
*Unrelated*, euvolemic & hypertensive when CTM started, post-10th dose and 5 days of exposure, resolved
**HEM-0115** (39 y/o) (“*persistent HTN*”)
*Unrelated* (43 days post-CTM), euvolemic when CTM started, resolved
**COR-0001** (54 y/o) (“*severe HTN not responding to meds*”)
*Related*, euvolemic & hypertensive when CTM started, resolved
**COR-0001** (60 y/o) (“*severe* *HTN*, *EMD*, *MI*, *CVA*”)
- HTN *related*, complications *unrelated*, euvolemic & hypertensive when CTM started, resolved

## FDA:“There are very limited clinical data on dose and rate of administration using HBOC-201 to support the RESUS dosing guidelines”

## 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

## 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*

## Extensive HEM-0115 clinical data with < 6 units of HBOC-201 predict reasonable risk (especially in younger subject) and support RESUS max. dose

- * 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*

## 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.*

## 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)

## 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

## Preclinical and clinical data support RESUS Dosing Guidelines

**Maximum dose**
- Extensive preclinical data
- Extensive clinical data with* reasonable* safety, especially in younger subjects (HEM-0115)
- Limited clinical trauma data with *favorable* safety (HEM-0125)
- Similar *SBP responses* in DCLHb prehospital trauma trial
**Infusion rate**
- Extensive preclinical data
- Limited clinical data with *reasonable* safety (HEM-0115)
- Limited clinical trauma data with *favorable* safety (HEM-0125)

## Non-serious AEs

## 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 ?

## 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***
**	**

## 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

## 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

## Definition of MI(ESC/ACC consensus, Alpert, 2000)

*	**“**Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI:*
*	**1) *_*Typical rise and gradual fall (troponin*__*)*_*...of biochemical markers of myocardial necrosis *_*with at least one of the following*_*:*
*	**	**a) **Ischemic symptoms*
*	**	**b) development of pathologic Q waves on the ECG;*
*	**	**c) **ECG changes** indicative of ischemia (ST segment elevation or **	**depression); or*
*	**	**d) coronary artery intervention (e.g., coronary angioplasty).*
*	**2) Pathologic findings of an acute MI*”

## 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*”

## That most were low level troponin T elevations and fewer met ESC/ACC definition in HEM-0115, predicts lower risk in RESUS

| Subject | ng/L | AHA Scientific Statement Criteria 
(Luepker RV, Circulation 2003)  |
| --- | --- | --- |
| 1 | 0.10 | Isolated |
| 2 | 0.12 | Isolated then detectable <  ROC |
| 3 | 0.12 | Isolated then detectable <  ROC |
| 4 | 0.12 | Isolated then detectable <  ROC |
| 5 | 0.12 | Isolated then detectable <  ROC |
| 6 | 0.12 | Isolated |
| 7 | 0.13 | Isolated then detectable <  ROC |
| 8 | 0.16 |  Pre-CTM  |
| 9 | 0.17 |  Pre-CTM  |
| 10 | 0.17 | Serial |
| 11 | 0.18 | Isolated |
| 12 | 0.24 | Isolated |
| 13 | 0.26 | Isolated then detectable <  ROC |
| 14 | 0.26 | Serial |
| 15 | 0.31 | Serial |
| 16 | 0.58 | Serial (MI) |
| 17 | 0.89 | Serial |
| 18 | 5.6 |  Pre-CTM* |

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

****** ** Lower group difference

- * Troponin I

## Low risk of troponin elevations in younger subjects in HEM-0115 predicts low risk in RESUS

**> ROC data**

## Troponin elevation was an isolated lab abnormality without significant effect on predicted benefit:risk in RESUS

**Less *****a priori***** significance (Alpert 2000, Luepker 2003)**
- CK-MB equivalent
**Questionable clinical significance**
- Only 1/18 associated with MI
- Low level elevations
**Lower group differences in younger subjects**
**No adverse signal in preclinical studies**
- Equivalent or improved myonecrosis and troponins in HS
- Decreased infarct size in acute coronary stenosis models
***RESUS***** risk mitigation strategies**

**Notes:**
Note: ESC/ACC  consensus: only 5-11/18 met typical rise and gradual fall requirement (Alpert 2000). AHA Scientific Statement: only 1/18 met diagnostic biomarkers case-definition (Luepker RV, 2003).

^  “Isolated” troponin elevations have been reported to often be “spurious” (e.g., Ng SM, 2001). 

## Semi-quantitative predictions of benefit:risk in RESUS

## 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*”

## 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)

## 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)

## Conclusions(RESUS target population)

- HS is the most common potentially preventable cause of death in trauma, most occurring during the prehospital phase
- 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

## Conclusions(RESUS preclinical database)

- The breadth and redundancy of improved outcome in preclinical HS studies predict *prospect for benefit* in humans in *RESUS*
- 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

## Conclusions(RESUS clinical database)

- 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*
- 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*
- 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*

## Conclusions(overall RESUS benefit:risk prediction)

- Qualitative analysis of preclinical and clinical studies predicts *highly* *favorable* benefit:risk in *RESUS*
- Semi-quantitative analyses of preclinical and clinical HBOC-201 studies robustly demonstrate *Excess SAE Score (ESS) <* 1, predicting *highly favorable* benefit:risk in *RESUS*
- Extensive protocol risk mitigation strategies further minimize risk in *RESUS*, strengthening prediction of *highly favorable* benefit:risk in *RESUS*

## Conclusions(regulatory requirements)

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

## BIRMINGHAM REGIONAL EMERGENCY MEDICAL SERVICES SYSTEM

- BREMSS/UAB
- Joe Acker  EMT-P, MPH
- Executive Director

## 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

## Why do we need the RESUS study ? 

- A – airway
- B- ventilation
- C- circulation

## 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 !

## IMPACT ON TRAUMA CARE

- Lewis J. Kaplan, MD, FACS, FCCM, FCCP
- Associate Professor Of Surgery
- Yale University School of Medicine
- Section of Trauma, Surgical Critical Care and Emergency General Surgery
- Director, SICU and Surgical Critical Care Fellowship

## IMPACT ON TRAUMA CARE

- Pre-hospital trauma care
- No significant advances since 1970’s
- “Load and go” care
- Trauma and critical care advances
- In-hospital
- Depends on receiving a sustainable patient
- Paradigm changes over the last 20 years
- HBOC-201
- Addresses pre-hospital needs
- blood is not available

## IMPACT ON TRAUMA CARE

- High-risk patient population
- Hospital course marked by AE’s and SAE’s as part of the disease process
- Benefits >> Risks
- Military and civilian arenas
- Trial design
- HBOC implementation
- Mass and single casualty survival