Healthcare Industry News: EKG
News Release - October 10, 2007
Multicenter PolyHeme Trauma Study Presented at the American College of Surgeons 93rd Annual Clinical Congress
Findings Presented by Lead Investigator Ernest E. "Gene" Moore, M.D., Chief of Surgery and Trauma Services, Denver HealthEVANSTON, Ill.--(HSMN NewsFeed)--Northfield Laboratories Inc. (Nasdaq: NFLD ) announced that Ernest E. "Gene" Moore, M.D., lead investigator of the Company's pivotal Phase III trial with PolyHeme® for the treatment of urgent, life-threatening blood loss in severely injured patients, reported study findings today at the American College of Surgeons 93rd Annual Clinical Congress in a presentation entitled Post-Injury Resuscitation with Human Polymerized Hemoglobin: The USA Multicenter Trial.
"PolyHeme can play a key role in trauma care by providing a survival benefit to bleeding patients who do not have access to blood. The study documents that it is feasible to carry PolyHeme in ambulances; therefore, PolyHeme can be useful in rural areas and on the battlefield, as well as in the hospital," said Dr. Moore.
Following is an overview of Dr. Moore's presentation. Tables may be found at the end of this press release.
Dr. Moore pointed out that the PolyHeme study was the first U.S. Phase III clinical trial of a "blood substitute" beginning at the scene of injury and continuing in the early hospital period. PolyHeme is a solution of chemically modified human hemoglobin that requires no cross matching and is therefore compatible with all blood types. The study was designed to evaluate the safety and efficacy of PolyHeme, when administered to severely injured and bleeding patients in hemorrhagic shock. The study explored two potential benefits of PolyHeme: providing early oxygen-carrying capacity when stored blood is not available, and reducing the immunoinflammatory consequences of early transfusion of stored red blood cells that can lead to multiple organ failure. The study was conducted under 21 CFR 50.24, a federal regulation allowing the enrollment of patients in emergency research with an exception from the requirement for informed consent. Thirty-two Level I trauma centers in 19 states participated in the study.
Patients were randomized and enrolled in the field by EMS first responders. There were 350 patients randomized to PolyHeme and 364 to control. The groups were matched in terms of age, sex, mechanism of injury, blood pressure upon entry, Injury Severity Score (ISS) and transport time. See Table 1.
Efficacy
The primary efficacy endpoint of the study was Day 30 mortality. As previously reported by Northfield, the study results (Table 2) did not meet the agreed upon statistical boundary for the primary efficacy endpoint in the primary Modified Intent to Treat population (patients analyzed in the group to which they were randomized). However, there was no statistically significant difference in mortality at Day 30 between patients who received PolyHeme beginning at the scene and continuing for up to 12 hours following injury or a dose of 6 units, and control patients who received the standard of care, including early blood transfusion, upon arrival at the hospital. A press release dated May 19, 2007 describing these results and the statistical analysis in detail is available at www.northfieldlabs.com.
Dr. Moore discussed mortality by mechanism of injury (blunt versus penetrating trauma) and the incidence of multiple organ failure. The analysis of Day 30 mortality by mechanism of injury revealed no treatment by mechanism interaction (p=0.11). The Day 30 mortality in patients with penetrating injury who received PolyHeme was 9% (16/183) compared with 10% (18/187) in control. In patients with blunt injury, the rate was 18% (30/165) in the PolyHeme group compared with 10% (18/175) in control.
Multiple organ failure (MOF) was prospectively evaluated by a blinded, independent adjudication committee, using the Denver MOF scoring system. MOF occurred in 7% (26/349) of PolyHeme patients and 6% (20/365) of control. However, it was observed that 23 of the 26 PolyHeme patients and 18 of the 20 control patients received six or more units of stored red blood cells. Dr. Moore noted that this finding is important because transfusion of six or more units of stored red blood cells is a major independent risk factor for the development of MOF.
Safety
The primary safety endpoints in the study were Day 1 mortality, Day 30 mortality, and durable serious adverse events (SAEs). Durable serious adverse events were prospectively defined as SAEs which resulted in a "permanently disabling" outcome. There was no statistically significant difference between the PolyHeme and control groups for any of these endpoints.
Adverse events and serious adverse events, as reported by investigators, were analyzed according to the treatment the patient actually received. As expected in any trial of seriously injured patients, adverse events were reported in virtually all patients: 93% (324/329) in the PolyHeme patients and 88% (322/365) in the control (p=0.04). Serious adverse events were reported in 40% (141/349) of PolyHeme and 35% (126/365) of control (p=0.12). The most common serious adverse events reported by investigators in addition to MOF are shown in Table 3.
There was an imbalance in the number of investigator-reported myocardial infarctions (MIs), with 11 reported in the PolyHeme group compared with three in control. This total includes one MI in each group that was not reported as a serious adverse event. The low overall incidence of MIs (2%) is in contrast to the higher rates of abnormal EKGs and elevated cardiac enzymes and biomarkers in both groups. Myocardial infarction and myocardial ischemia are traditionally assessed by EKGs and Troponin I and CK-MB levels, both of which can be altered by direct trauma. Approximately 75% of the patients in this study had abnormal EKGs or elevated cardiac enzymes. The breakdown of MIs by category is shown in Table 4. Cardiology evaluation recommended cardiac catheterization for one patient in each group; otherwise no interventions were necessary. Three PolyHeme and one control patient with MI died by Day 30. None of the MIs were considered by the investigators to be "possibly" or "probably" related to the investigational product.
Dr. Moore noted that the cardiovascular effects of this class of products have been of particular interest. Combined cardiac and vascular adverse events as reported by investigators, focusing on the categories of heart failure, serious rhythm disturbances and stroke, were similar in the two groups (Table 5).
"There is an undisputed need for an oxygen carrier for the treatment of bleeding patients when blood is not available. Based on the data from this study and data from previous in-hospital studies with PolyHeme, we believe PolyHeme can provide a survival benefit to bleeding patients who don't have access to blood," concluded Dr. Moore.
The PolyHeme Study Group is currently preparing a manuscript for publication. Investigators will be reporting trial results in communities in which the study was conducted as specified under 21 CFR 50.24.
Northfield intends to seek approval for PolyHeme by submitting a Biologics License Application to FDA with a request for priority review.
About Trauma
According to the Centers for Disease Control, trauma is the leading cause of death in Americans under the age of 45, claiming more than 140,000 lives and permanently disabling 80,000 people each year. Forty seven million Americans live more than an hour away from a trauma center, and only one in four lives in an area served by a coordinated trauma care system. Sixty percent of trauma deaths occur in rural settings, even though those areas account for only 20% of the U.S. population.
About Northfield Laboratories
Northfield Laboratories Inc. is a leader in developing an oxygen-carrying red blood cell substitute for the treatment of life-threatening blood loss, when an oxygen-carrying fluid is required and red blood cells are not available. PolyHeme® is a solution of chemically modified human hemoglobin that requires no cross matching and is therefore compatible with all blood types. It has a shelf life in excess of 12 months. For further information, visit www.northfieldlabs.com.
This press release may contain forward-looking statements concerning, among other things, Northfield's future business plans and strategies and clinical and regulatory developments affecting our PolyHeme red blood cell substitute product. These forward-looking statements are identified by the use of such terms as "intends," "expects," "plans," "estimates," "anticipates," "should," "believes" and similar terms. These forward-looking statements involve inherent risks and uncertainties. Our actual results may therefore differ materially from those predicted by the forward-looking statements because of various factors and possible events, including the possibility that since the data from our Phase III clinical trial have not been submitted to, or reviewed by, FDA, they may not be sufficient to demonstrate the safety or effectiveness of PolyHeme, our ability to obtain FDA approval to market PolyHeme commercially, our ability to obtain priority review, the availability of capital to finance our clinical trials and ongoing business operations, our ability to obtain adequate supplies of raw materials and to manufacture PolyHeme in commercial quantities, our ability to market PolyHeme successfully, the possibility that competitors will develop products that will render PolyHeme obsolete or non-competitive, our ability to protect our intellectual property rights, the outcome of certain governmental inquiries and purported class action lawsuit as described in our most recently filed annual report on Form 10-K and quarterly report on Form 10-Q, the possibility that we may be subject to product liability claims and other legal actions, our dependency on a limited number of key personnel, the uncertainty of third party reimbursement for our product and other risks and uncertainties described from time to time in our periodic reports filed with the Securities and Exchange Commission, including our most recently filed annual report on Form 10-K and quarterly report on Form 10-Q. These forward-looking statements speak only as of the date of this press release. We do not undertake any obligation to update or publicly release any revisions to forward-looking statements to reflect events, circumstances or changes in expectations after the time such statement is made. All subsequent written and oral forward-looking statements attributable to Northfield or any person acting on our behalf are qualified by this cautionary statement.
TABLES TO FOLLOW
Table 1
Patient Demographics
Study Entry PolyHeme(R) Control
(Prehospital) (n = 350) (n = 364)
----------------------------------------------------------------------
Age (+/-SEM(a)) - years 36 +/- 0.8 38 +/- 0.9
Male 78 % 79 %
Penetrating 53 % 52 %
SBP (+/-SEM) - mmHg(b) 78 +/- 0.7 78 +/- 0.6
ISS(c) (+/-SEM) 20 +/- 0.8 19 +/- 0.7
Transport time - min 26 26
----------------------------------------------------------------------
PT(d) greater than 17 secs 29% 20%
PTT(d) greater than 40 secs 23% 19%
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(a) +/-Standard error of the mean(b) Systolic blood pressure in millimeters of mercury
(c) Injury Severity Score
(d) Coagulation tests
Table 2
Day 30 Mortality
Study As As Per
Group Randomized(a) Treated(b) Protocol(c)
(n = 714) (n = 714) (n = 590)
----------------------------------------------------------------------
PolyHeme(R) 13% 13% 11%
(47/350) (46/349) (31/279)
----------------------------------------------------------------------
Control 10% 10% 9%
(35/364) (36/365) (29/311)
----------------------------------------------------------------------
(a) As Randomized
The As Randomized, or Modified Intent to Treat, population is comprised of all 714 patients both randomized and treated. In this population, patients were analyzed as they were randomized, and not based on the actual treatment they received. There were 21 patients randomized to PolyHeme who did not receive any PolyHeme but who were analyzed in the PolyHeme group. Similarly, there were 20 patients randomized to control who did receive PolyHeme and were who analyzed in the control group.
(b) As Treated (AT)
The AT population is also comprised of all 714 patients both randomized and treated. However, in this population all patients were analyzed according to the treatment they actually received. Therefore, all patients who did receive PolyHeme were analyzed in the PolyHeme group, and all patients who did not receive any PolyHeme were analyzed in the control group.
(c) Per Protocol (PP)
The PP population is comprised of the 590 patients both appropriately randomized and correctly treated. The PP population does not include 124 patients who had major protocol violations related to eligibility or treatment regimen, and therefore represents an opportunity to assess a treatment effect in patients who were treated exactly as specified in the study protocol.
Table 3
Most Common Serious Adverse Events (greater than 2%)
Adverse Event PolyHeme(R) Control
(Reported by PI) (n = 349) (n = 365)
----------------------------------------------------------------------
Pneumonia 8% 6%
(27) (21)
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Hemorrhagic shock 6% 4%
(20) (16)
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Respiratory failure 6% 5%
(21) (17)
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Hypercoagulable state 5% 3%
(18) (12)
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Coagulopathy 4% 1%
(13) (4)
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Sepsis 3% 3%
(12) (11)
----------------------------------------------------------------------
Myocardial infarction 3% 1%
(10) (2)
----------------------------------------------------------------------
Table 4
Myocardial Infarction by Category
Adverse Event PolyHeme(R) Control
(Reported by PI) (n = 349) (n = 365)
----------------------------------------------------------------------
Myocardial Infarction (total)(a) 11 (3%) 3 (1%)
----------------------------------------------------------------------
Myocardial Infarction 7 2
----------------------------------------------------------------------
NSTEMI 3 0
----------------------------------------------------------------------
Non Q Wave MI 0 1
----------------------------------------------------------------------
Acute Traumatic MI 1 0
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Requiring Intervention 1 1
----------------------------------------------------------------------
Death Within 30 Days 3 1
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(a) Two MIs, one in each group, were reported as adverse events, not
serious adverse events.
Table 5
Cardiovascular Events
Adverse Event PolyHeme(R) Control
(Reported by PI) (n=349) (n=365)
----------------------------------------------------------------------
Heart failure/CHF/PE/ 5% 5%
Fluid overload/Hypervolemia (17) (20)
----------------------------------------------------------------------
Cardiac arrest/EMD/V-fib/ 4% 2%
V-arrhythmia/V-tach / (14) (9)
----------------------------------------------------------------------
CVA/Cerebral ischemia/ 1% less than 1%
Cerebral infarction (3) (1)
----------------------------------------------------------------------
Source: Northfield Laboratories
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