Northfield Laboratories Releases Summary Observations from Its Elective Surgery Trial

Northfield Laboratories Inc. (NASDAQ: NFLD) announcedtoday that in light of heightened interest in its Phase III electivesurgery trial with PolyHeme conducted in the late 1990s, the Companywould provide an extended summary of the major observationsimmediately. This release is in lieu of the previously announcedpresentation of an abstract at the Network for Advancement ofTransfusion Alternatives (NATA) meeting in April. The purpose of thissummary is to describe the objectives of the study, the study design,the procedure of acute normovolemic hemodilution (ANH), the populationstudied, and the major safety and efficacy observations.

Key points about the study and summary observations are:

-- The study was designed to assess whether the use of PolyHeme would allow an increase in the volume of autologous blood collected during ANH and therefore avoid transfusion of donated blood.

-- The study demonstrated that a greater volume of the patient's blood could be collected during ANH with the use of PolyHeme.

-- The study did not achieve its objective of avoiding transfusion of donated blood.

-- The algorithm in the protocol resulted in multiple treatment differences between the two groups in the study.

-- Ten patients in the treatment group experienced myocardial infarction versus none in the control group. Two of these patients died, at 7 and 32 days.

-- The cardiovascular events noted are in sharp contrast to our trauma experience in which PolyHeme has been given in doses up to 20 units and has been well-tolerated.

-- It cannot be determined whether the cardiovascular events were due to the more extensive ANH in the treatment group, to the reinfusion of more blood following surgery in the treatment group or to PolyHeme(R) itself.

-- Northfield does not believe the cardiovascular events were due to a direct pharmacologic effect of PolyHeme, but to complex fluid management issues in these patients.

Acute Normovolemic Hemodilution (ANH) Study

Summary of Major Observations

Background

The Phase III elective surgery study discussed below was conductedbetween 1998 and 2000. Northfield was concurrently conducting a PhaseII study with PolyHeme in trauma patients in the hospital setting,with doses up to 20 units.

Enrollment in the elective surgery study progressed slowly due toa number of factors, as Northfield reported at the time. The protocolwas complex and required additional time in the operating room.Endovascular stent grafting was being developed and was changing thesurgical approach to repair of abdominal aortic aneurysm. The studywas originally slated to enroll 240 patients. However, in August 1998,FDA requested that the number of patients be increased to 600, basedon another sponsor's safety experience with a differenthemoglobin-based oxygen carrier in the trauma setting. A singleinterim analysis was scheduled to be conducted by an Independent DataMonitoring Committee (IDMC) after 120 patients were enrolled. At theinitial review, the IDMC noted certain differences between the twostudy groups. The IDMC asked that the data be unblinded and additionalanalysis be undertaken to assess whether the observed differences weredue to randomization failure, a treatment confounder, or a possiblestudy drug effect. At the time of this request, 138 patients had beenenrolled. The analysis revealed the myocardial infarctions (MIs) inthe treatment group, and also revealed that the incidence was notevenly distributed among participating sites, which would have beenexpected if the MIs were due to a direct effect of PolyHeme.

The above findings were reported to FDA. Northfield also informedFDA that in view of the complexity of the protocol and the slow rateof accrual, it had begun to close slow enrolling sites and wouldsubmit a study report to FDA.

Study Objectives

This was a randomized, controlled, open-label, multi-center,parallel group, Phase III protocol designed to evaluate the safety andefficacy of PolyHeme, an investigational human hemoglobin-based oxygencarrier, used as a red blood cell substitute during acute normovolemichemodilution (ANH) and the peri-operative period in adult patientsexperiencing planned acute blood loss during elective surgery forabdominal aortic aneurysm (AAA). ANH is a procedure of withdrawing aunit of blood from a patient and replacing the volume with colloidsolutions that replace the withdrawn volume, but do not carry oxygen.The goal of ANH is to minimize the loss of the patient's own(autologous) red cells during surgery and potentially reduce or avoidthe use of allogeneic (donated) transfusion. ANH is generally limitedto withdrawing only two units of the patient's own blood, because ifmore is withdrawn, the patient's hemoglobin falls to an unacceptablylow level.

The primary objective of this study was to evaluate whether usingPolyHeme during ANH would allow for the collection of larger volumesof the patient's own blood to be stored for later return to thepatient, thus potentially reducing or avoiding transfusion of donatedblood throughout the first seven days postoperatively. The potentialto avoid transfusion exists because PolyHeme is a colloid that alsoprovides supplemental hemoglobin to replace that withdrawn during ANH.Other protocol objectives were to evaluate the safety profile ofPolyHeme through assessment of patients' vital signs, laboratorymeasurements, and adverse events. Safety was assessed through 12 weeks(84 days) after surgery.

Two hundred and forty patients were to be randomized to one of twogroups: either the treatment group (replacement with standardsolutions and PolyHeme) or control group (replacement with standardsolutions only).

Study Design

The study was organized into four distinct phases: the periodbefore surgery, the period during surgery, the period following thesurgery, and the follow-up period. Up to six units of PolyHeme couldbe infused into the treatment group during the pre-operative andintra-operative periods only.

Before the Surgery

In order to be eligible for this study, patients were required tohave a total hemoglobin concentration of at least 11 g/dL (normaladult circulating hemoglobin concentration is approximately 12-14g/dL). There were no specific exclusion criteria related tocardiovascular disease or risk factors. All patients provided informedconsent. Patients underwent ANH in the operating room. ANH wasperformed by removing a 500 mL-unit of blood (ANH unit) and replacingit with a 500 mL colloid infusion. A maximum of approximately 60% ofthe blood volume of each patient, usually about 6 units, couldpotentially be collected based on body weight. The blood collectedduring ANH was replaced with the colloid Hespan for the first twounits, and then with the colloid 5% albumin, as long as the total (Hb)was greater than or equal to 9 g/dL. The use of Hespan was limited totwo units since more could produce coagulation disturbances. Totalhemoglobin concentrations were measured after each unit of blood hadbeen removed and the volume had been replaced.

If the patient's hemoglobin concentration fell to less than 9 g/dLbefore all planned units had been obtained, the treatment and controlgroups were treated differently. In the control group, ANH was stoppedbefore the maximum numbers of ANH units were collected. In thetreatment group, ANH continued using PolyHeme because PolyHeme, incontrast to Hespan or 5% albumin, provides supplemental hemoglobin toreplace the hemoglobin lost as blood was withdrawn during ANH.

In both the control and the treatment groups, ANH was to bestopped at any time if there was any evidence of unstable vital signs,cardiac ischemia, or other clinical evidence of the patient'sinability to tolerate further anemia. Even if ANH were stopped beforethe planned maximum number of units was collected, the patient wouldremain in the study for evaluation.

The following schematic illustrates the complexity of the ANHportion of the study. (See graph.)

During Surgery

The transfusion decision during surgery was made in theconventional manner in both groups, based on clinical signs, vitalsigns, and hemoglobin levels. Total hemoglobin was measured hourly.During the surgery, any blood the patient lost was also collected andreinfused prior to each hourly hemoglobin determination. If the totalhemoglobin was greater than or equal to 8 g/dL, and the patient wasclinically stable, no transfusion was given. If the patient's totalhemoglobin was less than 8 g/dL, the control group received atransfusion of either autologous blood (ANH units) or allogeneic bloodand the treatment group received either PolyHeme, ANH units orallogeneic blood, one unit at a time, until total hemoglobin wasgreater than or equal to 8 g/dL, even if the patient was clinicallystable.

In the control group, the first transfusions given during surgerywere the ANH units. The units were transfused on a "last unit out,first unit in" basis. In the treatment group, PolyHeme was transfusedfirst. If a total of six units of PolyHeme had been infused during thepre-operative and operative period and further transfusion wasrequired, ANH units were given, as needed, on the "last unit out,first unit in" basis.

In both groups, if all collected ANH units had been transfused andfurther transfusions were required, allogeneic blood was to beadministered unit-by-unit, as needed.

Following Surgery

When the operation had been completed, the collected ANH units orallogeneic blood were transfused as needed for patients to achievehemoglobin concentrations greater than or equal to 9 g/dL. Anyautologous blood not used within twenty-four hours was discarded, inaccordance with current blood banking standards.

Follow-up Period

At six and twelve weeks, patients returned to the hospital forassessment of vital signs, laboratory measurements, and adverseevents.

Study Population

One hundred and fifty two (152) patients were enrolled at 18different sites. The number of patients enrolled at participatingsites ranged from one patient at some centers to 43 patients at thehighest enrolling site. There were 81 patients randomized to receivePolyHeme (treatment group) and 71 randomized to the control group.Nearly half of the 152 patients (71 patients or 47%) were enrolled attwo sites (43 patients and 28 patients). Males comprised 93% of thepatients in the treatment group and 83% of the control group. The meanage in the treatment group was 70.1 years and 71.4 years in thecontrol group.

Study Design Confounders

The design of the protocol resulted in two different treatmentregimens in the treatment and control arms of the study. Differentvolumes of blood were removed and replaced as a part of ANH (2.8liters in the treatment group and 1.5 liters in the control group) anddifferent colloids were used as replacement fluids (Hespan, albumin,and PolyHeme versus only Hespan and albumin). The protocol designtherefore resulted in the administration of two different totalvolumes and different replacement fluids, representing twosubstantially different colloid loads. In addition, the total volumeof oxygen-carrying blood products returned to the treatment andcontrol groups during the first 24 hours was markedly different (4.4liters in the treatment group versus 2.2 liters in the control group).As a result, the treatment difference between the groups was notsimply the infusion of PolyHeme in the treatment arm. This representsa departure from the usual scientific design where only one variableat a time is changed between two study groups.

In summary, the treatment group experienced:

(1) Removal of larger volumes of autologous blood during ANH;

(2) Infusion of larger volumes of colloid replacement during ANH (Hespan, albumin, PolyHeme);

(3) Reinfusion of larger volumes of autologous blood, PolyHeme, and allogeneic blood throughout the perioperative period; and finally

(4) Infusion of up to six units of PolyHeme.

Evaluation of the Primary Study Objective: Avoidance of AllogeneicBlood

The primary study objective was to increase the number of patientswho avoided allogeneic blood (donated) transfusion in the treatmentgroup compared to the control group. Overall 38% of the patientsassigned to receive PolyHeme avoided allogeneic blood compared to 40%of the control group. This study did not meet its primary studyobjective.

Evaluation of Safety: Adverse Events

Adverse events (AEs) are defined as any untoward medicaloccurrences that occur in subjects administered any dose of a studydrug (in either group), regardless of whether there is a relationshipto the drug being studied. Serious adverse events (SAEs) are definedas any adverse drug experience, occurring at any dose that results inany of the following outcomes: (1) death (2) a life-threateningadverse drug experience (3) inpatient hospitalization or prolongationof existing hospitalization (4) a persistent or significantdisability/incapacity, or a congenital anomaly/birth defect or (5)other important medical events as judged by the investigator.

In any study, AEs and SAEs may be due to either the underlyingcondition of the patient, the treatment setting, the specifictreatment, or the investigational product. Investigators report theAEs and SAEs, characterize them as an AE or SAE based on prescribedregulatory definitions, and ascribe a relationship of theinvestigational product to the events ranging from "unrelated,""remotely related," "possibly related," to "probably related." In thisstudy, the investigators were not blinded to the treatment assignment.The attribution of an event in a patient who received several types ofsolutions, (Hespan, albumin, PolyHeme and autologous and donatedblood) would therefore be less straightforward than a patientreceiving only a single test solution.

At least one AE was reported for 99% of patients who receivedPolyHeme and 97% of patients who received control. In general,specific adverse events occurred with similar incidence in the twogroups. Serious adverse events were reported in 54% of patients whoreceived PolyHeme and in 28% of patients who received control. Theprincipal difference was the occurrence of myocardial infarction (MI)in the treatment group. None of the SAEs in either group was judged bythe investigator as "probably related" to study treatment. Only oneSAE (rash) in a patient receiving PolyHeme was reported as "possiblyrelated."

Myocardial infarction was reported for 10 of the 81 patients(12.3%) in the treatment group and none of the patients in the controlgroup. The patients who experienced MI ranged in age from 57 to 82years. All of these patients had at least one risk factor for heartdisease, such as hypertension or hypercholesterolemia, and eight ofthe ten patients were smokers. The MIs occurred within 0 to 7 daysafter AAA surgery. Nine of the 10 patients in the treatment group whohad MIs had adverse events consistent with fluid overload, includingatrial fibrillation, congestive heart failure, respiratoryinsufficiency, pulmonary edema and peripheral edema. Only one of the35 patients in the treatment group who were enrolled at the twohighest enrolling sites experienced MI.

Eight of the 10 patients with MI survived and two died (one at 7days and one at 32 days). Four of the MIs were reported as "remotelyrelated" to study treatment and six as "not related."

All patients had ECG tracings done in the operating room atbaseline and following completion of ANH. All of the ECG tracings wereread by an independent cardiologist who was blinded to the groupassignment. There were no differences in ECG tracings between thetreatment group and the control group. There were no differences inECG tracings before and after ANH following infusion of PolyHeme inthe treatment group. This is important because the historical concernhas been that some hemoglobin-based oxygen carriers have causedcoronary vasoconstriction that would reduce coronary perfusion andresult in myocardial ischemia.

Assessment of Safety: Mortality

A total of eight deaths (9.9%) in the treatment group and four(5.6%) in the control group were reported. The time of death isrelevant. Surgical mortality rates are traditionally defined as deathsthat occur within 30 days following surgery. All four deaths in thecontrol group occurred during this period for a mortality rate of 5.6%(at 3, 14, 17, and 22 days). In contrast, only three of the eightdeaths in the treatment group occurred during this period, for amortality rate of 3.7% (at 7, 15, and 18 days), while five were latedeaths (at 32, 42, 42, 75, and 96 days). Furthermore, five of theseeight patients died following discharge from the hospital. Althoughthe protocol defined the follow up to 84 days after surgery, anydeaths that were known by the investigators to have occurred afterthat follow-up period are also included in this analysis.

Key Observations

There are a number of important conclusions that can be drawnbased on the experience described here. ANH itself is a non-routineprocedure, traditionally limited to removal of approximately 20% to30% of a patient's blood volume. The goal in this study was to usePolyHeme to extend the ANH to 60% of the patient's blood volumebecause of the ability of PolyHeme to provide supplemental hemoglobinto replace that lost with removal of larger quantities of thepatient's own blood. The study was, therefore, designed to measure theavoidance of allogeneic blood and look for an improvement with the useof PolyHeme.

The results indicate that extended ANH, with removal of up to 60%,or 6 units, of the patient's blood volume can be accomplished withPolyHeme. However, the study did not achieve its endpoint of avoidanceof allogeneic blood.

This was a complex protocol with multiple treatment confounders.The protocol design resulted in the treatment group being differentfrom the control group in four important ways:

(1) Removal of twice as much blood during the ANH procedure, namely six units of blood versus three units of blood and thus,

(2) Infusion of twice as much fluid to replace the removed blood;

(3) Reinfusion or return of more blood and oxygen-carrying products during and after surgery; and lastly

(4) Infusion of up to six units of PolyHeme.

Ten patients in the treatment group experienced myocardialinfarction versus none in the control group. Two of these patientsdied, at 7 and 32 days. Because of the study design, it is notpossible to separate the influence of PolyHeme from the otherdifferences in the treatment group. We believe the accompanying largertotal volume infusions led to complex fluid management issues in thesepatients. We do not believe that these events are due to a directpharmacologic effect of PolyHeme.

About Northfield Laboratories

Northfield Laboratories Inc. is a leader in developing anoxygen-carrying resuscitative fluid, PolyHeme(R), for the treatment ofurgent, large volume blood loss in trauma and resultant surgicalsettings. PolyHeme(R) is a solution of chemically modified humanhemoglobin that requires no cross matching and is therefore compatiblewith all blood types. It has a shelf life in excess of 12 months.Enrollment is currently underway in a pivotal Phase III trial ofPolyHeme(R) beginning in the pre-hospital setting. For furtherinformation, visit www.northfieldlabs.com.

This press release may contain forward-looking statementsconcerning, among other things, Northfield's future business plans andstrategies and clinical and regulatory developments affecting ourPolyHeme(R) red blood cell substitute product. These forward-lookingstatements are identified by the use of such terms as "intends,""expects," "plans," "estimates," "anticipates," "should," "believes"and similar terms. These forward-looking statements involve inherentrisks and uncertainties. Our actual results may therefore differmaterially from those predicted by the forward-looking statementsbecause of various factors and possible events, including our abilityto obtain FDA approval to market PolyHeme commercially, theavailability of capital to finance our clinical trials and ongoingbusiness operations, our ability to obtain adequate supplies of rawmaterials and to manufacture PolyHeme in commercial quantities, ourability to market PolyHeme successfully, the possibility thatcompetitors will develop products that will render PolyHeme obsoleteor non-competitive, our ability to protect our intellectual propertyrights, the possibility that we may be subject to product liabilityclaims and other legal actions, our dependency on a limited number ofkey personnel, the uncertainty of third party reimbursement for ourproduct and other risks and uncertainties described from time to timein our periodic reports filed with the Securities and ExchangeCommission, including our most recently filed quarterly report on Form10-Q and annual report on Form 10-K. These forward-looking statementsspeak only as of the date of this press release. We do not undertakeany obligation to update or publicly release any revisions toforward-looking statements to reflect events, circumstances or changesin expectations after the time such statement is made. All subsequentwritten and oral forward-looking statements attributable to Northfieldor any person acting on our behalf are qualified by this cautionarystatement.