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Northfield Laboratories Releases Summary Observations from Its Elective Surgery Trial

EVANSTON, Ill.--(BUSINESS WIRE)--March 20, 2006--Northfield Laboratories Inc. (NASDAQ: NFLD) announced today that in light of heightened interest in its Phase III elective surgery trial with PolyHeme conducted in the late 1990s, the Company would provide an extended summary of the major observations immediately. This release is in lieu of the previously announced presentation of an abstract at the Network for Advancement of Transfusion Alternatives (NATA) meeting in April. The purpose of this summary is to describe the objectives of the study, the study design, the procedure of acute normovolemic hemodilution (ANH), the population studied, 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 conducted between 1998 and 2000. Northfield was concurrently conducting a Phase II 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 to a number of factors, as Northfield reported at the time. The protocol was complex and required additional time in the operating room. Endovascular stent grafting was being developed and was changing the surgical approach to repair of abdominal aortic aneurysm. The study was originally slated to enroll 240 patients. However, in August 1998, FDA requested that the number of patients be increased to 600, based on another sponsor's safety experience with a different hemoglobin-based oxygen carrier in the trauma setting. A single interim analysis was scheduled to be conducted by an Independent Data Monitoring Committee (IDMC) after 120 patients were enrolled. At the initial review, the IDMC noted certain differences between the two study groups. The IDMC asked that the data be unblinded and additional analysis be undertaken to assess whether the observed differences were due to randomization failure, a treatment confounder, or a possible study drug effect. At the time of this request, 138 patients had been enrolled. The analysis revealed the myocardial infarctions (MIs) in the treatment group, and also revealed that the incidence was not evenly distributed among participating sites, which would have been expected if the MIs were due to a direct effect of PolyHeme.

The above findings were reported to FDA. Northfield also informed FDA that in view of the complexity of the protocol and the slow rate of accrual, it had begun to close slow enrolling sites and would submit 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 and efficacy of PolyHeme, an investigational human hemoglobin-based oxygen carrier, used as a red blood cell substitute during acute normovolemic hemodilution (ANH) and the peri-operative period in adult patients experiencing planned acute blood loss during elective surgery for abdominal aortic aneurysm (AAA). ANH is a procedure of withdrawing a unit of blood from a patient and replacing the volume with colloid solutions 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 avoid the use of allogeneic (donated) transfusion. ANH is generally limited to withdrawing only two units of the patient's own blood, because if more is withdrawn, the patient's hemoglobin falls to an unacceptably low level.

The primary objective of this study was to evaluate whether using PolyHeme during ANH would allow for the collection of larger volumes of the patient's own blood to be stored for later return to the patient, thus potentially reducing or avoiding transfusion of donated blood throughout the first seven days postoperatively. The potential to avoid transfusion exists because PolyHeme is a colloid that also provides supplemental hemoglobin to replace that withdrawn during ANH. Other protocol objectives were to evaluate the safety profile of PolyHeme through assessment of patients' vital signs, laboratory measurements, 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 two groups: either the treatment group (replacement with standard solutions and PolyHeme) or control group (replacement with standard solutions only).

Study Design

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

Before the Surgery

In order to be eligible for this study, patients were required to have a total hemoglobin concentration of at least 11 g/dL (normal adult circulating hemoglobin concentration is approximately 12-14 g/dL). There were no specific exclusion criteria related to cardiovascular disease or risk factors. All patients provided informed consent. Patients underwent ANH in the operating room. ANH was performed by removing a 500 mL-unit of blood (ANH unit) and replacing it with a 500 mL colloid infusion. A maximum of approximately 60% of the blood volume of each patient, usually about 6 units, could potentially be collected based on body weight. The blood collected during ANH was replaced with the colloid Hespan for the first two units, 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 to two units since more could produce coagulation disturbances. Total hemoglobin concentrations were measured after each unit of blood had been removed and the volume had been replaced.

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

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

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

During Surgery

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

In the control group, the first transfusions given during surgery were the ANH units. The units were transfused on a "last unit out, first unit in" basis. In the treatment group, PolyHeme was transfused first. If a total of six units of PolyHeme had been infused during the pre-operative and operative period and further transfusion was required, 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 and further transfusions were required, allogeneic blood was to be administered unit-by-unit, as needed.

Following Surgery

When the operation had been completed, the collected ANH units or allogeneic blood were transfused as needed for patients to achieve hemoglobin concentrations greater than or equal to 9 g/dL. Any autologous blood not used within twenty-four hours was discarded, in accordance with current blood banking standards.

Follow-up Period

At six and twelve weeks, patients returned to the hospital for assessment of vital signs, laboratory measurements, and adverse events.

Study Population

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

Study Design Confounders

The design of the protocol resulted in two different treatment regimens in the treatment and control arms of the study. Different volumes of blood were removed and replaced as a part of ANH (2.8 liters in the treatment group and 1.5 liters in the control group) and different colloids were used as replacement fluids (Hespan, albumin, and PolyHeme versus only Hespan and albumin). The protocol design therefore resulted in the administration of two different total volumes and different replacement fluids, representing two substantially different colloid loads. In addition, the total volume of oxygen-carrying blood products returned to the treatment and control groups during the first 24 hours was markedly different (4.4 liters in the treatment group versus 2.2 liters in the control group). As a result, the treatment difference between the groups was not simply the infusion of PolyHeme in the treatment arm. This represents a departure from the usual scientific design where only one variable at 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 Allogeneic Blood

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

Evaluation of Safety: Adverse Events

Adverse events (AEs) are defined as any untoward medical occurrences that occur in subjects administered any dose of a study drug (in either group), regardless of whether there is a relationship to the drug being studied. Serious adverse events (SAEs) are defined as any adverse drug experience, occurring at any dose that results in any of the following outcomes: (1) death (2) a life-threatening adverse drug experience (3) inpatient hospitalization or prolongation of existing hospitalization (4) a persistent or significant disability/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 underlying condition of the patient, the treatment setting, the specific treatment, or the investigational product. Investigators report the AEs and SAEs, characterize them as an AE or SAE based on prescribed regulatory definitions, and ascribe a relationship of the investigational product to the events ranging from "unrelated," "remotely related," "possibly related," to "probably related." In this study, the investigators were not blinded to the treatment assignment. The attribution of an event in a patient who received several types of solutions, (Hespan, albumin, PolyHeme and autologous and donated blood) would therefore be less straightforward than a patient receiving only a single test solution.

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

Myocardial infarction was reported for 10 of the 81 patients (12.3%) in the treatment group and none of the patients in the control group. The patients who experienced MI ranged in age from 57 to 82 years. All of these patients had at least one risk factor for heart disease, such as hypertension or hypercholesterolemia, and eight of the ten patients were smokers. The MIs occurred within 0 to 7 days after AAA surgery. Nine of the 10 patients in the treatment group who had MIs had adverse events consistent with fluid overload, including atrial fibrillation, congestive heart failure, respiratory insufficiency, pulmonary edema and peripheral edema. Only one of the 35 patients in the treatment group who were enrolled at the two highest enrolling sites experienced MI.

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

All patients had ECG tracings done in the operating room at baseline and following completion of ANH. All of the ECG tracings were read by an independent cardiologist who was blinded to the group assignment. There were no differences in ECG tracings between the treatment group and the control group. There were no differences in ECG tracings before and after ANH following infusion of PolyHeme in the treatment group. This is important because the historical concern has been that some hemoglobin-based oxygen carriers have caused coronary vasoconstriction that would reduce coronary perfusion and result 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 is relevant. Surgical mortality rates are traditionally defined as deaths that occur within 30 days following surgery. All four deaths in the control 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 eight deaths in the treatment group occurred during this period, for a mortality rate of 3.7% (at 7, 15, and 18 days), while five were late deaths (at 32, 42, 42, 75, and 96 days). Furthermore, five of these eight patients died following discharge from the hospital. Although the protocol defined the follow up to 84 days after surgery, any deaths that were known by the investigators to have occurred after that follow-up period are also included in this analysis.

Key Observations

There are a number of important conclusions that can be drawn based on the experience described here. ANH itself is a non-routine procedure, traditionally limited to removal of approximately 20% to 30% of a patient's blood volume. The goal in this study was to use PolyHeme to extend the ANH to 60% of the patient's blood volume because of the ability of PolyHeme to provide supplemental hemoglobin to replace that lost with removal of larger quantities of the patient's own blood. The study was, therefore, designed to measure the avoidance of allogeneic blood and look for an improvement with the use of 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 with PolyHeme. However, the study did not achieve its endpoint of avoidance of allogeneic blood.

This was a complex protocol with multiple treatment confounders. The protocol design resulted in the treatment group being different from 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 myocardial infarction versus none in the control group. Two of these patients died, at 7 and 32 days. Because of the study design, it is not possible to separate the influence of PolyHeme from the other differences in the treatment group. We believe the accompanying larger total volume infusions led to complex fluid management issues in these patients. We do not believe that these events are due to a direct pharmacologic effect of PolyHeme.

About Northfield Laboratories

Northfield Laboratories Inc. is a leader in developing an oxygen-carrying resuscitative fluid, PolyHeme(R), for the treatment of urgent, large volume blood loss in trauma and resultant surgical settings. PolyHeme(R) 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. Enrollment is currently underway in a pivotal Phase III trial of PolyHeme(R) beginning in the pre-hospital setting. 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(R) 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 our ability to obtain FDA approval to market PolyHeme commercially, 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 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 quarterly report on Form 10-Q and annual report on Form 10-K. 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.


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http://www.businesswire.com/cgi-bin/mmg.cgi?eid=5106627



    CONTACT: Northfield Laboratories Inc.
             Sophia H. Twaddell, 847-864-3500
             stwaddell@northfieldlabs.com
             or
             Fleishman-Hillard
             Paula Waters, 847-840-6235
             watersp@fleishman.com

    SOURCE: Northfield Laboratories Inc.
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