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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