Polyheme trial results

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Was anyone surprised to see that Polyheme had the same percent of mortality vs. saline+blood in the Per Protocol portion of the trial?

In addition, what do you think about the 126 protocol violations out of the 712 enrolled?

Actually, day 1 mortality was the same. Day 30, Polyheme scored worse. Was that due to some lasting effect of Poly sfh, or some protocol related reason?

Ultimately, enrolled trauma victims will be categorized with an ISS score (injury severity score?). Could the severity of injury somehow favor one arm of the trial or the other?

As medics, if you have a victim who is at deaths door from blood loss, AND would expect this person to die, would you under the stress of the situation at least try the oxygen carrying solution as a last ditch effort to save this person?

EVANSTON, Ill.--(BUSINESS WIRE)--Dec. 19, 2006--Northfield Laboratories Inc. (Nasdaq: NFLD) announced today preliminary top-line results from its pivotal Phase III trial assessing the safety and efficacy of PolyHeme®, its human hemoglobin based oxygen-carrying red blood cell substitute in the treatment of severely injured and bleeding patients when blood is needed but not immediately available. However, because of discrepancies in the initial data, the database will be unlocked and corrected prior to finalizing the statistical Northfield Laboratories Reports Preliminary Top-Line Data in Pivotal Phase III Trauma Study

analyses.

Northfield received the initial draft top-line data from its contract research organization (CRO) on December 14, 2006. During its review and interpretation of these results, two discrepancies in the dates of death for patients in the study, in which mortality is the primary endpoint, were identified. The CRO was notified and agreed that these data points were inaccurate. It is necessary to unlock the study database to make the corrections. To ensure absolute accuracy before the database is relocked, Northfield has requested verification by the CRO of all critical variables and has also initiated an independent verification. FDA has been notified but the study results will not be submitted until final. Because of the interest in the study, however, Northfield has made the decision to report the preliminary results as provided.

The primary efficacy endpoint of the study is a dual superiority and noninferiority test of Day 30 mortality in the modified intent to treat population. In order to achieve the superiority endpoint, the upper limit of the confidence interval (CI) surrounding the observed difference in mortality between the treatment and control groups needed to be less than zero; for the noninferiority endpoint, the upper limit of the CI needed to be 7% or less. The noninferiority boundary is based on the potential to provide a benefit in situations where transfusion of blood is indicated but not available.

The preliminary results received by Northfield indicate that in the primary modified intent to treat (MITT) population (those who were randomized and received some treatment) the upper limit of the CI exceeded the 7% threshold by 0.3%. However, in the pre-specified per protocol (PP) population (those who both received the correct treatment and did not otherwise violate the protocol), the upper limit of the CI was below the threshold, at 5.8%.

"This was a logistically complex study with many variables and a high incidence of protocol violations. We believe these preliminary results in the per protocol population represent the clearest evidence to assess the potential benefit of PolyHeme in this setting. We continue to move forward toward submission of a Biologics License Application, and will review the data and submit to FDA once we receive the final results. We believe that there is an unmet medical need for a hemoglobin-based oxygen-carrying red blood cell substitute and that PolyHeme is that product," said Dr. Gould.

Efficacy Analysis

Of the total of 722 patients in the study, (intent to treat population, or ITT), 712 patients were randomized and received some study treatment (modified intent to treat population, or MITT); 349 in the PolyHeme group and 363 in the control group. Due to the complexity of the protocol, 20% of the PolyHeme group (70 patients) and 15% of the control group (56 patients) represented protocol violations, leaving a total of 586 patients (279 PolyHeme, 307 control) in the per protocol population (PP). Protocol violations include errors related to eligibility and treatment regimen. The per protocol group represents those patients appropriately randomized, enrolled, treated, and followed as specified in the study protocol. The MITT population is therefore the sum of the per protocol and protocol violation populations.

In the MITT population, there were 46 deaths (13.2%) in the PolyHeme group and 35 deaths (9.6%) in the control group, resulting in an upper CI limit of 7.3%. In the PP population, there were 30 deaths (10.8%) in the PolyHeme group and 28 deaths (9.1%) in the control, with an upper CI limit of 5.8%. In the protocol violation group, there were 16 deaths (22.8%) in the PolyHeme group and 7 deaths (12.5%) in control. The data are summarized in Table 1.

TABLE 1

DAY 30 MORTALITY

DRAFT ANALYSIS

POLYHEME CONTROL

(deaths/N) % (deaths/N) % Delta % CI

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MITT 46/349 13.2 35/363 9.6 3.5 7.3

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PP 30/279 10.8 28/307 9.1 1.6 5.8

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PROTOCOL

VIOLATIONS 16/70 22.9 7/56 12.5 10.4 --

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Safety Analysis

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 pre-defined as SAEs occurring in any subject which results in a "permanently disabling" outcome. The statistical test for these endpoints is inferiority to control.

With respect to Day 1 and Day 30 mortality in the MITT population, the preliminary analysis reveals there was no statistically significant difference between the treatment and control groups. There were 33 deaths (9.5%) in the PolyHeme group and 27 deaths (7.4%) in the control group on Day 1. The PP population was characterized by fewer deaths in the PolyHeme group (19 versus 21 deaths) and identical mortality rates (6.8%). There were two durable SAEs in each group. These data are summarized in Table 2.

TABLE 2

DAY 1 MORTALITY

DRAFT ANALYSIS

POLYHEME CONTROL

(deaths/N) % (deaths/N) % Delta %

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MITT 33/349 9.5 27/363 7.4 2.0

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PP 19/279 6.8 21/307 6.8 0.0

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PROTOCOL

VIOLATIONS 14/70 20.0 6/56 10.7 9.3

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Study Design

This randomized, controlled open-label, multi-center pivotal Phase III study was designed to evaluate the safety and efficacy of PolyHeme® when used to treat patients in hemorrhagic shock following traumatic injuries beginning in the prehospital setting. Treatment began at the scene of injury, continued in the ambulance during transport, and for up to 12 hours post-injury or a total of 6 units. Patients then received donated blood if they continued to bleed.

The study was conducted to seek an indication for the use of Polyheme that addresses a critical, unmet medical need. It was the first study in the U.S. to evaluate the use of an oxygen-carrying fluid starting at the scene, and was designed to assess the life-sustaining capability of PolyHeme when blood is indicated but not available. Blood is not commonly used in the prehospital setting or during ambulance transport to the hospital. The current approach to resuscitation of the trauma victim begins with the rapid infusion of a solution that does not carry oxygen, such as salt water. The second stage of resuscitation involves infusion of blood or red blood cells. At the hospital, patients requiring urgent blood transfusion have immediate access to Type O blood, but it takes approximately 45 minutes to one hour to obtain fully cross-matched compatible blood. PolyHeme provides volume replacement in lieu of salt water, and also provides oxygen-carrying capacity. Because PolyHeme is universally compatible, it is immediately available for use as an initial resuscitative fluid.

This challenging trial, in which more than 3500 emergency medical personnel and 300 ambulances participated, was conducted in 18 states throughout the U.S. , at 32 Level I trauma centers, and included more than 150 physicians and thousands of laboratory and other hospital staff.

This was an active-control dual superiority-noninferiority trial comparing the survival of PolyHeme patients to those who received standard treatment (salt water plus blood). Survival was assessed with respect to seven covariates: age, gender, injury severity score, mechanism of injury (blunt versus penetrating), systolic blood pressure at randomization, Glasgow Coma Score, and volume of crystalloid received prior to randomization. The noninferiority boundary was based on the potential to provide a benefit in situations where transfusion of blood was indicated but not available.

Future Announcements of Study Data

Once the preliminary study data have been verified and any discrepancies corrected, Northfield will issue a press release describing the final study data. It is possible that the final results may differ from the preliminary results provided today. In addition, Northfield expects that additional safety data will be provided by its CRO in four to six weeks; this will also be reported via press release.