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Nika · #1 (**permalink**) 04-08-2005, 10:27 PM

Haemophilia drug rFVIIa could soon change the way critical bleeding in blunt trauma is managed

28 March 2005

rFVIIa controls critical bleeding and reduces the risk of life-threatening complications following severe blunt trauma, the â€˜disease of the young' -

At International Symposium on Intensive Care and Emergency Medicine (ISICEM), Brussels encouraging data has been presented indicating that treatment with recombinant activated factor VII (rFVIIa, marketed as NovoSevenÂ®) controlled critical bleeding and reduced complications and intensive care requirements in severe blunt trauma patients enrolled into a randomised clinical trial.

Data from a new analysis of this trial was highly encouraging, enabling Novo Nordisk, the manufacturers of rFVIIa, to file for marketing approval of rFVIIa in blunt trauma with the EMEA in January 2005. It is hoped that rFVIIa will be approved for use in blunt trauma in Europe before the end of 2005.

Trauma is a major global health issue often referred to as â€˜the disease of the young'. Roughly half of trauma deaths are in people aged 15-44[1], with most being from motor vehicle accidents. In total, five million trauma deaths occur annually worldwide, accounting for 10% of global deaths[2]. Excessive bleeding is a major cause of preventable mortality and morbidity in trauma[3].Blood loss is a leading cause of mortality in the minutes and hours after trauma, while complications related to excessive bleeding are a leading cause of mortality and increased recovery time in the following days and weeks[4], [5]. Therefore the rapid control of blood loss is a high priority in trauma management.

Sub-analysis results - reducing complications and dependency

In order to assess the longer-term benefits of rFVIIa, the study sub-analysis excluded patients dying within 48 hours of rFVIIa administration. Following this exclusion, the longer-term benefits of rFVIIa treatment were apparent (see note to editors for supporting data):

-- Reduced complications: rFVIIa treatment significantly lowered incidences of acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF), two common and potentially fatal complications after trauma.

-- Reduced dependency on intensive care support: trends were observed towards less Intensive Care Unit (ICU) and ventilator dependency in rFVIIa patients compared to placebo in both blunt and penetrating trauma.

â€œThe sub-analysis suggests rFVIIa could be a great asset for trauma and critical care specialists,â€ said Dr Sandro Rizoli, a leading trial investigator and assistant professor of Surgery and Critical Care, University of Toronto. â€œWe knew rFVIIa treatment controls bleeding, shown by the reduced volume of required blood transfusions. Now from the sub-analysis we see reduced incidences of major complications as well as ICU dependency in patients given rFVIIa. These benefits may potentially contribute to fewer patient deaths, which is of course the ultimate objective of all professionals working within trauma management.â€

Mads Krogsgaard Thomsen, chief science officer, Novo Nordisk A/S said: â€œThis new data has highlighted the positive impact of rFVIIa on patient outcomes in the days and weeks after trauma. rFVIIa could offer trauma and critical care specialists a new advantage in their fight to save lives following trauma. Novo Nordisk is now taking the necessary steps to obtain approval for rFVIIa in this much-needed area.â€

Original study results - reducing blood product requirements

Prior to this sub-analysis, the study had demonstrated that blunt trauma patients receiving rFVIIa:

-- experienced improved bleeding control, measured by a significant reduction in the requirement of blood transfusions; an average of 2.6 red blood cell (RBC) units less than patients receiving placebo,

-- were 56% less likely to require massive blood transfusions of >20 units RBC.

MOF and ARDS are common and often fatal complications following severe trauma[6]. MOF is the primary cause of death in trauma patients surviving for seven days (61% of fatalities)[7], while ARDS leads to increased length of stay in ICU and hospital and increased cost of care[8]. The reduction in massive transfusions is particularly notable given that increased transfusion requirements lead to higher risk of MOF and ARDS.

Novo Nordisk is a healthcare company and a world leader in diabetes care. The company has the broadest diabetes product portfolio in the industry, including the most advanced products within the area of insulin delivery systems. In addition, Novo Nordisk has a leading position within areas such as haemostasis management, growth hormone therapy and hormone replacement therapy. Novo Nordisk manufactures and markets pharmaceutical products and services that make a significant difference to patients, the medical profession and society. With headquarters in Denmark, Novo Nordisk employs approximately 20,250 full-time employees in 78 countries, and markets its products in 179 countries. Novo Nordisk's B shares are listed on the stock exchanges in Copenhagen and London. Its ADRs are listed on the New York Stock Exchange under the symbol â€˜NVO'. For more information, visit novonordisk.com

For further information, please contact:
Elin K Hansen
Tel (direct): (+45) 4442 3450

1) Additional Study information:

Rationale for sub-analysis:

Sub-analysis excluded patients who had died within 48 hours because:

-- 48 hour transfusion requirements (a major study end point) could not be assessed in these patients,

-- patients that may have died within 48 hours due to failure of current managements (such as inability to surgically control blood loss) could not be identified for certain.

The exclusion of patients who died within 48 hours was a preplanned analysis for the primary endpoint (reduction in RBC requirement), but not preplanned for the secondary efficacy end points.

Data:

Sub-analysis excluded mortalities within 48 hours, resulting in a revised total patient population of 229 (117 blunt trauma patients and 112 penetrating trauma patients). Data from 111 blunt trauma patients was available for this efficacy analysis:

-- 18% of placebo patients experienced ARDS; 11.4% experienced MOF; 24.6% experienced ARDS and/or MOF. In the rFVIIa group these percentages fell to 5.4%, 5.4% and 8.9% respectively.

-- Patients treated with rFVIIa had more days off the ventilator in the ICU (expressed as ventilator-free days).

---- Of the first 30 days after trauma, patients given placebo experienced an average of 14 days without ventilator support and eight days with no ICU support. For patients given rFVIIa these numbers rose to 17 and 13 days respectively.

-- In severe blunt trauma, patient mortally rates within 30 days were lower in the rFVIIa-treated group (7% compared to 15% in the placebo group). This trend was also visible in the penetrating patients that were treated with rFVIIa (10% compared to 18% in the placebo group).

-- Compared to placebo there was a significant reduction in Fresh Frozen Plasma (FFP) and platelet supplement requirements for patients treated with rFVIIa.

Overall study results as presented in 2004 demonstrated that when used in trauma, rFVIIa was not associated with an increase in serious adverse events such as thromboembolic events[9].

2) rFVIIa: a unique therapy with broad potential

rFVIIa is a haemostatic agent that promotes coagulation directly at the site of vessel damage. rFVIIa is developed and produced by Novo Nordisk A/S.

rFVIIa has been used successfully for treatment of people with haemophilia with inhibitors since 1995, when it was first approved as NovoSevenÂ®. rFVIIa is approved in this indication in the US, Japan and the EU. In the EU rFVIIa is also indicated for the treatment of bleeding episodes or prevention of bleeding episodes during surgery or invasive procedures in people with congenital FVII deficiency or with Glanzmann's thrombasthenia with antibodies to GPIIb-IIIa and/or HLA, and with past or present refractoriness to platelet transfusions.

rFVIIa is also shown to be an effective treatment for limiting bleeding following intracerebral haemorrhage (ICH) - the most deadly and least treatable form of stroke - and patients undergoing intensive surgical procedures. Promising data has been observed in trials in these settings, with positive results from a recent clinical trial being published in the New England Journal of Medicine in February[10]. Novo Nordisk hopes to file for European approval of rFVIIa in ICH in 2005.

3) Trauma - a major and growing health issue affecting mainly the young

Trauma is defined as injury to the body and categorised into two groups. Blunt trauma is internal damage to the body caused by non-penetrating impacts such as vehicle accidents and falls. Penetrating trauma is damage caused by penetration of the body by external objects, most from stabbings and shootings. Blunt trauma accounts for roughly 80% of trauma cases in the Western world[11].

Trauma is a growing health risk internationally. By 2020, an estimated 8.4 million people will die as a result of trauma[12].

Trauma is a leading cause of death worldwide, particularly in the young. Roughly half of the five million people who die from trauma each year are aged 15-441. In 2002, road traffic accidents were responsible for a similar number of deaths as cancers of the lung, bronchus and trachea (1,239,000)1.

[1] Carrico CJ, Acad Emerg Med. 2002;9:621-26.

[2] Peden M, The injury chart book: a graphical overview of the global burden of injuries. Geneva, World Health Organization, 2002.

[3] Sauaia A, J Trauma 1995;38(2):185-93.

[4] Treggiari MM, Crit Care Med 2004;32:327-331

[5] Moore FA, J Trauma. 1996 Apr;40(4):501-10; discussion 510-2

[6] Como et al, Blood transfusion rates in the care of acute trauma, Transfusion. 2004 Jun;44(6):809-13.

[7] Sauaia A, J Trauma 1995;38(2):185-93.

[8] Treggiari MM, Crit Care Med 2004;32:327-331

[9] â€˜Recombinant Activated Factor VII (rFVIIa, NovoSevenÂ®) as Adjunctive Therapy for Bleeding Control in Severely Injured Trauma Patients: A Randomized, Placebo-controlled, Double-blind Clinical Trial', presented at the American Association for the Surgery of Trauma's 2004 Annual Meeting, September 2004

[10] Mayer, SA. et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005 Feb 24;352(8):777-85.

[11] George RL et al. J Trauma 2003;54:464-71

[12] Murray CJL, Lopez AD. Lancet 1997;349:1498-04

http://www.novonordisk.com