Baxter completes patient enrollment in phase III trial of BAX 855, extended half-life rFVIII to treat haemophilia A

Baxter International Inc. has completed enrollment in its phase III clinical trial of BAX 855, an investigational extended half-life, recombinant factor VIII (rFVIII) treatment for haemophilia A. The ongoing trial is aimed at assessing the efficacy of the compound in reducing annualized bleed rates (ABR) in both prophylaxis and on-demand treatment schedules, and will also evaluate its safety and pharmacokinetic profile.

BAX 855 was designed based on the full-length ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method] molecule, a product with 10 years of real-world experience. The BAX 855 molecule was modified with PEGylation technology designed to extend its duration of activity in the body.

"The BAX 855 development programme is a priority for Baxter as we evaluate the potential to provide an efficacious and safe treatment with an extended half-life for patients with hemophilia," said Anders Ullman, MD, Ph.D., vice president of global research and development in Baxter's BioScience business. "We are focused first and foremost on strategies to address optimal efficacy and minimize patients' bleeding episodes, while at the same time delivering on the convenience of less frequent dosing for this population with severe disease."

The phase II/III multi-centre, open-label study called PROLONG-ATE is evaluating BAX 855 among 146 adult patients with previously-treated severe haemophilia A. Patients participating in PROLONG-ATE receive treatment twice weekly (45 IU/kg) and are followed for six months. The primary endpoint of the study is the annualized bleed rate (ABR) during the treatment period. The study is also evaluating the safety and immunogenicity of the compound when administered on either prophylaxis and on-demand treatment regimens. Other outcome measures include number of infusions needed to treat bleeding episodes, time intervals between these episodes, pharmacokinetics and patient reported outcomes. To date, no inhibitors or safety issues have been reported in the study.

Based upon the results of the study, the company expects to complete the trial and file for regulatory approval late in 2014. Baxter is also initiating a continuation study for all patients who complete the pivotal phase II/III study, and expects to initiate a study of BAX 855 among pediatric patients in 2014.

The treatment protocol is based on the results of a phase I trial of BAX 855, assessing its safety, tolerability and pharmacokinetics. That trial found that the half-life (measuring the duration of activity of the drug in the body) of the investigational compound was approximately 1.5-fold higher compared to ADVATE. An extended half-life was achieved in all patients in the study using BAX 855, no patients developed inhibitors to either the base molecule, BAX 855 or to PEG, and no patients had allergic reactions. No treatment-related or serious adverse events were reported, and no patients withdrew from the study due to adverse events.

BAX 855 is built from the same native FVIII protein used in the production of ADVATE, and employs proprietary PEGylation technology from Nektar Therapeutics designed to extend the duration of activity of proteins. PEGylation technology has been widely used in various approved treatments.

ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method] is indicated for the control and prevention of bleeding episodes in adults and children (0-16 years) with haemophilia A. ADVATE is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children (0-16 years) with haemophilia A. ADVATE is not indicated for the treatment of von Willebrand disease.

ADVATE has a demonstrated efficacy profile and a low rate of inhibitor development. ADVATE is a full-length (derived from the complete FVIII gene) recombinant FVIII product that is processed without any blood-based additives. Because no blood-derived components are added at any stage of the manufacturing process, the potential risk of transmitting pathogens that may be carried in blood-based additives is eliminated. There have been no confirmed reports of transmission of HIV, HBV or HCV with rFVIII treatments.

ADVATE is approved in 60 countries worldwide including the United States, Canada, 27 countries in the European Union, Argentina, Australia, Brazil, Chile, China, Colombia, Croatia, Ecuador, Hong Kong, Iceland, Iraq, Japan, Kuwait, Macau, Malaysia, Mexico, New Zealand, Norway, Panama, Puerto Rico, Serbia, Singapore, South Korea, Suriname, Switzerland, Taiwan, Tunisia, Turkey, Ukraine, Uruguay, and Venezuela.

TRALI - further evidence to minimize transfusion

TRALI 

Transfusion-Related Acute Lung Injury (TRALI) is a syndrome characterized by acute respiratory distress following transfusion. All plasma-containing blood products have been implicated including rare reports of IVIG and cryoprecipitate. It is a rare complication of allogeneic blood transfusion but the incidence has not been well established due to difficulty in defining the syndrome and to variable reporting mechanisms worldwide. Various studies have estimated the overall frequency of TRALI to be between 1/1,120 and 1/57,810 units transfused. However, there is wide discrepancy in the literature with the reported frequency is as low as 1/557,000 RBC units and as high as 1/432 platelet units.

TRALI is associated with a high morbidity with the majority of patients requiring ventilatory support. However, the lung injury is generally transient with PO2 levels returning to pretransfusion levels within 48 -96 hours and CXR returning to normal within 96 hours. TRALI is associated with a significant mortality rate, often approximated at 5 to 10%. Given the gains in safety made within the blood component production industry, particularly with respect to transmission of infectious diseases, TRALI is now among the three leading causes of transfusion related fatalities along with ABO incompatibility and bacterial contamination.

Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study.

Rana R, Fernández-Pérez ER, Khan SA, Rana S, Winters JL, Lesnick TG, Moore SB, Gajic O.

Source

Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Abstract

BACKGROUND:

Using the recent Consensus Panel recommendations, we sought to describe the incidence of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in critically ill patients.

STUDY DESIGN AND METHODS:

Consecutive patients at four intensive care units (ICUs) who did not require respiratory support at the time of transfusion were identified with custom electronic surveillance system that prospectively tracks the time of transfusion and onset of respiratory support. Respiratory failure was defined as the onset of noninvasive or invasive ventilator support within 6 hours of transfusion. Experts blinded to specific transfusion factors categorized the cases of pulmonary edema as permeability edema (suspected or possible TRALI) or hydrostatic edema (TACO) according to predefined algorithm. In a nested case-control design, transfusion variables and lung injury risk factors were compared between the TRALI cases and controls matched by age, sex, and admission diagnosis.

RESULTS:

There were 8902 units transfused in 1351 patients of whom 94 required new respiratory support within 6 hours of transfusion. Among 49 patients with confirmed acute pulmonary edema, experts identified 7 cases with suspected TRALI, 17 patients with possible TRALI, and 25 cases with TACO. The incidence of suspected TRALI was 1 in 1271 units transfused; possible TRALI, 1 in 534 per unit transfused; and TACO, 1 in 356 per unit transfused. When adjusted for sepsis and fluid balance in a stepwise conditional logistic regression analysis, patients who developed acute lung injury (suspected or possible TRALI) received larger amount of plasma (odds ratio 3.4, 95% confidence interval 1.2-10.2, for each liter infused; p = 0.023).

CONCLUSION:

In the ICU, pulmonary edema frequently occurs after blood transfusion. The association between infusion of plasma and the development of suspected or possible TRALI may have important implications with regards to etiology and prevention of this syndrome.

Link: http://www.ncbi.nlm.nih.gov/pubmed/16965572

FDA Approves Surgical Adhesive for U.S. Study

The Food and Drug Administration has issued Investigational Device Exemption approval to Cohera Medical's TissuGlu surgical adhesive, opening the door for a prospective, multi-center, randomized clinical trial of the product in the U.S.

According to the Pittsburgh, Pa.-based manufacturer, the absorbable internal surgical adhesive, intended for the sealing of tissue in large-flap surgeries such as abdominoplasty, can prevent fluid accumulation in post-op wounds. This would reduce the need for surgical drains and possibly speed patients' recoveries.

At present, says Cohera Medical, no synthetic adhesive product is available or in clinical trials for use in large-flap tissue surgeries. TissuGlu received the European Union's safety and effectiveness approval last year, and is scheduled to begin U.S. testing in the first quarter of this year.

Dangers of bleeding control in Kidney surgery

Interrupting the blood flow for more than 20 to 25 minutes during kidney cancer surgery leads to a greater risk for patients developing chronic kidney disease, Mayo Clinic researchers have found. The team’s study was published today in the journal European Urology.
Researchers analyzed outcomes of 362 patients with only one kidney who underwent surgery between 1990 and 2008 at Mayo Clinic and Cleveland Clinic for renal cortical tumors. Using a technique called warm ischemia, surgeons kept the patient’s kidneys body temperature during the partial nephrectomy. Ischemia involves cutting off the blood supply to the kidney with clamps in order to control bleeding and to keep blood from obscuring the surgeon’s view of the kidney. Ischemia can cause tissue damage from a lack of oxygen and nutrients.
Researchers found that each additional minute of warm ischemia is associated with a five-to-six-percent increase in the odds of developing acute renal failure or reduced kidney functioning and is associated with a six percent increased risk of new onset Stage IV chronic kidney disease during long-term follow-up.
“This is the largest evaluation of warm ischemia time in patients with a single kidney who are undergoing a partial nephrectomy,” says R. Houston Thompson, M.D., a urologist at Mayo Clinic and study primary investigator. “These results suggest that every minute counts when the renal arteries and veins are clamped. When planning for the surgery, surgeons should make efforts to minimize ischemia time, especially in situations where a person only has one kidney,” says Dr. Thompson.

Vascular Closure an interesting comparison

All VCDs have demonstrated rapid hemostasis and a decreased time to ambulation when compared to manual compression(1-4). Vasoseal™ has been associated with the highest risk of infection, while Angiolink™ and Starclose™ are felt to have the lowest risk (1-4). Angioseal™ theoretically has a higher risk of thromboembolic events due to the intravascular collagen anchor. The suture-mediated devices utilize primary healing (end to end anastomosis at the arteriotomy site), but are the most complex technically and have the highest rate of device and operator failure. Collagen and ProcoagulantsThe Vasoseal™ closure device (Datascope Corp., Montvale, NJ) was introduced in 1995 (revised in 1999and 2002) and utilizes an extravascular Type-1 collagen produced from bovine tendons. When deployed at the arteriotomy site the collagen initiates coagulation by activating platelets (secondary healing). Vasoseal™ isFDA approved for both diagnostic and interventional procedures, with a single device used for 5-8 French sheath sizes. The Angio-Seal™ device (St. Jude Medical, St. Paul, MN) achieves hemostasis by sandwiching the puncture site between an intravascular bio-absorbable (over 8-12 weeks) anchor and an extravascular bovine.......................Read more HERE (its a verified safe download from Adrive)

For Current US Vascular Closure Trials go HERE

Clinical Trials

Interested to find out what hemostasis clinical trials are being conducted in the USA?
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