Immunomodulatory Device for Treatment of Pediatric Acute Renal Failure Patients

DESCRIPTION (provided by applicant): The Problem: The lack of devices specifically designed for pediatric applications has been recognized by directives in the Pediatric Medical Device Safety and Improvement Act of 2007, included in Public Law 110-85, andthe Institutes of Medicine, which has recommended pediatric studies to begin at the end of Phase II clinical trials involving adults. Acute kidney injury (AKI) and septic shock associated AKI (SSAKI) requiring renal replacement therapy (RTT) are significant complications in ICU patients with an associated mortality rate exceeding 50 percent. As with so many therapeutics, even the available sub-optimal treatment improvements for AKI and SSAKI have been predominantly targeted for use in adult AKI/SSAKI-RRT patients, with little consideration given to any adaption that would be required for pediatric application. The need for novel therapeutics that are specifically developed for pediatric AKI/SSAKI-RRT use is driven by the nearly 50% mortality rates of pediatric patients with MOD receiving RRT. The Product: The cSCD is a novel compact Selective Cytopheretic Device containing bundled biomimetic polysulfone fibers which selectively bind/sequester and deactivate leukocytes (LE) in a dialysis extracorporeal blood circuit, resulting in an immunomodulatory effect in the systemic inflammatory response associated with AKI and SSAKI. The cSCD is targeted to treat pediatric AKI/SSAKI-RRT patients Innovation: The SCD, combined with regional citrate anticoagulation, is a novel therapeutic application utilizing biocompatible membranes that allow LE attachment in a [iCa]low environment resulting in a diminution in the LE activated state. The SCD has demonstrated, in clinical trials of AKI, to be effective in reducing mortalityrate from the historcal matched control of 63% to 31%. i. Long Term Goal: To develop a cSCD with optimal flow characteristics, an effective surface area (SA) and a blood fill volume that is easily tolerated by pediatric AKI/SSAKI-RRT patients. Expected Outcome: SSAKI pigs treated with cSCD+RRT will demonstrate therapeutic efficacy when compared to SSAKI pigs treated with RTT alone. The following aims will guide this study plan: Specific Aim 1. Evaluate cSCD prototype designs in silico and via flow visualization system studies. Specific Aim 2. In Vitro Blood Circuit testing of cSCD to assess hemocompatibility and determine impact of SA on LE sequestration/modulation. Specific Aim 3. Assess cSCD efficacy using a 10kg porcine model of SSAKI. Phase II objective: Completion of the Phase I aims will demonstrate proof-of-concept for use of the cSCD in the treatment of pediatric AKI-RRT patients. The Phase II plan will treat additional SSAKI pigs with the cSCD to increase the preclinical data and to further defineoptimization of cSCD dose, for inclusion of regulatory submissions. With successful completion of the Phase II studies, IBT plans to apply for an IDE approval from the FDA to initiate a clinical trial for the evaluation of cSCD therapy in pediatric patients with AKI- RRT. IBT would seek either a corporate partner or private equity investors to undertake these clinical trials. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop a compact Selective Cytopheretic Device (cSCD), an extracorporeal membrane device that can sequester activated leukocytes and inhibit their inflammatory activity in order to reduce tissue accumulation and resulting damage in patients. The cSCD would specifically be designed for use inpediatric patients that have acute kidney injury or septic shock associated acute kidney injury requiring renal replacement therapy. There is nearly a 50% mortality rate of pediatric patients with multiorgan dysfunction requiring renal replacement therapy.The lack of medical devices specifically designed for pediatric applications has been recognized by directives in the Pediatric Medical Device Safety and Improvement Act of 2007, included in Public Law 110-85, and the Institutes of Medicine, which has recommended pediatric studies to begin at the end of Phase II clinical trials involving adults Inflammatory. The relevance of this proposal to public health is tat the cSCD would greatly reduce the multiorgan effects in pediatric patients suffering from acute kidney injury or septic shock associated acute kidney injury, thus improving the clinical outcome of these pediatric patients affected by these disease processes.