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Introduction Moroctocog alfa albumin-free cell culture (AF-CC) increases plasma levels of factor VIII (FVIII) activity and, in China, is indicated for the control and prevention of bleeding episodes in patients with hemophilia A. This study aimed to evaluate the efficacy, safety, and recovery data of moroctocog alfa (AF-CC) in patients with hemophilia participating in two open-label studies, both conducted in China. Methods The authorization study (clinicaltrials.gov identifier NCT00868530) enrolled patients aged ≥6 years, previously treated with ≥1 exposure day of FVIII replacement therapy. The real-world study (clinicaltrials.gov identifier NCT02492984) enrolled patients of any age who were previously untreated or requiring surgical prophylaxis. In both studies, on-demand treatment was administered over 6 months. Key assessments included response to treatment, FVIII inhibitor development, and recovery. Results In the authorization study (N = 53; mean age, 23.2 years; severe hemophilia, 23%), response was excellent/good for 90% of infusions at 24 hours. Seven patients developed inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.77 (0.50) and 1.67 (0.45) (IU/dL)/(IU/kg), respectively. In the real-world study (N = 85; mean age, 9.5 years; severe hemophilia, 58%), response was rated as excellent or good for most (87%) on-demand infusions and for all surgical prophylaxis patients (n = 14). Seven patients developed FVIII inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.71 (0.50) and 1.68 (0.31) (IU/dL)/(IU/kg), respectively. No new safety signals were observed in either study. Conclusion On-demand treatment and surgical prophylaxis with moroctocog alfa (AF-CC) is safe and effective for both previously treated and previously untreated Chinese patients with hemophilia A.

WOS: 000442583600048, PubMed ID: 29582525, IntroductionThe pharmacokinetics (PK), efficacy and safety of moroctocog alfa (AF-CC) have been demonstrated in haemophilia A patients aged 6years. AimThese studies aimed to further describe moroctocog alfa (AF-CC) experience in paediatric patients (, PfizerPfizer, Pfizer

Background: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B. Methods: In this open-label, multicenter study (clinicaltrials.gov identifier NCT02336178), patients received on-demand or prophylactic treatment with intravenous nonacog alfa for approximately 6 months or 50 exposure days, whichever occurred first. The primary safety outcome was medically important events (i.e., development of FIX inhibitors, allergic reactions, and thrombotic events). Key secondary efficacy outcomes included the annualized bleeding rate for on-demand treatment and prophylaxis, response to on-demand treatment, the number of infusions per bleeding event, and the number of breakthrough bleeding events within 48 hours of prophylaxis. Results: Seventy male patients (mean [standard deviation] age 7.8 [7.2] years) were enrolled (on-demand, n = 37; prophylaxis, n = 57 [24 patients were included in both groups]). Thirty-eight (54%) patients had up to 50 FIX exposure days before the study. The only medically important event was a transient low-titer FIX inhibitor (incidence 1.4%, 95% confidence interval, 0–7.7). The mean annualized bleeding rate was 26.3 for on-demand treatment and 6.5 for prophylaxis. A mean (standard deviation) of 1.5 (1.7) nonacog alfa infusions were given per bleeding episode; 78.8% of episodes resolved with 1 infusion. Response was “excellent” or “good” for 88% of the on-demand infusions. Twenty-three bleeding events (n = 11 patients) occurred within 48 hours of 2032 prophylaxis doses (1.13%). Conclusion: In the real-world setting, nonacog alfa is safe and effective for on-demand treatment and for prophylaxis for patients with hemophilia B in China.

Hemophilia A represents up to 80% of all hemophilia cases in China. In patients with this condition, bleeding can be prevented and controlled by administering clotting factor VIII (FVIII). Since their initial availability, recombinant FVIII products have undergone several iterations to enhance their safety. Moroctocog alfa albumin-free cell culture (AF-CC) is among the third generation of recombinant FVIII products and received regulatory approval in China in August 2012. The present study characterizes the single-dose pharmacokinetic parameters of FVIII activity (FVIII:C) after administration of moroctocog alfa (AF-CC) in male Chinese patients with hemophilia A.This multicenter, open-label, single-dose study enrolled 13 male Chinese patients diagnosed with severe hemophilia A (FVIII:C1%) and a history of at least 150 exposure-days to any FVIII-containing product. Eligible patients received a single dose of moroctocog alfa (AF-CC) 50 IU/kg IV within 10 minutes. Blood samples were collected within 2 hours before administration and through 72 hours after dosing.Pharmacokinetic parameters were assessed based on FVIII:C and were analyzed by age groups: ages 6 to12 years (n = 3) and ≥12 years (n = 10). The mean plasma concentration-time profile for FVIII:C activity was consistently lower in patients aged 6 to12 years compared with those aged ≥12 years. Geometric AUCThis is the first report of the pharmacokinetic parameters of FVIII:C after moroctocog alfa (AF-CC) in an all-Chinese population of males with hemophilia A. The pharmacokinetic profile in older patients was similar to that previously reported with recombinant FVIII products in studies with a predominantly white population; younger patients had reduced exposure to FVIII:C. The single doses of moroctocog alfa (AF-CC) were well tolerated; 2 cases of transient, low-titer FVIII inhibitor development were observed. ClinicalTrials.gov identifier: NCT02461992.

Background: Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation. Methods: Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone. Results: Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups. Conclusions: In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

We describe the implementation of a streaming client-server system for object-based audio-visual presentations in general and MPEG-4 content in particular. The system augments the MPEG-4 demonstration software implementation (IM1) for PCs by adding network-based operation with full support for the Delivery Multimedia Integration Framework (DMIF) specification, a streaming PC-based server with DMIF support (via Xbind Inc.'s XDMIF suite), and multiplexing software. We describe XDMIF, the first reference implementation of the DMIF specification. The MPEG-4 server is designed for delivering object-based audio-visual presentation. We discuss the issues in the design and implementation of MPEG-4 servers. The system also implements a novel architecture for client-server interaction in object-based audio-visual presentations, using the mechanism of command routes and command descriptors. This new concept of command routes and command descriptors is useful in developing sophisticated interactive applications.

This article discusses the need for standard software interfaces for programming of networks, specifically for service and signaling control, through programming interfaces. The objective is to enable the development of open signaling, control, and management applications as well as higher-level multimedia services on networks. The scope of this effort includes ATM switches, circuit switches, IP routers, and hybrid switches such as those that provide for fast switching of IP packets over an ATM backbone. The basic ideas represented herein are in the process of development as a standard for application programming interfaces for networks under IEEE Standards Project IEEE P1520.

MPEG-4 is an emerging international standard based on the encoding of audiovisual data using object description techniques. This novel approach to encoding allows MPEG-4-based multimedia applications to dynamically compose complex scenes from one or more elementary stream objects. These stream objects are carried within potentially hundreds of channels. As a result, the underlying transport system must support the rapid creation and release of such channels with QoS guarantees. In addition to defining the format, structure and rules of composition of these objects, MPEG-4 also specifies a general application and transport delivery framework called the delivery multimedia integration framework (DMIF). DMIF's main purpose is to hide the details of the transport network from the user, as well as to ensure signaling and transport interoperability between end-systems. We describe the first reference implementation of the MPEG-4 DMIF standard for the ISO, including a full specification of the DMIF application interface. The DAI offers the required functionality for realizing multimedia applications without any concerns regarding the selected communication protocol. The realization of DMIF is greatly facilitated by xbind, a broadband kernel that provides connection management, routing, QoS mapping, and intelligent selection of suitable transport protocol stacks. The resulting system, called XDMIF, supports different QoS requirements, and the rapid creation and release of numerous transport channels, along with efficient management of network resources.

A framework for studying ATM network QOS mapping between various levels in the information transport protocol stack and a platform for evaluating the mapping rules by performing concurrent network and application level measurements of QOS are presented. An empirical loss mapping rule between the application (frame) level and network (cell) level is given. The rule was tested using two 10 minute motion JPEG video clips and a 30 minute MPEG-2 VBR video clip under 55 different network load conditions and gives results within a 3% error margin.

A framework for studying the end-to-end QOS mapping between the various levels of the transport protocol stack is presented. A platform for evaluating end-to-end QOS that supports concurrent network, transport and application level measurements is described. QOS measurements for various video clips indicate that the loss bound obtained under the assumption of uniformly distributed cell losses within a video frame is too conservative.

We describe a prototype implementation of a broadband kernel, an open programming environment that facilitates the easy creation of network services and provides mechanisms for efficient resource allocation. We present a service creation methodology and show how scalable multimedia network services can be constructed from a set of broadband kernel services. As a proof of concept, we built a multi-party teleconferencing service upon the broadband kernel. The service creation framework has the following characteristics: binding of different classes of transport protocols to the application, dynamic renegotiation of application QOS using the signalling network and, support for multiple resource reservation algorithms.