Phase 3 Clinical Trial: Perioperative Use of Nonacog Gamma, a Recombinant Factor IX, in Previously Treated Patients With Moderate/Severe Hemophilia B.

Hemostatic management is essential for ensuring the safety of patients with hemophilia during surgery. This phase 3, prospective, uncontrolled trial, evaluated hemostatic efficacy, consumption, and safety of a recombinant factor IX concentrate, nonacog gamma (BAX 326, Rixubis® [Baxalta US Inc., a Takeda company, Lexington, MA, USA]), in intraoperative and postoperative settings in previously treated patients (PTPs) with severe or moderately severe hemophilia B undergoing elective surgery (N = 38 surgeries; 21 major, 17 minor). Predefined preoperative hemostatic factor IX levels (80-100% of normal for major and 30-60% for minor surgeries) were maintained for each patient. Intraoperative efficacy was rated as "excellent" or "good" for all surgeries. Postoperative hemostatic efficacy on day of discharge was rated as "excellent," "good," and "fair," respectively, for 29 (76.3%), 7 (18.4%), and 2 (5.3%) surgical procedures. All adverse events were considered unrelated to study drug; most frequently reported was mild procedural pain (9 patients). No thrombotic events, severe allergic reactions, or inhibitor formation were observed. Nonacog gamma was well tolerated and effective for intraoperative and postoperative hemostatic management of PTPs with hemophilia B.NCT01507896, EudraCT: 2011-000413-39.

Feasibility of a paediatric radiology escape room for undergraduate education.

OBJECTIVES: To develop a paediatric radiology themed escape room session for undergraduate education and secondly, to determine participant satisfaction and improvement in knowledge. METHODS: A paediatric radiology escape room with accompanying tutorial was developed around key learning objectives set within the RCR and ESR undergraduate curriculum. Students were recruited from two different universities and undertook the escape room themed teaching. An 8-question single best answer (SBA) test was completed before, immediately after and at 2 weeks post-teaching to determine participant improvement and retention of knowledge. The general feedback was also collected. RESULTS: The escape room sessions were held three times, for 19 students (6-7 students per session). All groups completed the escape room in ≤ 20 min. Students enjoyed the experience, assigning an average satisfaction score of 9.4/10 (range 7-10). The majority (17/19, 89.5%) preferred this method of teaching to a lecture-based tutorial alone, although all said they found the tutorial component useful. For the SBA test, there was an average increase in 3.6 marks (range 1-6 marks) per participant between before and after the escape room. This improved knowledge was mostly sustained after 2 weeks, with an average increase of 3.4 marks difference (range 1 to 6) per participant compared to before the teaching. CONCLUSIONS: A paediatric radiology themed escape room is a feasible teaching method, enjoyed by participants and associated with an increase in radiological knowledge. Further work with larger sample size and direct comparison with other traditional teaching methods is required.

Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease.

This phase 3 trial evaluated the safety and hemostatic efficacy of a recombinant von Willebrand factor (rVWF) for treatment of bleeds in severe von Willebrand disease (VWD). rVWF was initially administered together with recombinant factor VIII (rFVIII) and subsequently alone, as long as hemostatic factor VIII activity (FVIII : C) levels were maintained. Pharmacokinetics (PK) were evaluated in a randomized cross-over design (rVWF vs rVWF:rFVIII at 50 IU VWF:ristocetin cofactor activity [RCo]/kg). Bleed control for all treated bleeds (N = 192 bleeds in 22 subjects) was rated good or excellent (96.9% excellent; 119 of 122 minor, 59 of 61 moderate, and 6 of 7 major bleeds) on a 4-point scale (4 = none to 1 = excellent). A single infusion was effective in 81.8% of bleeds. Treatment success, defined as the number of subjects with a mean efficacy rating of <2.5, was 100%. The PK profile of rVWF was not influenced by rFVIII (mean VWF:RCo terminal half-life: 21.9 hours for rVWF and 19.6 hours for rVWF:rFVIII). FVIII : C levels increased rapidly after rVWF alone, with hemostatic levels achieved within 6 hours and sustained through 72 hours after infusion. Eight adverse events (AEs; 6 nonserious AEs in 4 subjects and 2 serious AEs [chest discomfort and increased heart rate, without cardiac symptomatology] concurrently in 1 subject) were associated with rVWF. There were no thrombotic events or severe allergic reactions. No VWF or FVIII inhibitors, anti-VWF binding antibodies, or antibodies against host cell proteins were detected. These results show that rVWF was safe and effective in treating bleeds in VWD patients and stabilizes endogenous FVIII : C, which may eliminate the need for rFVIII after the first infusion. This trial was registered at www.clinicaltrials.gov as #NCT01410227.

Nonacog gamma, a novel recombinant factor IX with low factor IXa content for treatment and prophylaxis of bleeding episodes.

Nonacog gamma is a new recombinant factor IX to treat factor IX deficiency. It is indicated for control of bleeding episodes, perioperative management and routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia B. Nonacog gamma was first approved in the USA in June 2013 under the trade name RIXUBIS followed by market approvals in Australia and the EU in 2014, and marketing authorization decision is pending in Japan. Nonacog gamma is derived from a recombinant Chinese hamster ovary cell line using a state of the art biotechnological manufacturing process. Recombinant factor IX is produced by Baxter's protein-free fermentation technology, which was first developed for ADVATE. The product is purified and formulated in the absence of any human or animal-derived protein. Nonacog gamma was characterized both in comprehensive in vitro and in vivo non-clinical studies as well as in an extensive clinical trial program.

Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

Bone formation with a biphasic calcium phosphate combined with fibrin sealant in maxillary sinus floor elevation for delayed dental implant.

OBJECTIVES: The aim of this study was to evaluate the extent and quality of new bone 6 months after sinus lift with biphasic micro- and macroporous calcium phosphate combined with fibrin sealant (MBCP-FS) and the 1-year implant success rate in the augmented site. MATERIAL AND METHODS: MBCP-FS was applied to one sinus in 96 subjects requiring augmentation for delayed dental implant placement. In subjects who required bilateral lifts (N = 33), the MBCP-FS sinus was randomly selected; the contralateral sinus was grafted with autologous bone (mixed with Bio-Oss when harvested bone volume was insufficient. Panoramic views were taken periodically prior to and up to 18 months post-lift. Histomorphometric analysis was conducted on biopsies taken during implant placement 6 months after augmentation. Implant functionality and prosthesis success were assessed clinically 1 year after implant placement. RESULTS: In MBCP-FS sinuses, 20.6 ± 8.5% new, mainly lamellar bone was observed. Implants were placed as planned in 78/85 evaluable subjects (91.8%) 6 months after sinus lift. Graft heights remained stable 1 year after placement; 94.7% (142/150) of implants were functional. The amount and quality of new bone and implant success rates with MBCP-FS were similar to autologous bone graft (mixed with Bio-Oss in 30/31 evaluable subjects). MBCP-FS was safe and well-tolerated. CONCLUSIONS: MBCP-FS is safe and effective in sinus floor elevation for dental implant placement, supporting bone regeneration and with high 1-year implant success rates similar to autologous bone mixed with Bio-Oss.