In this phase 1 study, a chemically modified RNA interference therapy designed to target antithrombin was administered to participants with hemophilia A or B. Antithrombin levels decreased and the ...generation of thrombin increased.
Bioceramics are used to treat bone defects but in general do not induce formation of new bone, which is essential for regeneration process. Many aspects related to bioceramics synthesis, properties ...and biological response that are still unknown and, there is a great need for further development. In the most recent research efforts were aimed on creation of materials from biological precursors of apatite formation in humans. One possible precursor is octacalcium phosphate (OCP), which is believed to not only exhibit osteoconductivity but possess osteoinductive quality, the ability to induce bone formation. Here we propose a relatively simple route for OCP ceramics preparation with a specifically designed microstructure. Comprehensive study for OCP ceramics including biodegradation, osteogenic properties in ortopic and heterotopic models and limited clinical trials were performed that demonstrated enhanced biological behavior. Our results provide a possible new concept for the clinical applications of OCP ceramics.
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IJS, KILJ, NUK, PNG, UL, UM
In search for a new pro-angiogenic scaffold material suitable for skin bioengineering and grafting therapy, we have fabricated a number of composite sodium alginate (AG)-fibrinogen (FG) sponge ...scaffolds using the freeze-drying approach. Thrombin was added to drive FG/fibrin conversion, while -aminocapronic acid ( Ac) was used as antifibrinolytic component. The slow rates of scaffold biodegradation were achieved by using Ca2+ and Mg2+ cations as cross-linking agents. The novel thrombin-modified AG-FG scaffolds with highly interconnected porous structure were evaluated using scanning electron microscopy, tensile testing and pycnometric analysis. The scaffolds were characterized by high porosity and tensile strength, possessing average pore size from about 60 to 300 m depending on AG/FG ratio and fibrin stabilization. The biocompatibility of thrombin-modified scaffolds with a different AG/FG ratio was tested on human cells with potential applicability to skin tissue engineering: immortalized epidermal keratinocytes (N-TERT), primary skin fibroblasts, endothelial cells (HUVEC) and subcutaneous adipose-derived stromal cells. The scaffolds with low (15%) FG content have shown the highest adhesiveness and survival rates for all types of cells, as compared to the scaffolds with higher FG content. In unstabilized scaffolds, the addition of FG did not stimulate the aortic ring sprouting. At the same time, fibrin stabilization by Ac resulted in significant increase of aortic ring sprouting and more efficient formation of microvascular network. Altogether, obtained results suggest that thrombin-modified alginate sponges can be successfully used as a grafting material by itself to promote skin healing and regeneration and also as a scaffold for three-dimensional bioequivalent construction.
In the present study, porous three-dimensional (3D) printed titanium (Ti) implants of complex shape and predefined architecture were produced by selective laser sintering (SLS) technique. ...Electrochemical deposition combined with biomimetic approach was applied to low-temperature coating of these implants with metastable octacalcium phosphate (OCP) achieved via chemical transformation of dicalcium phosphate dehydrate (DCPD). X-ray diffraction (XRD), Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and compressive strength analyses were applied to study the chemical composition, morphology and mechanical properties of the final OCP coating on the titanium surface. In vivo comparative study of the porous 3D printed Ti and OCP coated Ti implants has been performed using critical-size crania model, porous 3D printed Ti and coated implants were compared. A statistically significant difference in the newly formed bone thickness for OCP coated Ti implants was detected already at 6 weeks after implantation. Our results provide an experimental proof of a new concept of OCP coating for cranioplasty clinical applications.
•Developed route to produce octacalcium phosphate coatings on 3D printed implants.•The octacalcium phosphate coatings exhibit a simulated new bone formation.•The octacalcium phosphate coatings could provide a proper osseointegration.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This phase 3, prospective, open-label, multicenter, continuation study (NCT01286779) investigated the use of a recombinant factor IX (FIX), nonacog gamma (BAX 326, RIXUBIS®) in patients with severe ...or moderately severe hemophilia B. The study population included 85 patients transitioning from a phase 1/3 pivotal study (NCT01174446), a pediatric study (NCT01488994), and 30 newly recruited patients, naïve to nonacog gamma. Patients received nonacog gamma as prophylaxis treatment (standard, modified or PK-tailored) or on-demand, as determined by the investigator. Treatment was assessed for safety, immunogenicity, hemostatic efficacy and consumption. In this study, after ≥100 exposure days, nonacog gamma resulted in no treatment-related serious adverse events, and no patients developed inhibitory antibodies to FIX. Nonacog gamma was efficacious at controlling bleeding episodes, with an 89.1% overall hemostatic efficacy rating of excellent or good, and 56% of bleeds resolved with one infusion. The annualized bleeding rate was considerably lower during prophylactic treatment (median ABR of 1.3 in 108 patients) than during on-demand treatment (median ABR of 16.5 in 13 patients). These results show that in previously treated patients and nonacog gamma-naïve patients, long-term use of nonacog gamma had acceptable safety and tolerability, and was efficacious as a prophylactic treatment for the management of bleeding episodes.
NCT01286779, EudraCT: 2010-022726-33
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
Background
Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors.
...Objectives
To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors.
Patients/Methods
In this open‐label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once‐monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient‐reported outcomes (exploratory).
Results
The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean SEM) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean standard deviation 69.4 16.3 days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (−9.2 2.9) and physical health (−12.3 3.9) domain scores suggested clinically meaningful improvement.
Conclusions
Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction
In patients with haemophilia A undergoing surgery, factor VIII (FVIII) replacement therapy by continuous infusion (CI) may offer an alternative to bolus infusion (BI).
Aim
To compare the ...perioperative haemostatic efficacy and safety of antihaemophilic factor (recombinant) (ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) CI or BI administration.
Methods
In this multicentre, phase III/IV, controlled study (NCT00357656), 60 previously treated adult patients with severe or moderately severe disease undergoing elective unilateral major orthopaedic surgery (knee replacement, n = 48; hip surgery, n = 4; other, n = 8) requiring drain placement were randomized to receive antihaemophilic factor (recombinant) CI (n = 29) or BI (n = 31) through postoperative day 7. Primary outcome measure was cumulative packed red blood cell (PRBC)/blood volume in the drainage fluid within 24 h after surgery, used to establish non‐inferiority of CI to BI.
Results
CI:BI ratio of cumulative PRBC volume in the 24‐h drainage fluid was 0.92 (p‐value <.001 for non‐inferiority; 95% confidence interval, 0.82–1.05). Total antihaemophilic factor (recombinant) dose per kg body weight received in the combined trans‐ and postoperative periods was similar with CI and BI to maintain targeted FVIII levels during/after surgery. Treatment‐related adverse events (AEs) were reported in five patients treated by CI (eight events) and five treated by BI (six events), including two serious AEs in each arm.
Conclusion
CI administration of antihaemophilic factor (recombinant) is a viable alternative to BI in patients with haemophilia A undergoing major orthopaedic surgery, providing comparable efficacy and safety.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Management of hemostasis with factor IX replacement during surgical procedures on patients with hemophilia B is vital to patient safety. A recombinant factor IX (rFIX, nonacog gamma, RIXUBIS, BAX ...326) presents a treatment alternative for hemophilia B; nonacog gamma is manufactured with no materials of human or animal origin, and includes as two-step virus inactivation (solvent/detergent treatment and nanofiltration). This multi-national clinical trial was conducted to investigate the efficacy and safety of nonacog gamma for perioperative use in previously-treated patients with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B. Interim results of 14 (11 major) surgeries showed that nonacog gamma is safe and effective in maintaining hemostasis in the surgical setting;1 the results of all 38 surgeries are presented here.
Previously-treated hemophilia B immunocompetent patients aged 12 to 65 years with no evidence of a history of FIX inhibitors were eligible for participation if they were either: 1) participating in another trial with nonacog gamma and required an emergency or elective major or minor surgical, dental, or other invasive procedure; or 2) if not participating in any other nonacog gamma clinical study, they required elective major surgery and had been treated previously with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 150 exposure days. Pre-operative FIX levels were targeted at 80%-100% of normal for major, and 30%-60% of normal for minor surgeries, through an individualized nonacog gamma dosing approach. Hemostatic efficacy was evaluated intra- and post-operatively by determination of actual versus predicted blood loss and a semi-quantitative 4-point hemostatic efficacy rating scale (excellent, good, fair, none); safety was assessed in terms of the occurrence of adverse events.
Thirty patients participated in this study, 10 of whom underwent multiple surgeries and were re-enrolled for each surgery. Of a total of 38 surgeries performed, 21 were major (14 orthopedic) and 17 were minor.
Hemostatic efficacy for 37/38 surgeries (including 20/21 major surgeries) had a rating of 'excellent' and one was 'good' (a knee joint replacement). At drain removal (n=14), the ratings for all major surgeries were either 'excellent' (10/14) or 'good' (4/14). On postoperative day 3, 6 of 7 major surgeries where no drain was employed had a rating of 'excellent', and one had a rating of 'good'. At discharge from hospital, 12/21 were 'excellent', 7/21 were 'good' and 2 were 'fair' (both had ratings of 'excellent' intraoperatively and at drain removal).
For 16/21 major surgeries, the actual blood loss was below (n=8) or equal to (n=8) the average predicted blood loss and the mean post-operative blood loss was 552.4 mL (range: 11-1100 mL) in subjects who had a drain placed. For 12/17 minor surgeries, actual intraoperative blood loss was below the average predicted blood loss, for 4/17 minor surgeries, the actual intraoperative blood loss matched the average predicted blood loss, and for 1 minor surgery (intra-articular infiltration) actual blood loss was between the average predicted and maximum predicted blood loss.
Nonacog gamma was safe and well tolerated. One possibly related AE (hemorrhagic anemia) was reported. This event was resolved at the completion of the study. No thrombogenic events or severe allergic reactions, nor induction of inhibitory antibodies to FIX or total binding antibodies to FIX were observed.
Conclusion: Nonacog gamma provides a safe and effective treatment alternative for perioperative management of hemostasis in hemophilia B patients in a variety of surgical settings.
References
1 Windyga J, Lissitchkov T, Stasyshyn O, et al. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia. 2014 Sep;20(5):651-8.
Windyga:CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker’s honorarium. Mamonov:Baxalta (Now part of Shire): Research Funding. Chapman:Baxalta (Now part of Shire): Employment, Equity Ownership. Tangada:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Introduction VONCENTO® (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate, which contains a high level of von Willebrand factor (VWF) ...high-molecular-weight multimers and a VWF/factor VIII (FVIII) ratio of ~ 2.4:1, similar to Haemate® P (CSL Behring). Methods The pharmacokinetic, efficacy and safety profiles of VONCENTO® were investigated in this multicentre, double-blind, randomised study. Subjects aged ≥ 12 years with haemophilia A who required treatment of non-surgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO® or BIOSTATE® reference product (Biostate-RP) (Day 1; Day 8 n = 16, repeated on Day 180 VONCENTO® only; n = 15). Efficacy and safety analyses were performed either during on-demand treatment (n = 52) or prophylaxis (n = 29) for ≥ 6 months and ≥ 50 exposure days, respectively. Results Besides the confirmation of bioequivalence between VONCENTO® and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either ‘excellent’ or ‘good’ in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject range was significantly lower in the prophylaxis group (2.0 0.0–34.6) than in the on-demand group (14.0 0.0–87.8, p = 0.0013).VONCENTO® was well tolerated and no inhibitory antibodies were identified during the study period. Conclusions This study demonstrated the bioequivalence of VONCENTO® to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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