Kooperativer Bibliotheksverbund

Berlin Brandenburg


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  • 1
    Language: English
    In: Blood, 07 April 2016, Vol.127(14), pp.1761-9
    Description: A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P〈 .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274.
    Keywords: Albumins -- Administration & Dosage ; Factor IX -- Administration & Dosage ; Hemophilia B -- Blood
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 2
    In: The New England Journal of Medicine, 2017, Vol.377(9), pp.819-828
    Description: Background Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1 ), is in development to address these and other limitations. Methods In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. Results No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Conclusions Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .) 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.
    Keywords: Adult–Antagonists & Inhibitors ; Antithrombin III–Blood ; Antithrombins–Blood ; Dose-Response Relationship, Drug–Therapy ; Healthy Volunteers–Blood ; Hemophilia A–Therapy ; Hemophilia B–Biosynthesis ; Humans–Biosynthesis ; Injections, Subcutaneous–Biosynthesis ; Male–Biosynthesis ; Middle Aged–Biosynthesis ; Rnai Therapeutics–Biosynthesis ; Single-Blind Method–Biosynthesis ; Thrombin–Biosynthesis ; Young Adult–Biosynthesis ; Abridged ; Antithrombins ; Serpinc1 Protein, Human ; Antithrombin III ; Thrombin;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 3
    In: Transfusion, February 2018, Vol.58(2), pp.413-422
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/trf.14421/abstract Byline: Toshko Lissitchkov, Bella Madan, Claudia Djambas Khayat, Nadezhda Zozulya, Cecil Ross, Mehran Karimi, Kaan Kavakli, Guillermo R. De Angulo, Abdulkareem Almomen, Bruce A. Schwartz, Cristina Solomon, Sigurd Knaub, Flora Peyvandi BACKGROUND Fibrinogen concentrate is the preferred choice for fibrinogen replacement in congenital fibrinogen deficiency. This study investigated hemostatic efficacy of a new plasma-derived, double virus-inactivated (using two dedicated virus inactivation/elimination steps) human fibrinogen concentrate for on-demand treatment of bleeding episodes (BEs) and surgical prophylaxis. STUDY DESIGN AND METHODS In this planned interim analysis of a prospective, multinational Phase III study (NCT02267226), 13 patients with afibrinogenemia (a[yen]12 years) received fibrinogen concentrate (FIBRYGA, Octapharma AG). Hemostatic efficacy was assessed by investigators and an independent data monitoring and endpoint adjudication committee (IDMEAC) using objective four-point criteria and by thromboelastometry maximum clot firmness (MCF). RESULTS Fibrinogen concentrate was used on-demand to treat 23 BEs in 11 patients, with 21 (91.3%) requiring a single infusion only. Treatment success was 95.7% (90% confidence interval [CI], 0.81-1.00; assessment missing for one BE) by investigators and 100% (90% CI, 0.88-1.00) by IDMEAC. Mean MCF increased significantly from 0.0 to 6.5 mm (95% CI, 5.65-7.40; p〈0.0001) at 1 hour postinfusion of a median (range) dose of 58.8 (33.9-101.7) mg/kg per BE. Four patients received fibrinogen concentrate as surgical prophylaxis, with intraoperative and postoperative treatment success rated 100% (90% CI, 0.50-1.00) by investigators and IDMEAC (median [range] dose per surgery 93.5 [34.1-225.4] mg/kg). No additional hemostatic interventions were required. No deaths, thromboses, or seroconversions were reported. CONCLUSION These data showed that the new fibrinogen concentrate was efficacious for on-demand treatment of acute bleeding and surgical prophylaxis in congenital afibrinogenemia patients. Article Note: Octapharma provided research funding. This article was published online on 30 November 2017. An error was subsequently identified. This notice is included in the online versions to indicate that have been corrected 26 December 2017. Supporting information: Additional Supporting Information may be found in the online version of this article Additional Supporting Information may be found in the online version of this article. CAPTION(S): Table S1. Objective four-point criteria sets used for the clinical assessment of hemostatic efficacy for on-demand treatment of bleeding episodes and surgical prophylaxis (intra-operative efficacy and post-operative efficacy).
    Keywords: Genetic Disorders -- Care And Treatment ; Genetic Disorders -- Analysis ; Clinical Trials -- Analysis ; Fibrinogen -- Analysis ; Plants (Organisms) -- Analysis ; Medical Research -- Analysis ; Fibrin -- Product Development ; Fibrin -- Analysis;
    ISSN: 0041-1132
    E-ISSN: 1537-2995
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  • 4
    Language: English
    In: Clinical pharmacokinetics, September 2017, Vol.56(9), pp.1045-1055
    Description: BAY 81-8973 is a full-length, unmodified, recombinant human factor VIII (FVIII) for the treatment of hemophilia A. The aim of this study was to compare the pharmacokinetic (PK) profile of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) PATIENTS/METHODS: In this phase I, open-label, crossover study, men aged 18-65 years with severe hemophilia A and ≥150 exposure days to FVIII were randomized to receive a single intravenous infusion of 50 IU/kg BAY 81-8973 or rAHF-PFM, followed by crossover to a single infusion of the other treatment. FVIII levels were measured in plasma over 48 h using one-stage and chromogenic assays. PK parameters, including area under the curve from time zero to the last data point (AUC; primary outcome) and half-life (t ) were calculated. A population PK model was developed to simulate various treatment scenarios. Eighteen patients were randomized and analyzed. Using both assays, geometric mean (coefficient of variation [%CV]) AUC was significantly higher, and t was significantly longer, for BAY 81-8973 versus rAHF-PFM (one-stage, AUC: 1660 IU·h/dL [29.4] vs. 1310 IU·h/dL [29.0], p 1 IU/dL could be maintained with 14.4 IU/kg BAY 81-8973 or 39.1 IU/kg rAHF-PFM 3×/week. BAY 81-8973 showed a superior PK profile versus rAHF-PFM. The same FVIII trough threshold level could be achieved with lower doses of BAY 81-8973 versus rAHF-PFM. ClinicalTrials.gov: NCT02483208.
    Keywords: Chromogenic Assay ; Fviii Activity ; Mean Residence Time ; Severe Hemophilia ; Trough Level ; Severity of Illness Index ; Factor VIII -- Administration & Dosage ; Hemophilia A -- Blood ; Serum Albumin -- Metabolism
    ISSN: 03125963
    E-ISSN: 1179-1926
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  • 5
    In: Blood Coagulation & Fibrinolysis, 2017, Vol.28(2), pp.152-162
    Description: VONCENTO (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived, high concentration, lower volume [relative to HAEMATE P (CSL Behring)], high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a VWF/FVIII ratio similar to HAEMATE P. This open-label, multicentre study investigated the pharmacokinetic, haemostatic efficacy, and safety profiles of VONCENTO in study participants at least 12 years of age with von Willebrand disease (VWD) who required treatment of nonsurgical bleeding (NSB) events or underwent surgery or prophylaxis. The first 12-month on-demand treatment period comprised a pharmacokinetic investigation and an efficacy analysis. After 12 months, qualifying study participants were switched to prophylactic therapy and included in a further 12-month efficacy analysis. In total, 21 study participants (including three adolescents, and 13 study participants with VWD type 3) received VONCENTO as on-demand treatment for 12 months. ‘Excellent’/‘good’ haemostatic efficacy was achieved in 98.3% of the 407 NSB events assessed by investigators. Following the switch to prophylactic treatment, the total number of NSBs in eight patients markedly decreased from 304 to 10 (with haemostatic efficacy judged to be ‘excellent’ for all). The annualised bleeding rate also significantly decreased from a median of 26.5 events to one event. Safety assessments showed no inhibitory antibodies to either FVIII or VWF, no transmission of infectious agents, no thromboembolic events and no treatment-related serious adverse events. VONCENTO was shown to be well tolerated and provided excellent haemostatic efficacy in the treatment of bleeds or during prophylaxis in study participants with VWD, including also those with type 3, the severest form of VWD.
    Keywords: Factor VIII -- Therapeutic Use ; Hemostatics -- Therapeutic Use ; Von Willebrand Diseases -- Drug Therapy ; Von Willebrand Factor -- Therapeutic Use;
    ISSN: 0957-5235
    E-ISSN: 14735733
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  • 6
    Language: English
    In: Thrombosis Research, January 2016, Vol.137, pp.119-125
    Description: 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). 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. 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. This study demonstrated the bioequivalence of VONCENTO® to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.
    Keywords: Hemostatic Efficacy ; Hemostatic Safety ; On-Demand Therapy ; Prophylaxis ; Surgery ; Annual Bleeding Rate ; Medicine
    ISSN: 0049-3848
    E-ISSN: 1879-2472
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  • 7
    In: British Journal of Haematology, October 2012, Vol.159(1), pp.67-77
    Description: The efficacy of bendamustine chlorambucil in a phase trial of previously untreated patients with inet stage chronic lymphocytic leukaemia () was re‐evaluated after a median observation time of 54 months in ay 2010. Overall survival () was analysed for the first time. At follow‐up, investigator‐assessed complete response () rate (21·0% vs 10·8%), median progression‐free survival (21·2 vs 8·8 months; 65 years, responders and non‐responders. However, patients with objective response or a experienced a significantly longer than non‐responders or those without a . Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; =0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated patients, with the achievement of a or objective response appearing to prolong . Bendamustine should be considered as a preferred first‐line option over chlorambucil for patients ineligible for fludarabine, cyclophosphamide and rituximab.
    Keywords: Bendamustine ; Chlorambucil ; Chronic Lymphocytic Leukaemia ; Complete Response ; Overall Survival
    ISSN: 0007-1048
    E-ISSN: 1365-2141
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  • 8
    Language: English
    In: Haemophilia, 2017, Vol.23(2), p.264(9)
    Description: Byline: A. Srivastava, M. Serban, S. Werner, B. A. Schwartz, C. M. Kessler,, Salam Alkindi, Shashikant Janardan Apte, Giancarlo Castaman, Joan Cox Gill, Andrzej Hellmann, Kaan Kavakli, Peter A. Kouides, Philip Kuriakose, Toshko Lissitchkov, Alice Ma, Johnny Mahlangu, Massimo Morfini, Ellis J. Neufeld, Flora Peyvandi, Mark Reding, Nidra I. Rodriguez, Cecil Ross, Luminita Rusen, Amy Shapiro, Valentina Uscatescu, Jerzy Windyga, Bulent Zulfikar Keywords: coagulation factor VIII; surgery; von Willebrand disease; von Willebrand factor; wilate.sub.[R] Introduction Surgical procedures in von Willebrand disease (VWD) patients may require prophylactic treatment with exogenous von Willebrand factor (VWF) and coagulation factor VIII (FVIII) to prevent excessive bleeding. Wilate.sub.[R] is a plasma-derived, double virus-inactivated, highly purified, freeze-dried VWF/FVIII concentrate, containing both factors in a physiological activity ratio of 1:1. Aim To investigate the efficacy and safety of wilate.sub.[R] in maintaining haemostasis in VWD patients undergoing surgical procedures. Methods This prospective, open-label multinational clinical study documents 28 individuals who underwent 30 surgical procedures managed with wilate.sub.[R]. Twenty-one patients had VWD Type 3, and 21 surgeries were major. Efficacy was assessed intra- and postoperatively by the surgeon and investigator, respectively, and adjudicated by an Independent Data Monitoring Committee, using an objective scale based on blood loss, transfusion requirements and postoperative bleeding and oozing. Treatment success (primary endpoint) was determined using a composite assessment algorithm and was formally assessed. Results Surgical prophylaxis with wilate.sub.[R] was successful in 29 of 30 procedures. The overall rate of success was 96.7% (98.75% CI: 0.784, 1.000). All 21 surgeries in patients with VWD Type 3 were managed successfully. There was no accumulation of VWF or FVIII after multiple dosing, and no thromboembolic events or inhibitors to VWF or FVIII were observed. Conclusions Wilate.sub.[R] demonstrated effective prevention and treatment of bleeding in inherited VWD patients undergoing surgery, with no clinically significant safety concerns.
    Keywords: Von Willebrand Factor – Genetic Aspects ; Plants (Organisms) – Genetic Aspects ; Factor VIII – Genetic Aspects
    ISSN: 1351-8216
    E-ISSN: 13652516
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  • 9
    Language: English
    In: Blood, Vol.114, pp.934-935
    Keywords: Medicin Och Hälsovetenskap ; Klinisk Medicin ; Hematologi ; Medical And Health Sciences ; Clinical Medicine ; Hematology
    ISSN: 1528-0020
    ISSN: 00064971
    Source: SwePub (National Library of Sweden)
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  • 10
    In: Cancer Gene Therapy, 2003, Vol.10(12), p.907
    Description: The ability of two plasmid DNA vaccines to stimulate lymphocytes from normal human donors and to generate antigen-specific responses is demonstrated. The first vaccine (truncated; tPSMA) encodes for only the extracellular domain of prostate-specific membrane antigen (PSMA). The product, expressed following transfection with this vector, is retained in the cytosol and degraded by the proteasomes. For the "secreted" (sPMSA) vaccine, a signal peptide sequence is added to the expression cassette and the expressed protein is glycosylated and directed to the secretory pathway. Monocyte-derived dendritic cells (DCs) are transiently transfected with either sPSMA or tPSMA plasmids. The DCs are then used to activate autologous lymphocytes in an in vitro model of DNA vaccination. Lymphocytes are boosted following priming with transfected DCs or with peptide-pulsed monocytes. Their reactivity is tested against tumor cells or peptide-pulsed T2 target cells. Both tPSMA DCs and sPSMA DCs generate antigen-specific cytotoxic T-cell responses. The immune response is restricted toward one of the four PSMA-derived epitopes when priming and boosting is performed with sPSMA. In contrast, tPSMA-transfected DCs prime T cells toward several PSMA-derived epitopes. Subsequent repeated boosting with transfected DCs, however, restricts the immune response to a single epitope due to immunodominance.
    Keywords: Medicine ; Biology;
    ISSN: 0929-1903
    E-ISSN: 14765500
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