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  • 1
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    A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia A or B
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 551-551
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 551-551
    Abstract: Background: Hemophilia A and B are bleeding disorders characterized by a profound defect in thrombin generation (TG). Furthermore, in the presence of normal levels of endogenous anticoagulants a deficiency in factor VIII and IX results in major hemostatic imbalance and a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin (AT) that aims to restore the hemostatic balance by increasing TG. Methods: We are conducting a phase 1 multi-center study (NCT02035605) in healthy volunteers and patients with moderate to severe hemophilia A or B. Part A of this study has been completed and assessed a single ascending dose study in healthy volunteers. Parts B and C are multiple ascending dose studies in patients with hemophilia who are receiving weekly or monthly dosing, respectively. Primary endpoints are safety and tolerability. Secondary endpoints include PK, AT knockdown; change in thrombin generation and whole blood clot formation as measured by Calibrated Automated Thrombin generation and ROTEM thromboelastometry. Exploratory endpoints include evaluations of bleed pattern and control. Results: Part A enrolled 4 healthy volunteers, randomized (3:1) to 30 mcg/kg ALN-AT3 or placebo; no serious adverse events (SAE) or injection site reactions were observed. A total of 12 patients with severe hemophilia (10 hemohilia A; 2 hemophilia B) were enrolled in Part B and received 3 weekly subcutaneous doses of ALN-AT3 at 15 (n=3), 45 (n=6), and 75 (n=3) mcg/kg. Similar to part A, weekly administration of ALT-AT3 was generally safe and well tolerated in patients with hemophilia; no SAEs, discontinuations, clinical thromboembolic events or clinically significant D-dimer increases were reported. In the 75 mcg/kg dosing cohort, the mean maximum AT knockdown was 59% (p 〈 0.05, relative to baseline), with nadir levels achieved between days 28 and 42. Maximum plasma AT knockdown of 86% was achieved, resulting in thrombin generation increases that correlated with AT knockdown and a bleed-free period of 114 days in the patient achieving the highest level of AT knockdown. The association between AT KD and TG was assessed in a post hoc exploratory analysis in which AT KD was categorized into tertiles. Part C aims to enroll several cohorts (n=3 per cohort) and will assess a monthly dosing schedule (x3 doses) of ALN-AT3. Patients in cohort 1 and 2 were dosed at 225 and 450 mcg/kg, respectively. Up to 4 additional cohorts may be enrolled within Part C. Updated safety, PK, AT knockdown, TG results as well as bleed patterns from Parts B and C will be presented. Conclusions: Emerging clinical data suggest that targeting AT could be a promising approach for restoring hemostatic balance in hemophilia. The potential for low volume subcutaneous administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make ALN-AT3 a potentially encouraging investigational therapy. Disclosures Pasi: Octapharma: Research Funding; Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria. Off Label Use: ALN-AT3 is an investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin.. Mant:Quintiles: Employment, Equity Ownership. Creagh:Bayer Healthcare UK: Honoraria. Austin:SOBI: Other: member of advisory board and received educational support; Pfizer: Other: member of advisory board and received educational support; Novo Nordisk: Other: member of advisory board and received educational support; CSL Behring: Other: member of advisory board and received educational support; Bio Products Laboratory: Other: member of advisory board and received educational support; Bayer: Other: member of advisory board and received educational support; Baxter: Other: member of advisory board and received educational support. Brand:Alnylam: Honoraria. Chowdary:Bayer: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; SOBI: Consultancy. Ragni:Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dimension: Research Funding; Bayer: Research Funding; SPARK: Research Funding; Genentech Roche: Research Funding; Pfizer: Research Funding; Vascular Medicine Institute: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; CSL Behring: Research Funding. Chen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Rangarajan:Octapharma: Other: Investigator.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.551.551
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 2
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    The TRUST Trial: Anti-Drug Antibody Formation In a Patient With Hemophilia With Inhibitors After Receiving The Activated Factor VII Product Bay 86-6150
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 573-573
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 573-573
    Abstract: Introduction Up to 30% of patients with hemophilia A and 5% of patients with hemophilia B develop neutralizing antibodies (inhibitors) against replacement factor VIII or factor IX, respectively. Acute bleeding episodes in these patients with inhibitors are treated with bypassing agents, which include activated recombinant factor VII (rFVIIa). BAY 86-6150 is a modified rFVIIa which in preclinical studies was shown to have prolonged half-life and improved potency compared with currently available rFVIIa. In a phase 1, randomized, double-blind trial, BAY 86-6150 was not associated with any clinically significant adverse events (AEs). We report the immunologic response to BAY 86-6150 in a phase 2/3 clinical trial in patients with hemophilia with inhibitors. Methods TRUST (Treatment with Unique Recombinant FVII Study) was a multicenter, open-label, 2-part study (part A and part B) which included males aged 12−62 years with moderate or severe hemophilia A or B, with a history of high-titer inhibitors (≥5 Bethesda units), and ≥4 bleeding episodes in the 6 months prior to enrollment. Part A was a sequential dose-escalation study of 4 BAY 86-6150 dose levels (6.5, 20, 50, and 90 μg/kg body weight; n≥10/cohort). Dose escalation was dependent on both efficacy and an Independent Data Monitoring Committee (IDMC) approval of safety in 10 patients per cohort who had ≥1 bleeding episode treated with BAY 86-6150. Part B was designed as a single-arm investigation of the efficacy and safety of the recommended dose of BAY 86-6150 determined in all patients from Part A. Safety endpoints were AEs and immunogenicity. Anti-drug antibody testing was performed at screening (prior to exposure), after the second exposure, then every fifth exposure, and at the end of study visit in both part A and part B. Anti-BAY 86-6150 binding antibodies were measured using a validated enzyme-linked immunosorbent assay (ELISA). Samples that revealed a specific immunoreactivity in this assay were further characterized for neutralizing activity using a validated platelet-activated clotting assay. Additional functional assays were performed to determine the cross-reactive neutralizing effect on rFVIIa (NovoSeven®) of any detected anti-BAY 86-6150 antibodies. The presence of neutralizing antibodies was considered a serious adverse event (SAE) requiring prompt IDMC review. Results In cohort 1, 10 patients (mean age, 27.4 years) were treated with 6.5 mg/kg BAY 86-6150. These patients had a total of 73 bleeding events and received a total of 84 study drug injections. No anti-drug antibodies or anti-FVIIa was detected in the patients at screening prior to exposure to the study drug. BAY 86-6150 was well tolerated in all patients with no clinical or laboratory symptoms or signs of venous thromboembolism. Binding antibodies to BAY 86-6150 were detected on a scheduled screening visit in 1 patient after 3 exposures to BAY 86-6150; these anti-BAY 86-6150 antibodies displayed neutralizing activity against BAY 86-6150 and were also cross-reactive and neutralizing for rFVIIa. The affected patient had received rFVIIa before entry into the study. At the time of diagnosis of binding and neutralizing antibodies, the affected patient was not bleeding and did not require emergency treatment. Exposure to BAY 86-6150 was stopped and the trial was terminated at the first cohort. Subsequent bleeding episodes in this patient were successfully managed with FEIBATM (Factor Eight Inhibitor Bypass Activity). No other treatment-related AEs or SAEs were reported in this study. Additionally, the IDMC has recommended safety follow-up assessments for all the patients who actively participated in the trial. Conclusions The TRUST trial has been discontinued as a precautionary measure because of potential safety concerns related to the detection of the antidrug antibodies in 1 patient. Development of neutralizing antibodies against BAY 86-6150 that had a cross-reactive neutralizing effect on rFVIIa was considered a serious risk because of the limited treatment options in patients with inhibitors. These results underline the fact that it is currently not possible to predict immunologic response based on preclinical and phase 1 studies. Disclosures: Hardtke: Bayer Pharma AG: Employment. Schroeder:Bayer Pharma AG: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.573.573
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    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 3
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    First-in-human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4630-4630
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4630-4630
    Abstract: Background: Gene therapy for hemophilia A has the potential to reduce the treatment burden for care-providers and patients, by eliminating the need for regular factor VIII (FVIII) prophylaxis through the long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. BAY 2599023 (AAVhu37FVIII) is a non-replicating adeno-associated virus (AAV) vector, based on the AAV serotype hu37, which contains a single-stranded DNA genome encoding a B-domain deleted FVIII, under the control of a liver-specific promotor/enhancer combination optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic Clade E family and has been selected based on nonclinical studies demonstrating efficient liver-directed FVIII gene transfer, favorable biodistribution as well as durable FVIII expression. BAY 2599023 is the first clinical-stage AAV gene therapy vector based on the AAVhu37 serotype. This analysis reports safety and FVIII activity following a single intravenous infusion of BAY 2599023 in the first-dose cohort of a phase I/II open-label, first time in human dose-finding study (NCT03588299) of previously treated, severe hemophilia A patients. Patients/Methods: Two participants were enrolled sequentially; each received a single infusion of AAVhu37 (0.5 x 1013 GC/kg). Patients were males ≥18 years with no history of FVIII inhibitor development, no detectable immunity to the AAVhu37 capsid, and 〉 150 exposure days to FVIII products. Primary endpoints were adverse events (AEs), serious AEs and AEs/SAEs of special interest (S/AESI); the secondary endpoint was change in FVIII activity from baseline. Informed patient consent, and ethics committee approval at each local site, were obtained. Results: Following more than 15 weeks of safety observation, no SAEs, AEs related to study drug, nor S/AESI were reported. Liver enzymes (alanine aminotransferase and aspartate aminotransferase) remained 〈 1.5 of baseline. Corticosteroids were not used in either patient. Clear evidence of FVIII expression was observed in both patients with stable values of ~5% and ~17% in the first and second patient, respectively. An early read-out also indicated hemostatic efficacy in both; the first patient had successfully halted prophylaxis for 6 weeks, while the second one, treated on-demand with 99 bleeds recorded in the 12 months prior to gene transfer, has been bleed free for over 5.5 months to date. Conclusions: BAY 2599023 was previously shown in non-clinical studies to have a good safety profile, with the potential to achieve endogenous expression of FVIII at therapeutic levels, over an extended period of time. In this first-in-human clinical study with BAY 2599023, two patients have been treated with BAY 2599023 at the starting dose of 0.5 x 1013 GC/kg and no safety concerns have been reported to date. Measurable expression of endogenous FVIII and an early read-out of hemostatic efficacy have been demonstrated in both patients. Overall, data generated from this first dose cohort demonstrate that successful translation from pre-clinical to clinical development and proof-of-mechanism for BAY 2599023 was achieved. Disclosures Pipe: HEMA Biologics: Consultancy; Shire: Consultancy; Roche/Genentech: Consultancy; Sanofi: Consultancy; Freeline: Consultancy; Apcintex: Consultancy; Novo Nordisk: Consultancy; Catalyst Bioscience: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; uniQure: Consultancy; BioMarin: Consultancy; Pfizer: Consultancy; Spark Therapeutics: Consultancy. Becka:Bayer: Employment. Detering:Bayer: Employment. Vanevski:Bayer: Employment. Lissitchkov:Octapharma: Equity Ownership, Research Funding; Bayer: Consultancy, Equity Ownership, Honoraria, Other: Principal investigator for clinical trials, Research Funding; Sobi: Consultancy, Equity Ownership, Honoraria; Sanofi: Equity Ownership, Research Funding; Roche: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Shire: Consultancy, Equity Ownership, Honoraria, Speakers Bureau. OffLabel Disclosure: Gene therapy for haemophilia treatment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-125764
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 4
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    A New Dosing Model Based on Body Mass Index to Guide Factor VIII Dosing in Patients with Hemophilia A
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2491-2491
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2491-2491
    Abstract: See attached image file Disclosures Tiede: Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Consultancy; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Honoraria; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Research Funding. Goldmann:Novo Nordisk and other companies: Honoraria; Novo Nordisk and other companies: Consultancy. Miljić:Novo Nordisk: Other: Investigator fees as a participant of the clinical trial. Korsholm:Novo Nordisk A/S: Employment; Novo Nordisk A/S: Other: Owns stocks. Matytsina:Novo Nordisk A/S: Other: Owns stocks; Novo Nordisk A/S: Employment. Persson:Novo Nordisk A/S: Employment; Novo Nordisk A/S: Other: Owns stocks. Lissitchkov:Novo Nordisk: Other: Investigator fees as a participant of the clinical trial.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-111269
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    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 5
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    Bendamustine in the Treatment of Chronic Lymphocytic Leukemia -Consistent Superiority Over Chlorambucil in Elderly Patients and Across Clinically Defined Risk Groups.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2367-2367
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2367-2367
    Abstract: Abstract 2367 Poster Board II-344 Introduction: Bendamustine is a purine analog/alkylator hybrid agent with a unique mechanism of action, which has shown good clinical efficacy and acceptable tolerability in various hematological malignancies. Chronic lymphocytic leukemia (CLL) is a disease of the elderly, and presents with a variety of clinical characteristics which influence the prognosis. We analyzed tolerability and efficacy of bendamustine (BEN) in comparison to chlorambucil (CLB) in clinical risk groups defined by age and specific indicators of disease activity. Patients and Methods: The efficacy and safety of BEN and CLB have been compared in a randomized, open-label, multicenter, phase III trial in patients with previously untreated advanced (Binet stage B/C) CLL. Patients were randomized to receive BEN (100 mg/m2 on days 1 + 2) or CLB (0.8 mg/kg on days 1 and 15) for up to 6 treatment cycles. The primary endpoints were overall remission rate (ORR), which was defined as complete or partial response, and progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. The response to treatment was evaluated by a blinded Independent Response Assessment Committee. Results: A total of 319 patients were randomized (162 bendamustine, 157 chlorambucil), of whom all were included in the efficacy analysis, while 312 were evaluable for safety. Median age was 64 years (35 to 78). The median number of treatment cycles was 6 in both study arms, regardless of an age above or below 65 years. The median observation time was 35 months. ORR was significantly higher with BEN than with CLB (68% versus 31%, P 〈 0.0001). The median PFS was 21.6 months with BEN and 8.3 months with CLB (P 〈 0.0001). So far, there is no difference in OS (median not reached with BEN versus 65.4 months with CLB; p = 0.16). No significant difference in the remission rates became apparent when comparing patients below and above the age of 65 years (ORR 71.6 % versus 63.5 % with BEN, p 〉 0.3; and 28.4 % versus 32.5 % with CLB, p 〉 0.6). PFS was not influenced by age above 65 years, stage of disease (Binet stage B versus C), or elevated LDH. However, patients without B symptoms had a longer median PFS with BEN than those patients with B symptoms (30.4 months versus 17.7 months; p 〈 0.0001), whereas median PFS was not affected by the presence of B symptoms in patients with CLB (8.9 months in both patient groups). Conclusion: This study has shown that bendamustine offers significantly greater efficacy than chlorambucil in the elderly and across clinically defined major risk groups, even in the presence of B symptoms. BEN should be considered as first-line chemotherapy for patients with advanced CLL. Disclosures: Knauf: mundipharma: Consultancy, Honoraria; cephalon: Consultancy, Honoraria. Klein:mundipharma: Consultancy, Honoraria. Merkle:mundipharma: Consultancy, Honoraria. Montillo:mundipharma Italy: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2367.2367
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
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    Use of thrombopoietin receptor agonists in adults with immune thrombocytopenia: a systematic review and Central European expert consensus
    Springer Science and Business Media LLC ; 2023
    In:  Annals of Hematology Vol. 102, No. 4 ( 2023-04), p. 715-727
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    In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 102, No. 4 ( 2023-04), p. 715-727
    Abstract: There are currently three thrombopoietin receptor agonists (TPO-RAs) approved in Europe for treating patients with immune thrombocytopenia (ITP): romiplostim (Nplate®), eltrombopag (Revolade®), and avatrombopag (Doptelet®). However, comparative clinical data between these TPO-RAs are limited. Therefore, the purpose of this study was to perform a literature review and seek expert opinion on the relevance and strength of the evidence concerning the use of TPO-RAs in adults with ITP. A systematic search was conducted in PubMed and Embase within the last 10 years and until June 20, 2022. A total of 478 unique articles were retrieved and reviewed for relevance. The expert consensus panel comprised ITP senior hematologists from eight countries across Central Europe. The modified Delphi method, consisting of two survey rounds, a teleconference and email correspondence, was used to reach consensus. Forty articles met the relevancy criteria and are included as supporting evidence, including five meta-analyses analyzing all three European-licensed TPO-RAs and comprising a total of 31 unique randomized controlled trials (RCTs). Consensus was reached on seven statements for the second-line use of TPO-RAs in the management of adult ITP patients. In addition, the expert panel discussed TPO-RA treatment in chronic ITP patients with mild/moderate COVID-19 and ITP patients in the first-line setting but failed to reach consensus. This work will facilitate informed decision-making for healthcare providers treating adult ITP patients with TPO-RAs. However, further studies are needed on the use of TPO-RAs in the first-line setting and specific patient populations.
    Type of Medium: Online Resource
    ISSN: 0939-5555 , 1432-0584
    URL: Article
    DOI: 10.1007/s00277-023-05114-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 7
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    Improved Pharmacokinetics with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method: A Randomized Pharmacokinetic Study in Patients with Severe Hemophilia A
    Springer Science and Business Media LLC ; 2017
    In:  Clinical Pharmacokinetics Vol. 56, No. 9 ( 2017-09), p. 1045-1055
    Details
    In: Clinical Pharmacokinetics, Springer Science and Business Media LLC, Vol. 56, No. 9 ( 2017-09), p. 1045-1055
    Type of Medium: Online Resource
    ISSN: 0312-5963 , 1179-1926
    URL: Article
    DOI: 10.1007/s40262-016-0492-2
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2043781-X
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  • 8
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    Safety, Immunogenicity, and Hemostatic Efficacy of Nonacog Gamma in Patients With Severe or Moderately Severe Hemophilia B: A Continuation Study
    SAGE Publications ; 2020
    In:  Clinical and Applied Thrombosis/Hemostasis Vol. 26 ( 2020-01-01)
    Details
    In: Clinical and Applied Thrombosis/Hemostasis, SAGE Publications, Vol. 26 ( 2020-01-01)
    Abstract: 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
    Type of Medium: Online Resource
    ISSN: 1076-0296 , 1938-2723
    URL: Article
    DOI: 10.1177/1076029620950836
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2020
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  • 9
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    Bendamustine Versus Chlorambucil in Treatment-Naive B-CLL Patients.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 4817-4817
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 4817-4817
    Abstract: Introduction: Bendamustine (BEN) provides effective treatment of hematologic as well as of non-hematologic malignancies. It is characterized by an unique activity profile which differs from common nitrogen mustard drugs. In particular, it causes only partial cross resistance to other alkylating agents, anthracyclines and anti-metabolites, respectively. BEN is used in patients with chemo naïve, relapsed or refractory chronic lymphocytic leukemia (CLL), however, no head-to-head study has been performed so far. Therefore, a multicenter, international phase III study was initiated to compare the activity of BEN against chlorambucil in treatment-naive B-CLL patients with Binet stage B/C. Patients and Methods: Patients are randomized to either Arm A (BEN 100 mg/m2, d 1+2) or to Arm B (chlorambucil 0,8mg/kg Broca’s weight, d 1+15) to receive a maximum of 6 treatment cycles. Primary objectives are overall remission rate and progression-free survival. The anticipated effects are an overall remission rate of 60% vs. 30% and a median progression free survival of 20 vs.14 months. Secondary objectives are additional efficacy parameters, safety, and quality of life. The study design is adaptive with four interim analyses to adjust the final number of patients, plus one safety analysis. A maximum of 350 patients is planned. Toxicities regarding hemoglobin, platelets and neutrophils are graded according to the NCIWG for CLL, while leukocyte and lymphocyte counts are graded according to CTC as in many other CLL trials. Results and Summary: To assess safety, twenty patients in each treatment arm with at least one completed treatment cycle have been evaluated. The results have been reviewed by an independent data monitoring committee (IDMC). It was concluded that the dosages selected for both treatment arms are safe and that the study is to be continued. Furthermore, another safety analysis was performed with respect to the rate of major infections in the same patient cohort after having completed study treatment. While the infection rate has been reported to be 29% in patients treated with fludarabine as published by Rai et al., in our study two BEN-patients (10%) experienced major infections whereas none occurred in the chlorambucil arm. One BEN-patient developed fever CTC grade 3 without neutropenia. Another patient experienced pneumonia CTC grade 2 requiring hospitalization and intravenous antibiotic treatment. In the BEN-arm, 87% of the scheduled dose was applied whereas 89% was given in the chlorambucil arm. Patients treated with BEN remained longer on study as compared to the chlorambucil patients. The toxicity rate, both hematologic and non-hematologic, was in favour for chlorambucil. In total, three patients were withdrawn from study due to toxicity: one patient in each treatment arm due to infection and one BEN-patient due to an allergic reaction. Meanwhile, the first planned interim analysis on remission rate was done. 43 patients in each treatment arm were evaluated. The IDMC recommended to continue the study. A second interim analysis will be performed after 160 patients will have completed the first tumor evaluation to adjust the number of patients finally required.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.4817.4817
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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    Recombinant Factor VIII Combined With Recombinant Von Willebrand Factor In Patients With Severe Hemophilia A: A Prospective Clinical Study Of Safety and Pharmacokinetics
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 336-336
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 336-336
    Abstract: Hemophilia A is an X-linked recessive, congenital bleeding disorder caused by a deficiency of circulating coagulation FVIII. Treatment regimens include on-demand or prophylactic FVIII substitution. An important challenge for patient compliance and treatment success is the need for frequent infusions due to the short circulating terminal half-life (T1/2) of FVIII (8 to 14 h). In vivo, FVIII binds to, and is stabilized by, von Willebrand factor (VWF). Studies have shown that the T1/2 of FVIII is positively correlated to baseline levels of VWF. The present study hypothesizes that co-administration of recombinant FVIII (rFVIII) with recombinant VWF can improve the pharmacokinetic (PK) properties of rFVIII. The PK and safety of a rFVIII (ADVATE, Baxter) co-administered with an investigational rVWF were investigated in a prospective clinical trial of 12 previously-treated patients with severe hemophilia A (FVIII:C 〈 1%), aged 18 to 60 years. Subjects were administered 3 infusions 8 to 14 days apart with: 1) rFVIII alone, 2) rFVIII combined with rVWF (low VWF ristocetin co-factor activity [VWF:RCo] dose), and 3) rFVIII combined with rVWF (high VWF:RCo dose). rFVIII was administered at the same dose for each PK infusion. FVIII activity was assessed using a one-stage clotting assay. rFVIII co-administered with rVWF up to the highest investigated dose was well tolerated and safe in hemophilia A patients. No serious adverse events (AEs) and no treatment related AEs occurred, including no signs or symptoms of thrombosis, development of neutralizing antibodies to rVWF or rFVIII, or hypersensitivity reactions were observed. A trend suggesting a prolongation of FVIII activity by the addition of rVWF was observed as shown by an increased area under the concentration curve (AUC), mean residence time (MRT) and T1/2 after infusion of rFVIII combined with rVWF as compared with rFVIII alone, with a greater improvement associated with the higher of the 2 rVWF doses investigated (Table 1). An association between VWF antigen (VWF:Ag) level and rFVIII T1/2 was observed. Subjects with lower VWF:Ag levels at baseline tended to have a more pronounced increase in rFVIII T1/2 after infusion with rFVIII combined with rVWF compared with rFVIII alone (Table 2). Table 1 FVIII PK up to 120 hours after infusion with rFVIII alone or combined with rVWF PK Parameter Infusion N Geometric mean (GM) 95% confidence interval for GM AUC0-120h  [h*IU/mL] rFVIII 12 1376.58 847.67 to 2235.52 rFVIII + rVWF (low dose) 12 1396.94 889.90 to 2192.88 rFVIII + rVWF (high dose) 11 1963.30 1602.77 to 2404.93 AUC0-inf  [h*IU/mL] rFVIII 12 1410.06 877.76 to 2265.17 rFVIII + rVWF (low dose) 12 1433.29 928.97 to 2211.39 rFVIII + rVWF (high dose) 11 1994.53 1632.55 to 2436.76 Mean residence time [h] rFVIII 12 15.17 11.62 to 19.81 rFVIII + rVWF (low dose) 12 16.38 13.23 to 20.27 rFVIII + rVWF (high dose) 11 18.06 14.97 to 21.79 Clearance [mL/kg/h] rFVIII 12 0.035 0.022 to 0.057 rFVIII + rVWF (low dose) 12 0.035 0.023 to 0.054 rFVIII + rVWF (high dose) 11 0.025 0.021 to 0.031 Terminal Half-Life [h] rFVIII 12 12.05 8.95 to 16.24 rFVIII + rVWF (low dose) 12 12.74 10.11 to 16.05 rFVIII + rVWF (high dose) 11 13.74 11.44 to 16.52 Volume at a steady state [mL/kg] rFVIII 12 0.54 0.36 to 0.79 rFVIII + rVWF (low dose) 12 0.57 0.40 to 0.82 rFVIII + rVWF (high dose) 11 0.46 0.39 to 0.54 AUC: area under the plasma concentration/time curve from time Table 2 Baseline VWF:Ag levels and geometric mean FVIII:C in individual patients after infusion Subject Baseline VWF:AG FVIII T ½ after rFVIII alone FVIII T½ after rFVIII + rVWF (high dose) Ratio of T½ after rFVIII + rVWF (high dose) over T½ after rFVIII alone 1 106 16.65 15.22 0.91 2 298 26.63 23.97 0.90 3 90 9.12 10.34 1.13 4 121 13.26 13.78 1.04 5 126 10.63 12.24 1.15 6 90 8.24 12.17 1.48 7 79 5.81 8.75 1.51 8 108 9.36 12.13 1.30 9 139 14.68 15.93 1.09 10 181 26.60 18.16 0.68 11 161 11.88 13.91 1.17 In summary, rVWF was safe and well tolerated when co-administered with rFVIII in hemophilia A patients and slightly sustained FVIII activity, with the highest improvement in circulating FVIII T1/2 associated with lower baseline VWF:Ag levels. These findings provide insight into the FVIII/VWF interaction and its potential impact on therapy. Disclosures: Windyga: Baxter, Bayer, Behring, Novo Nordisk, Octapharma, Pfizer: Honoraria, Research Funding. Draxler:Baxter: Employment. Chapman:Baxter: Employment. Wong:Baxter: Employment. Sørensen:Baxter: Employment. Ewenstein:Baxter: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.336.336
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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