Journal articles: 'Ingelheim (Germany)' – Grafiati (2024)

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Abstract Empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany) has been replaced with empagliflozin (Jardiance, Boehringer Ingelheim, Ingelheim, Germany/Eli Lilly and Company, Indianapolis, IN, USA). Sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK) has been replaced with sitagliptin (Januvia, Merck Sharp & Dohme Limited, Kenilworth, NJ, USA).

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Professor Angela Märten speaks to Rachel Jenkins, Commissioning Editor Angela Märten earned her PhD at Humboldt University of Berlin, Germany, in 2000, after working for several years as an oncology nurse. Upon completion of her PhD, she assumed responsibility for Phase I trials and translational research for the University Hospital of Bonn, Germany. In 2002, the University Hospital of Bonn appointed her as Assistant Professor for Experimental Haematology and Oncology. In 2003, she accepted a new position at the University of Heidelberg, Germany, heading the Immunotherapeutic Group and the Oncology Trial Department. The University of Heidelberg appointed her as Associate Professor in 2006 while she completed her Master of Sciences in Clinical Research in 2008. Professor Märten has been principal investigator of several clinical trials and has published more than 100 papers, with a particular focus on pancreatic carcinoma and lung cancer. She joined Boehringer Ingelheim in 2009, where she built up the German Medical Affairs Oncology team, before joining the Global Afatinib team in 2013. She is currently Global Senior Medical Advisor, Therapeutic Area of Oncology at Boehringer Ingelheim.

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In growing lambs a high proportion of protein retained (0.2-0.3) may be stored in wool. Protein retention is known to be increased by treating sheep with B agonists and there are indications that the extra protein is stored mainly in the carcass (Williams, 1987; Fiems, 1987). Wool growth rate at any time is determined by the relative availability of nutrients to all body tissues and is affected by, for example, pregnancy. It is also dependent on the kinetics of all competing biochemical reactions, which are altered by hormones (Black and Reis, 1979).To investigate the partition of protein between wool and other body tissues, a nitrogen balance trial was carried out with lambs fed on a diet with or without the B agonist, Cimaterol (Boehringer Ingelheim, Ingelheim, West Germany).

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Abstract BI 836909 is a Bispecific T cell Engager (BiTE®), designed to redirect the body's endogenous T cells towards cells expressing B cell maturation antigen (BCMA) on the cell surface. BCMA is a highly plasma cell specific antigen and shows hom*ogeneous expression on the cell surface of multiple myeloma, plasma cell leukemia and plasmacytoma cells. In normal tissues, BCMA expression is restricted to plasma cells, while other normal tissues do not express BCMA. This highly selective expression pattern makes BCMA an ideal target for T cell redirecting therapy. The pharmacological effect of BI 836909 depends on its simultaneous binding to both the CD3 epsilon subunit of the T cell receptor complex on T cells as well as to BCMA on multiple myeloma cells, resulting in the lysis of the BCMA-expressing cells. In vitro, unstimulated peripheral blood mononuclear cells (PBMCs) were co-cultured with several multiple myeloma cell lines and increasing concentrations of BI 836909, and tumor cell lysis, T cell activation, and induction of cytokine release were assessed. BI 836909 induced dose-dependent redirected lysis of human multiple myeloma cell lines with EC90 values ranging from 16 to 810 pg/mL. Viability of BCMA-negative cells was not affected, demonstrating the specificity of BI 836909 for BCMA. The expression of the activation markers CD69 and CD25 on T cells and the release of cytokines by T cells were target-dependent and occurred only in the presence of BCMA-positive cells. In vivo anti-tumor activity of BI 836909 was assessed in NOD/SCID mice reconstituted with human T cells and bearing subcutaneous or orthotopic xenografts derived from human multiple myeloma cell lines. In the subcutaneous NCI-H929 xenograft model, animals were treated with BI 836909 by daily intravenous or subcutaneous bolus injections. Statistically significant dose-dependent anti-tumor activity was observed at doses of 50 µg/kg/day and higher. The efficacy of BI 836909 was comparable after intravenous and subcutaneous administration, when the difference in bioavailability of the different routes was considered. In an orthotopic L-363 xenograft model, treatment with BI 836909 resulted in a statistically significant prolonged survival at doses of 5 µg/kg/day and higher. BI 836909 shows comparable cross-reactive binding to both BCMA and CD3 epsilon of human and macaque origin at picomolar and low nanomolar affinities respectively, thus allowing the assessment of pharmacodynamics, pharmaco*kinetics, and safety in non-human primates. In toxicity studies, cynomolgus monkeys were administered doses of up to 135 µg/kg/day of BI 836909 via continuous intravenous infusion, and up to 405 µg/kg/day via daily subcutaneous injection for up to 28 days. A dose- dependent decrease in plasma cells was observed in the bone marrow of treated animals compared to the vehicle control group, consistent with BCMA expression on cynomolgus monkey plasma cells, this demonstrated the pharmacological activity of BI 836909. These pre-clinical data demonstrate that BI 836909 is a highly potent, efficacious and BCMA-selective T cell redirecting agent and support clinical testing of BI 836909 in multiple myeloma patients. Disclosures Hipp: Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria: Employment. Deegen:Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany: Employment. Wahl:Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany: Employment. Blanset:Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA: Employment. Thomas:Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany: Employment. Rattel:Amgen Research (Munich) GmbH, Staffelseestrasse 2, 81477 Munich, Germany: Employment. Adam:Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria: Employment. Friedrich:Amgen Research (Munich) GmbH: Employment.

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Background:RISE-SSc (NCT02283762) was a multicenter, double-blind, Phase IIb study of riociguat in early dcSSc. Primary endpoint was change in mRSS from baseline to Wk 52.Objectives:Exploratory, descriptive analyses of riociguat target engagement and effects on disease biomarkers in RISE-SSc and their relationship with effects on the primary endpoint. All biomarker p-values are for information only.Methods:Pts with dcSSc (duration ≤18 mo; modified Rodnan skin score [mRSS] 10–22 units) were randomized to riociguat 0.5−2.5 mg tid (n=60) or placebo (n=61). Biomarkers of target engagement (cGMP), inflammation and/or vascular/endothelial function (e.g. high-sensitivity C-reactive protein [hsCRP], soluble platelet endothelial cell adhesion molecule 1 [sPECAM-1], soluble E-selectin, chemokine ligand 4 [CXCL-4]), and fibrosis (e.g. alpha-smooth muscle cell actin [alphaSMA], pro-collagen mRNA expression) were measured in plasma, serum, and skin biopsies at baseline and Wk 14.Results:Mean±SD change from baseline in mRSS was –2.09±5.66 (n=57) with riociguat and –0.77±8.24 (n=52) with placebo (p=0.08). From baseline to Wk 14, plasma cGMP rose by mean (SD) 94% (78%) (n=52) with riociguat and 10% (39%) (n=52) with placebo (nominal p<0.001). Serum sPECAM-1 and CXCL-4 fell with riociguat vs placebo; changes in hsCRP or E-selectin differed little between groups (Fig 1). Pts with higher baseline sPECAM-1 showed larger mRSS reductions with riociguat vs placebo than pts with lower levels (nominal interaction p=0.004). In baseline skin biopsies, 34% and 31% of pts in the riociguat and placebo groups, respectively, had no alphaSMA-positive cells; other pts had +ve cells (alphaSMA counts 0.1–99.5, median 2.5), a potential indicator of higher disease activity. Pts with +ve baseline alphaSMA counts showed a reduction of mRSS with riociguat vs placebo (Fig 2). Skin collagen mRNA expression biomarkers in skin biopsies showed no differences between groups.Conclusion:Primary study endpoint (change in mRSS) was not met. Plasma cGMP rose with riociguat, confirming engagement with the NO-sGC-cGMP pathway. Serum sPECAM-1 (marker of endothelial activation) and CXCL-4 (marker of progressive SSc) fell with riociguat; hsCRP and E-selectin did not. Some serum and skin biomarkers of higher disease activity at baseline were associated with a greater effect of riociguat on skin fibrosis.Acknowledgments:RISE-SSc was jointly funded by Bayer AG and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Disclosure of Interests:Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Frank Kramer Employee of: Bayer AG, Josef Höfler Employee of: Josef Höfler is an employee of Staburo GmbH, Munich, Germany, contracted by Bayer AG to perform the biomarker analyses, Mercedeh Ghadessi Employee of: Bayer AG, Peter Sandner Employee of: Bayer AG, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Radim Bečvář Consultant of: Actelion, Roche, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Ellen De Langhe Consultant of: member of advisory board for Boehringer, Eric Hachlla: None declared, Tomonori Ishii: None declared, Osamu Ishikawa: None declared, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Kaisa Laapas Employee of: Partly in-sourced to Bayer, Valeria Riccieri: None declared, Elena Schiopu: None declared, Richard Silver: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Chiara Stagnaro: None declared, Viginia Steen Grant/research support from: The associated affiliation has received grants/research from Boehringer Ingelheim, Corbus Pharmaceuticals, CSL Behring, Eicos, Galapagos, Immune Tolerance Network, Reata, Consultant of: Virginia Steen has acted as a consultant for Boehringer Ingelheim, Corbus, CSL Behring, Eicos, Forbius, Wendy Stevens: None declared, Gabriella Szücs: None declared, Marie-Elise Truchetet: None declared, Melanie Wosnitza Employee of: Bayer AG, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB

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Background:Current treatments for systemic sclerosis-associated interstitial lung disease (SSc-ILD) are characterised by different attributes such as mode of administration, adverse events (AE) and efficacy. Physicians and patients often have different perspectives on treatments, thus shared decision-making between patients and physicians is essential. An understanding of patients’ decision processes when weighing treatment attributes and the trade-offs they are willing to make is important for shared decision-making.Objectives:The study aimed to 1) identify relevant treatment attributes, 2) elicit patient preferences for these attributes and 3) quantify preference as relative attribute importance (RAI; a higher RAI indicates that more of the variability in patients’ responses may be explained by changes in the attribute); and maximum acceptable risk (MAR) of diarrhoea, nausea and/or vomiting (MAR is a trade-off measure that evaluates attributes in risk-equivalences as a unit of measurement).Methods:A discrete choice experiment (DCE) was created, based on a literature review, a patient advisory board, qualitative patient interviews, and a workshop involving SSc-ILD expert physicians. Seven SSc-ILD treatment attributes were identified: 1) mode of administration; 2) shortness of breath; 3) skin tightness; 4) cough; 5) tiredness; 6) risk of gastrointestinal tract (GIT) AEs; and 7) risk of serious and non-serious infections. The levels of AE risk were informed by frequencies observed in clinical trials and patient input during the interviews. The DCE was integrated into an online survey, which asked patients to make repeated choices between two alternatives described by varying levels of included attributes. Patients with SSc-ILD were recruited by physician referral from Switzerland, Norway, France, Germany and the USA. DCE data were analysed using a logit model, and RAI and MAR measures were calculated.Results:A total of 231 patients with physician-confirmed SSc-ILD (mean age 52.6±13.2 years; 54% diagnosed for >5 years) completed the survey. Patients with SSc-ILD mostly preferred twice-daily oral treatments (p<0.001) and infusion every 6–12 months (p<0.001) over monthly infusions. Patients’ choices were mostly affected by the risk of GIT AEs (RAI=25%; 95% CI 22–28%) and risk of infections (RAI=20%; 95% CI 16–24%). Improvements in shortness of breath and type and severity of cough were jointly more important than improvement in skin tightness (p<0.001).Patients accepted an additional 21% risk (95% CI 13–29%) of GIT AEs if they could reduce the frequency of infusions from monthly to 6–12 monthly, or accepted an extra 15% (95% CI 7–23%) increase in risk if changing to an oral treatment twice daily. Among symptoms, an additional 28% (95% CI 20–36%) risk of GIT AEs was considered acceptable if the severity of patients’ persistent cough was reduced to a level that was easier to tolerate, even if it remained persistent. Similarly, a 37% (95% CI 28–46%) increase in the risk of GIT AEs was acceptable if it resulted in breathlessness during routine activities rather than breathlessness at rest. Finally, patients were willing to accept an additional 36% risk (95% CI 27–45%) of GIT AEs if it reduced their risk of non-serious infections from 30% to 15% and of serious infections from 10% to 5%.Conclusion:This is the first study to quantitatively elicit patients’ preferences for attributes of SSc-ILD treatments. Preferences were driven by safety, efficacy and technical considerations. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in routine clinical practice.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Gruppo Italiano Lotta alla Scleroderma (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Scleroderma Trial and Research (EUSTAR), Foundation for Research in Rheumatology (FOREUM)., Sebastian Heidenreich Consultant of: Sebastian Heidenreich, PhD is employed by Evidera Inc, a business unit of PPD. Evidera is a CRO that offers paid research services to pharmaceutical companies., Ashley Duenas Consultant of: Yes. I am an employee of Evidera which received funding from Boehringer Ingelheim for work related to this study., Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Merck Sharp & Dohme, Lilly, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli Grant/research support from: Pfizer Bhering, Yannick Allanore Consultant of: Honorarium received from Boehringer, Medsenic,Sanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Emmanuel Chatelus: None declared, Jörg H.W. Distler Shareholder of: JHWD is stock owner of 4D Science, Consultant of: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Eric Hachulla: None declared, Vivian Hsu Speakers bureau: I am a speaker for Boehringer Ingelheim Pharmaceuticals, Consultant of: with Boehringer Ingelheim Pharmaceuticals, Grant/research support from: Principal Investigator for several clinical trials, currently with Genentech, Corbus Pharmaceutical, and EICOS, Nicolas Hunzelmann Speakers bureau: Boehringer, Roche, Sanofi, Dinesh Khanna Shareholder of: Eicos Sciences, Inc (less than 5%), Consultant of: Paid Consultant for: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics, Grant/research support from: Research Grant support from: Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc – recieves a stipend for role as Chief Medical Officer, which would technically qualify as emplyoment., Marie-Elise Truchetet Speakers bureau: Abbvie, Lilly, Sobi, Boehringer, Paid instructor for: Lilly, Consultant of: UCB, Sobi, Abbvie, Grant/research support from: UCB, Gilead, Ulrich Walker Shareholder of: Bayer, NASDAQ, MSCI-World ETF’s, Speakers bureau: All companies producing pharmaceuticals used in AIDS, Paid instructor for: Roche, Abbvie, Novartis, Consultant of: All companies producing pharmaceuticals used in AIDS, Grant/research support from: Gilead, Abbvie, (in the last two years). Other companies in previous years., Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Employee of Boehringer Ingelheim International GmbH, Lesley Ann Saketkoo Speakers bureau: Boehringer Ingelheim, Actelion, Janssen, Mallinckrodt, United Therapeutics, Consultant of: Actelion, Boehringer Ingelheim, Bayer, Bristol Meyer Squibb, Corbus, EICOS, Janssen, Horizon, United Therapeutics, Inc, Grant/research support from: Mallinckrodt, United Therapeutics, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, Consultant of: OD has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years):Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe

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The historical database represents the spontaneous, i.e. normal changes of characters, in laboratory animals, and is a must for the assessment of toxic effects of compounds. For the Himalayan rabbit (CHBB:HM, SPF) background data were collected from the control groups of regulatory studies between 1968-1999 in the Biberach laboratory of Boehringer Ingelheim (Germany). In the present study these data were compared with the background data from the years 1974-1984, with those from the Ingelheim laboratory, Germany (1977-1984) and those from the breeding colony at Kawanishi, Japan (1971-1991, 1972-1984). Fertility in the Biberach laboratory was relatively constant through the years, due to the strict breeding system. Litter parameters (corpora lutea, implantations and viable fetuses), including fetal sex distribution and fetal weight, were constant in the Biberach laboratory through the years and compared well with the data from Ingelheim and Kawanishi. From these three laboratories the results of spontaneous changes in fetal morphology above 0.1% incidence suggest a pattern of deviations from the Bauplan (fundamental body plan). These comprise synosteosis of sternebrae, lumbar (additional) ribs, hypoplasia of 12th rib, status of ossification, aplasia of gall bladder, hypoplasia of gall bladder, incompletely subdivided lung, dilated ventricle of heart, deviations at the A. carotis and at the aortic arch and flexure of paw. The absence of a time-dependent statistical trend indicates that the spontaneous change of endpoints remained constant through the time axis. Comparison with the spontaneously changed fetal morphology of the other strains (NZW, JW, SF rabbits) does not provide support for their being a totally strain-specific pattern, and this pattern may be closer to the species than specific to a single strain. The firm patterns of deviations in fetal morphology provide suitable and valuable markers for assessing toxic effects on ontogenesis. According to our experience these morphological endpoints react very sensitively to teratogenic compounds, which is demonstrated by increased incidences. Our knowledge of evolution of organisms and of mechanisms leading to morphological deviations points to a strict selection of phenotypes. For laboratory animals the decisive selection factors are defined by man. These are nutritive factors, environmental conditions, the mating system, handling and treatment, and experimental design. All these factors have to be held constant through the years, which is an absolute pre-condition for the application of valid historical data. The Himalayan rabbit is highly suitable for use in developmental toxicity studies due to the stability of reproductive data within the same laboratory over a period of more than 30 years, due to the similarity of reproductive data among three different laboratories, and due to an absence of relevant differences to the reproductive data of other rabbit strains.

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Background:Patients with systemic lupus erythematosus (SLE), even compared to those with other rheumatic diseases, are thought to often experience a long delay from the onset of symptoms to diagnosis.Objectives:Our aim was to study the association of this delay to the long-term outcome of the disease.Methods:Information on demographics, onset of first symptoms, first physicians visit, time of diagnosis and organ involvement was assessed by self-reported questionnaires among SLE patients in Germany in 2011 (LuLa cohort, n=585). Disease related damage (Brief Index of Lupus Damage; BILD), disease activity (Systemic Lupus Activity Questionnaire; SLAQ) and health related quality of life (SF-12) were chosen as proxies for outcome. The association to the outcome of the disease was analyzed by linear regression analysis, adjusted for age, disease duration, organ involvement and sex.Results:In our cohort, the mean reported duration between the onset of symptoms and the diagnosis of SLE was 46 months (SD 73), which includes 13 months (SD 41) between the onset of symptoms and the first physicians visit. The participating patients were diagnosed between 1960 and 2004.Linear regression analysis revealed that longer time to diagnosis was associated with (i) higher disease activity (SLAQ, p<0.0001, β=0.199), (ii) higher disease-related damage (BILD, p=0.002, β=0.137) and (iii) lower health-related quality of life (SF-12 physical p=0.004, β=-0.136, SF-12 mental p=0.004, β=-0.143) in the year 2011. The organ involvement at the time of diagnosis did not alter these results.Conclusion:A delay in diagnosis was associated with a worse outcome in SLE (disease activity, disease-related damage and health-related quality of life). Therefore, an early diagnosis seems to be important to improve the long-term outcome of the disease. It will be interesting to see whether adopting the new EULAR/ACR 2019 classification criteria can contribute to a faster diagnosis and a better outcome in consequence.The LuLa study is supported by unrestricted grants from GlaxoSmithKline and UCB Pharma.Disclosure of Interests:Anna Kernder Grant/research support from: Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Jutta Richter Grant/research support from: Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Rebecca Fischer-Betz Consultant of: UCB, Speakers bureau: Abbvie, Amgen, Biogen, BMS, Celgene, Chugai, GSK, Janssen, Lilly, Medac, MSD, Novartis, Roche, UCB, Pfizer., Borgi Winkler-Rohlfing: None declared, Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche, Matthias Schneider Grant/research support from: GSK, UCB, Abbvie, Consultant of: Abbvie, Alexion, Astra Zeneca, BMS, Boehringer Ingelheim, Gilead, Lilly, Sanofi, UCB, Speakers bureau: Abbvie, Astra Zeneca, BMS, Chugai, GSK, Lilly, Pfizer, Sanofi, Gamal Chehab Grant/research support from: Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study.

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Abstract Background The current standard of therapy in superficial vein thrombosis (SVT) comprises subcutaneous injections of the indirect factorXainhibitorfondaparinuxfor up to 45 days, which was highlyeffectivecompared to placebo in the CALISTO trial. However,fondaparinuxis expensive, requires daily injections and cost-effectiveness in SVT therapy has been questioned. Rivaroxaban is a direct oral factorXainhibitor which has been shown to be effective in the prevention and treatment of venous thromboembolism (VTE). We hypothesizedthat SVT patientsat high risk for VTE complications may be treated as efficacious and safe with rivaroxaban as withfondaparinux. Methods The SURPRISE trial, a randomized, open-label blinded outcome event adjudication trial, compared rivaroxaban 10 mg once daily withfondaparinux2.5 mg once daily in patients with SVT at high risk of VTE complications (defined assupragenualSVT + age > 65 years, male sex, previous VTE, cancer, autoimmune disease or SVT of non-varicose veins). Treatment duration for both treatments was 45+5 days with an observational period until day 90+10. The primary efficacy outcome was a composite endpoint of deep vein thrombosis, pulmonary embolism, SVT progression towards thesaphenofemoraljunction, SVT recurrence or all cause death in the per-protocol analysis at day 45. A predefined sensitivity analysis was performed in all randomized patients (full analysis set). The primary safety outcome was the rate of ISTH major bleeding during treatment. Further outcome measures included the composite efficacy outcome up to day 90, each component of the primary efficacy outcome, rates of surgical treatment of SVT and rates of major VTE (composite of symptomatic PE or symptomatic proximal DVT or VTE-related death) at days 45 and 90. The trial was designed to test for non-inferiority of rivaroxaban compared tofondaparinuxwith respect to the primary efficacy outcome and to the rates of ISTH major bleeding. Results A total of 472 patients were randomized (mean age 60.3 years; 60.4% female) and treated with rivaroxaban (n=236) orfondaparinux(n=236). Mean treatment duration was 44.0 days for rivaroxaban and 44.8 days forfondaparinux. Until day 45+5, the primary efficacy outcome (n=435 in per-protocol analysis set) occurred in 3.3% (95%-CI 0.90; 5.73) of patients treated with rivaroxaban and 1.8% (95%-CI 0.05; 3.52) of patients receivingfondaparinux(absolute difference between rivaroxaban andfondaparinuxwas 1.53%; one-sided upper CI limit 4.03%; p-value for non-inferiority 0.025; table 1 and figure 1). Until day 90+10, the respective rates were 7.1% for rivaroxaban and 6.7% forfondaparinux(absolute difference 0.41;one-sided upper CI limit 4.41%;p-value for non-inferiority 0.047). Non-inferiority of rivaroxaban vs.fondaparinuxwas preserved in the full analysis set. No major bleeding occurred and rates of non-major, clinically relevant bleeding were 2.5 vs. 0.4% for day 45+5 and 2.5 vs. 0.9% for day 90+10 in safety set for rivaroxaban andfondaparinux, respectively (table 1).Mean±SDadherence (pill/syringe count at day 45) was 98.9±13.4% for rivaroxaban and 99.3±6.2% forfondaparinux(full analysis set). Conclusions In high-risk SVT patients, rivaroxaban was non-inferior tofondaparinuxin preventing thromboembolic complications with comparable safety. VTE events were predominantly SVT recurrence. Few cases of DVT and PE occurred, which indicates that a 45 days course of rivaroxaban 10 mg orfondaparinux2.5 mg is sufficient to prevent serious complications in this specific subset of SVT patients. As to whether oral rivaroxaban offers a better quality of life compared to 45 days of injections, this has to be investigated in future studies. We found higher SVT complications rates in both treatment arms compared to thefondaparinuxarm in the CALISTO trial. Therefore, patients at higher VTE risk can be identified by use of a simple risk factor assessment, which may help to improve cost-effectiveness of SVT therapy. However, the concept of SVT risk stratification needs to be further investigated, since patients without additional risk factors may not need anticoagulant therapy at all. (Funded by Bayer Vital GmbH, Germany, ClinicalTrials.gov NCT01499953) In response to a pre-submission enquiry, the New England Journal of Medicine indicated potential interest in the study results and a simultaneous publication/presentation is targeted. Disclosures Beyer-Westendorf: Daichii Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding. Schellong:Bayer: Honoraria; Pfizer: Honoraria; Boehringer-Ingelheim: Honoraria; Daichii Sankyo: Honoraria; LeoPharma: Honoraria. Gerlach:ASPEN: Honoraria; Bayer: Honoraria; Boehringer-Ingelheim: Honoraria; LeoPharma.: Honoraria. Rabe:Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daichii-Sankyo: Honoraria; LeoPharma: Honoraria; Pfizer: Honoraria. Bauersachs:Bayer: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; BristolMyers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; ASPEN: Honoraria, Research Funding.

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Background Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium–glucose co-transporter 2 (SGLT2) inhibitors. Objective To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Boehringer Ingelheim, Ingelheim, Germany/Eli Lilly and Company, Indianapolis, IN, USA), in monotherapy in people who cannot take metformin. Sources MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. Methods Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. Results We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). Limitations There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. Conclusions Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Merck Sharp & Dohme Limited, Kenilworth, NJ, USA). Funding The National Institute for Health Research Health Technology Assessment programme.

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Background Intravenous thrombolysis with alteplase within a time window up to 4.5 h is the only approved pharmacological treatment for acute ischemic stroke. We studied whether acute ischemic stroke patients with penumbral tissue identified on magnetic resonance imaging 4.5–9 h after symptom onset benefit from intravenous thrombolysis compared to placebo. Methods Acute ischemic stroke patients with salvageable brain tissue identified on a magnetic resonance imaging were randomly assigned to receive standard dose alteplase or placebo. The primary end point was disability at 90 days assessed by the modified Rankin scale, which has a range of 0–6 (with 0 indicating no symptoms at all and 6 indicating death). Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. Results The trial was stopped early for slow recruitment after the enrollment of 119 (61 alteplase, 58 placebo) of 264 patients planned. Median time to intravenous thrombolysis was 7 h 42 min. The primary endpoint showed no significant difference in the modified Rankin scale distribution at day 90 (odds ratio alteplase versus placebo, 1.20; 95% CI, 0.63–2.27, P = 0.58). One symptomatic intracranial hemorrhage occurred in the alteplase group. Mortality at 90 days did not differ significantly between the two groups (11.5 and 6.8%, respectively; P = 0.53). Conclusions Intravenous alteplase administered between 4.5 and 9 h after the onset of symptoms in patients with salvageable tissue did not result in a significant benefit over placebo. (Supported by Boehringer Ingelheim, Germany; ISRCTN 71616222).

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Recently, the popularization of obligatory preventive use of multivitamin preparations has been observed, and, as a result of this, they have become an integral part of the modern lifestyle. This is precisely what determines the relevance and necessity of researching the market of vitamin and mineral complexes in Ukraine. A feature of the current state of the vitamin market is their positioning in the form of both drugs and dietary supplements (DS). In view of this, research of the assortment dynamics of product range, the features of the competitive environment for this group of drugs are important. Therefore, the purpose of our work was to analyze the dynamics of the range of vitamin drugs and compare them with the range of vitamin DS. The material of the study was an assortment of vitamin drugs and DS according to the manuals «Compendium. Medicines» of different years of publication in period from1999 to 2019 and Compendium.online site as of February 2019. Such research methods of market conditions analysis for vitamin products as generalization, systematization, comparative analysis were used. The analysis of the dynamics of the range of vitamin medicines in Ukraine during 1999-2019 was conducted. It was determined that the maximum amount of vitamin products was presented in the pharmaceutical market of Ukraine in 2007 (267 items by trade names), the minimum – in 2016 (119 preparations). At the beginning of 2019 the number of vitamin medicines is 170. 21 Ukrainian producers offered 84 vitamin drugs, which is almost half of the registered positions (49,4%). Another 86 drugs (51,6% of the analyzed population) are represented by 30 manufacturers from 18 countries of the world. Among the foreign producers, the largest number of positions is offered by manufacturers from the USA (22), Germany (15), Israel (9), and Slovenia (8). On the Compendium.online information resource in the section «Dietary Supplements», there were 325 presented items of vitamin supplements from 126 manufacturers, which is almost twice the number of registered vitamin medicines (170). All 16 vitamin drug manufacturers also have diet supplements in their portfolio. For 5 producers, the amount of supplements exceeds the supply of drugs in the investigated segment: Queisser Pharma, Bayer, Beringer Ingelheim, Dr. Theiss Naturwaren (all – Germany), Polfarma (Poland) and Valeant (Canada).

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Introduction. A fixed dose combination of telmisartan and amlodipine is widely used in clinical practice during hypertension treatment. Combination of telmisartan and amlodipine demonstrates potentiating synergistic effect on blood pressure decrease. A bioequivalence study of Telzap® AM with coadministered Mikardis® and Norvask® was conducted with 60 volunteers.Aim. The purpose of the bioequivalence trial was a comparative study of the pharmaco*kinetics and evidence of the bioequivalence of the fixed dose combination drug product Telzap® AM (telmisartan + amlodipine, tablets, 80 + 10 mg, Zentiva ks company, Czech Republic) and coadministrated monocomponent drug products Mikardis® (telmisartan, tablets 80 mg, Beringer Ingelheim International GmbH, Germany) and Norvask® [amlodipine, tablets 10 mg, Pfizer HCP Corporation (USA), Russia] in healthy volunteers after a single administration under fasting.Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover four-period replicate clinical trial was conducted. The concentrations of amlodipine and telmisartan in plasma samples were determined by a validated HPLC-MS/MS method. A pharmaco*kinetic and statistical analysis was performed and confidence intervals for the pharmaco*kinetic parameters Cmax and AUC0-72 were calculated.Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmaco*kinetic parameters of amlodipine and telmisartan. All 90 % confidence intervals for the estimated pharmaco*kinetic parameters of amlodipine were in the range of 80–125 %, 90 % confidence intervals for telmisartan were within the bioequivalence range of 80–125 % for AUC0-72, and 76.73–130.32 % for Cmax.Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent.

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One of the crucial risk factors for development of severe postthrombotic disease (PTD) is the recurrence of deep vein thrombosis (DVT). New opportunities for pharmacological thromboprophylaxis of secondary thrombophilia were associated with the direct thrombin inhibitor—Dabigatran (Pradaxa; Boehringer Ingelheim, Germany). We aimed to investigate the daily pharmacodynamics of dabigatran in healthy volunteers and patients with PTD. Treatment with dabigatran in patients with PTD having chronic chronometric hypercoagulation and structural hypocoagulation before the administration of the drug is fraught with excessive anticoagulation and a high risk of clinically significant bleeding. In patients with PTD with detected chronometric and structural hypercoagulability before taking a direct thrombin inhibitor, treatment with dabigatran is fraught with possible inadequate anticoagulation and a high risk of clinically significant relapses of thromboses. According to our data, markers of risk of hemorrhagic complications under Dabigatran are the thromboelastography indicators lying within the reference values of the healthy before the administration of the drug: fibrin–platelet clot formation, maximum amplitude of TEG; total lytic activity of blood, and thrombodynamic potential index . Monitoring the effects of the targeted anticoagulant demonstrated the need for correction of dosage and discrete use of the drug in prevention and treatment for thrombohemorrhagic complications in this category of patients. The results of the study prove the efficiency of the therapy with dabigatran and “behavior” of hemostatic potential in patients being taken into account and controlled. Therapy may be long term but requires dynamic monitoring of patients with timely dose adjustment to achieve and maintain the target level of hemostatic potential.

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Background:Although seronegative RA patients often present with substantial disease burden [1], patients are underrepresented in research cohorts or clinical trials. Consequently, less knowledge about this subgroup has been accumulated.Objectives:To describe outcome of seronegative vs. seropositive RA patients treated with sarilumab in regular care in Germany.Methods:The prospective, observational, 24-month single-arm PROSARA study (SARILL08661) is currently running in Germany at 96 sites, aiming to enroll up to 750 RA patients treated with sarilumab. RA patients are prospectively selected at physician’s discretion according to label, and medical history is documented before treatment. This interim analysis included patients with data available up to 24 months. Here we focus on sustained treatment response after 6 and 12 months, respectively. Patients were stratified according to serostatus (RF- AND ACPA- as seronegative or RF+ AND/OR ACPA+ as seropositive). All analyses are descriptive only.Results:To date 473 patients were included in the study, of which 22.2% (n=105) were seronegative and 59.0% (n=279) were seropositive (Table 1). For 89 patients (18.8%) serostatus was not specified.Table 1.Baseline data regarding patient characteristics, prior treatment and disease activityseronegativeseropositivepatients [n] (%)105(22.2)279(59.0)patient characteristicsSex female [n] (%)81(77.1)207(74.2)Age mean [years] (SD)56.6(12.5)59.6(10.9)BMI mean (SD) [kg/m2]29.2(6.7)28(6.0)Smoking history current/former [%]22.1/11.525.5/20.4Time since diagnosis of RA mean [years] (SD)7.9(7.6)11.5(9.9)prior RA treatmentcsDMARD [n] (%)102(97.1)273(97.8)bDMARD (TNFi) [n] (%)54(51.4)167(59.9)bDMARD (non-TNFi) [n] (%)32(30.5)83(29.7)tsDMARD (JAKi) [n] (%)25(23.8)57(20.4)disease activityCRP [mg/l] (SD)12.9(30.9)14.2(31.0)ESR [mm/h] (SD)23.7(20.5)25.3(22.4)SJC mean (SD)5.3(5.5)4.6(4.8)TJC mean (SD)10.2(8.2)7.2(6.6)HAQ-DI mean (SD)1.4(0.7)1.2(0.7)DAS28-ESR mean (SD)5.0(1.5)4.6(1.5)CDAI mean (SD)27.7(14.7)23.0(12.9)Fatigue [VAS] (SD)64.0(25.5)51.1(28.1)The mean time since diagnosis of RA was shorter in seronegative than in seropositive patients (7.9±7.6 years vs. 11.5±9.9 years) (Table 1).At baseline, CDAI score was 27.7±14.7 (n=104) and 23.0±12.9 (n=272) in seronegative and seropositive patients, respectively. After 12 months of sarilumab treatment, CDAI improved to 15.6±12.3 (n=38) and 9.1±8.7 (n=101) in seronegative and seropositive, respectively, for patients with post-baseline data available. At that time, remission/low disease activity according to CDAI was reached by 5.3% (n=2/38) / 39.5% (n=15/38) of seronegative patients, respectively and by 26.7% (n=27/101) / 68.3% (n=69/101) of seropositive patients, respectively (Fig. 1A, B).Figure 1.CDAI (A, B) and HAQ-DI (C) outcomes in seronegative and seropositive patientsPhysical function, assessed by HAQ-DI, was slightly more impaired in seronegative patients (1.4±0.7) than in seropositive patients (1.2±0.7) at baseline. HAQ-DI improved over 12 months to 0.9±0.7 in seropositive patients (n=90) but showed no change in seronegative patients (1.4±0.7; n=37) (Fig. 1C).Safety was consistent with the anticipated profile of IL-6-R-inhibition and no new safety signals occurred. Adverse events and serious adverse events were described in 61.7% and 12.8% of seronegative patients, respectively and in 55.2% and 13.7% of seropositive patients, respectively.Conclusion:Sarilumab treatment ameliorated CDAI in both seronegative (ΔCDAI -17.0±16.5) and seropositive (ΔCDAI -15.4±14.3) patients to the same extent over the course of 12 months, with a higher remission rate in seropositive patients. Functional capacity improved meaningfully in the seropositive cohort but had no significant impact in seronegative patients. The safety profile was consistent with data reported from controlled clinical trials.References:[1]Choi S-T et al. (2018) PLoS ONE 13(4): e0195550.Acknowledgements:We thank Cornelia Kühne (Haldensleben) for substantial contribution to patient recruitment in PROSARA.Disclosure of Interests:Harald Burkhardt Speakers bureau: Sanofi, Pfizer, Roche, Abb- vie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scribb, Janssen, and Novartis, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Grant/research support from: Pfizer, Roche, Abbvie, Hans-Peter Tony Consultant of: AbbVie, Astra-Zeneca, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, Peer-Malte Aries Speakers bureau: Abbvie, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Consultant of: Abbvie, Celgene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Silke Zinke: None declared, Klaus Krueger Speakers bureau: Sanofi, Jonas Ahlers Employee of: Sanofi, Rolf Hecker Employee of: Sanofi, Inka Albrecht Employee of: Sanofi, Stefanie Kalus Consultant of: Sanofi, Oliver Bley Employee of: Sanofi, Patrizia Sternad: None declared, Ann-Dörthe Holst: None declared, Niklas Thomas Baerlecken: None declared, Thilo Klopsch: None declared, Martin Welcker Speakers bureau: Abbvie, Aescu, Amgen, Biogen, Berlin Chemie, Celgene, GSK, Hexal, Mylan, Novartis, Pfizer, UCB, Consultant of: Abbvie, Actelion, Aescu, Amgen, Cel- gene, Hexal, Janssen, Medac, Novartis, Pfizer, Sanofi, UCB, Grant/research support from: Abbvie, Novartis, UCB, Hexal, BMS, Lilly, Roche, Celgene, Sanofi, Eugen Feist Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi

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Background:Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis (SSc). To date, the progression of SSc-ILD is judged by the accrual of lung damage on computed tomography (CT) and functional decline (forced vital capacity). However, this approach does not directly assess the activity of tissue remodeling. Moreover, prediction of the course of ILD in individual SSc patients remains challenging. Fibroblast Activation Protein (FAP) is a specific, ex vivo validated marker for activated fibroblasts.Objectives:The aims of this study were: 1. To assess differences in the uptake of 68GA-FAPI 04 in SSc-ILD patients compared to controls, to analyze 2. whether 68GA-FAPI 04 uptake at baseline correlates with other risk factors of disease progression and 3. Whether 68GA-FAPI 04 uptake is associated with the course of SSc-ILD.Methods:Between September 2018 and April 2020, 21 patients with SSc-ILD confirmed by HRCT and onset of SSc-ILD within ≤ 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent 68Ga-FAPI-04 PET/CT imaging and standard-of-care procedures including HRCT and lung function testing (PFT) at baseline. Patients with SSc-ILD patients were followed-up for 6 months with HRCT and PFT. Follow-up 68Ga-FAPI-04 PET/CT scans were obtained in a subset of patients treated with nintedanib. We compared baseline 68Ga-FAPI-04 PET/CT uptake to standard diagnostic tools and currently used predictors of ILD progression. The association of 68Ga-FAPI-04 uptake with changes in FVC was analyzed using mixed-effects models.Results:68Ga-FAPI-04 accumulated in fibrotic areas of the lungs in SSc-ILD compared to controls with a median (q1-q3 interval) wlSUVmean of 0.8 (0.6 to 2.1) in the SSc-ILD group and 0.5 (0.4 to 0.5) in the control group (p<0.0001 with Mann-Whitney test) and a median whole lung maximal standardized uptake value (wlSUVmax) of 4.4 (3.05 to 5.2) in the SSc-ILD group compared to 0.7 (0.65 to 0.7) in the control group (p<0.0001). wlFAPI-MAV and wlTL-FAPI were not measurable in control subjects, as no 68Ga-FAPI-04 uptake above background level was observed. In the SSc-ILD group the median wlFAPI-MAV was 254cm3 (163.4 to 442.3) and the median wlTL-FAPI was 183.6 cm3 (98.04 to 960.7). 68Ga-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression or high EUSTAR activity scores. Increased 68Ga-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive 68Ga-FAPI-04-PET/CTs, changes in 68Ga-FAPI-04 uptake was concordant with the observed response to the fibroblast-targeting antifibrotic agent nintedanib.Conclusion:Our study presents first in human evidence that 68Ga-FAPI-04-fibroblast uptake correlates with fibrotic activity and disease progression in the lungs of SSc-ILD patients and that 68Ga-FAPI-04-PET/CT may be of potential to improve risk assessment of SSc-ILD.Figure 1.A and B:68Ga-FAPI-04 PET/CT scan from a patient with SSc-ILD with selective 68Ga-FAPI-04 uptake in fibrotic areas of the left- and right lower lung lobes (red arrows), but not in non-fibrotic areas such as the middle lobe (green arrow). B Corresponding CT component.Acknowledgements:We gratefully acknowledge Prof. Uwe Haberkorn (University Hospital Heidelberg and DKFZ, Heidelberg, Germany) and iTheranostics Inc. (Dulles, VA, USA) for providing the precursor FAPI-04.Disclosure of Interests:Christina Bergmann: None declared, Jörg H.W. Distler Speakers bureau: Actelion, Anamar, ARXX, Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Christoph Treutlein: None declared, Koray Tascilar Speakers bureau: Gilead sciences GmbH, Pfizer Turkey, UCB Turkey, Anna-Theresa Mueller: None declared, Armin Atzinger: None declared, Alexandru-Emil Matei: None declared, Johannes Knitza: None declared, Andrea-Hermina Györfi: None declared, Anja Lueck: None declared, Clara Dees: None declared, Alina Soare: None declared, Andreas Ramming: None declared, Verena Schönau: None declared, Oliver Distler Speakers bureau: Arxx Therapeutics, Baecon Discovery, Blade Therapeutics,Bayer, Böhringer Ingelheim, Catenion,Competitive Drug Development International Ltd, Corbuspharma, CSL Behring, ChemomAb, Horizon Pharmaceuticals, Ergonex, Galaapagos NV, Glenmark Pharmaceuticals,GSK, Inventiva, Italfarmaco, IQvia, Kymera, Lilly, Medac, Medscape, MSD, Novartis, Pfizer, Roche, Sanofi, Taget Bio Sciencec, UCB, Grant/research support from: Bayer,Böhringer Ingelheim, Mitsubishi Tanabe Pharma, Olaf Prante: None declared, Philipp Ritt: None declared, Theresa Ida Goetz: None declared, Markus Koehner: None declared, Michael Cordes: None declared, Tobias Baeuerle: None declared, Torsten Kuwert Speakers bureau: Honoraria for occasional lectures by Siemens Healthineers, Grant/research support from: Research grant to the Clinic of Nuclear Medicine by this entity covering projects in the field of SPECT/CT, Georg Schett: None declared, Christian Schmidkonz: None declared

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SummaryDabigatran is a reversible and selective, direct thrombin inhibitor (DTI) undergoing advanced clinical development as its orally active prodrug, dabigatran etexilate.This study set out to determine the molecular potency and anticoagulant efficacy of dabigatran and its prodrug dabigatran etexilate.This was achieved through enzyme inhibition and selectivity analyses, surface plasmon resonance studies, platelet aggregation, thrombin generation and clotting assays in vitro and ex vivo.These studies demonstrated that dabigatran selectively and reversibly inhibited human thrombin (Ki: 4.5 nM) as well as thrombin-induced platelet aggregation (IC50: 10 nM), while showing no inhibitory effect on other platelet-stimulating agents.Thrombin generation in platelet-poor plasma (PPP), measured as the endogenous thrombin potential (ETP) was inhibited concentration-dependently (IC50: 0.56 μM). Dabigatran demonstrated concentration-dependent anticoagulant effects in various species in vitro, doubling the activated partial thromboplastin time (aPTT), prothrombin time (PT) and ecarin clotting time (ECT) in human PPP at concentrations of 0.23, 0.83 and 0.18 μM, respectively. In vivo, dabigatran prolonged the aPTT dose-dependently after intravenous administration in rats (0.3, 1 and 3 mg/kg) and rhesus monkeys (0.15, 0.3 and 0.6 mg/kg). Dose- and time-dependent anticoagulant effects were observed with dabigatran etexilate administered orally to conscious rats (10, 20 and 50 mg/kg) or rhesus monkeys (1, 2.5 or 5 mg/kg), with maximum effects observed between 30 and 120 min after administration, respectively. These data suggest that dabigatran is a potent, selective thrombin inhibitor and an orally active anticoagulant as the prodrug, dabigatran etexilate.Footnote: Parts of this study were presented at the XVIII Congress of the International Society on Thrombosis and Haemostasis, Paris, July 2001. Thromb Haemost 2001; 86 (Suppl): Abstracts P755, P763.Institution where work was carried out: Boehringer Ingelheim Pharma GmbH &Co KG, 88397 Biberach, Germany.

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Abstract Abstract 2057 Purpose of the study: Chemotherapy (CT) induced neutropenia (CIN) is a common complication in the treatment of cancer and often leads to modifications of antineoplastic treatment. Granulocyte-colony stimulating factors (G-CSF) are frequently used to prevent or treat CIN in cancer patients. The non-interventional observational study HEXAFIL on the use of biosimilar filgrastim (EP-2006) was conducted to provide further insight into its therapeutic efficacy and routine clinical use in Germany, especially in compliance with guidelines on the use of G-CSF (EORTC, ASCO). Methods: 1460 patients who signed informed consents are to be enrolled at 100 German sites. Data is documented for up to 3 consecutive filgrastim-supported CT-cycles. Rates of modified CT-treatments (dose modification/discontinuation of drug) are calculated by the number and percentage of patients affected; data presented are based on the first CT-cycle. Inclusion/Exclusion criteria: www.germanctr.de. Results: By 7/2012, data of 955 patients were available. Patients' mean age was 59 years (19 to 89), 75% of them being female. Most common tumour entities were breast cancer (57.2%), NHL (10.7%), lung cancer (7.6%), ovarian cancer (4.0%) and Hodgkin lymphoma (3.1%). Substances most commonly used for chemotherapy were cyclophosphamide (50.7%), epirubicin (33.2%), docetaxel (23.6%), 5-fluorouracil (20.9%) and doxorubicin (15.6%). In line with published data only 1.9% of all patients experienced febrile neutropenia (FN), 8.7% neutropenic complications and 14% had leukopenia CTC 4 at nadir. As expected and according to guidelines the majority of patients received primary (39.3%, PP) or secondary prophylaxis (32.9%, SP) with biosimilar filgrastim, however, 25.8% were treated on demand (TX, i.e. after having experienced neutropenic complications in the first documented CT cycle or a drop in leukocytes putting the patient at acute risk of neutropenic complications). Interestingly, if viewed by the presence of baseline leukopenia, 76.9% of all patients without leukopenia (CTC 0) received G-CSF prophylaxis (PP/SP) but only 46.1% of all patients with leukopenia CTC 3/4. In patients without baseline leukopenia receiving filgrastim for PP, leukopenia CTC 3/4 at nadir was present in 32.9%, whereas in SP it was 50.6% and in TX 70.8%. Median filgrastim treatment duration was 4 d (1 to 14). Patients with PP received median 5 days of treatment starting on median day 6 after CT, whereas SP and TX patients were treated on median day 8 and 9, respectively, for a median duration of 3 days each. Accordingly, patients with neutropenic complications received treatment starting on median day 8 for 3 days (median), whereas patients without neutropenic complications started on median day 7 for 5 days (median); moreover, patients with FN only started biosimilar filgrastim therapy on median day 9. 93.9% of all documented patients received CT without any modification; in 4.6% of patients the dose of chemotherapy was modified and in 1.4% a chemotherapy drug was discontinued. Data indicate that patients with earlier and longer filgrastim treatment showed less chemotherapy disturbances, FN and neutropenic complications. Conclusions: Approximately 94% of all documented patients received filgrastim-supported CT-cycles without any modification of the CT-regimen. Yet, there is still room for improvement in prevention of CIN/FN in cancer patients as reflected by median start/treatment days and number of neutropenic complications. Moreover, daily injections should not impact the prophylactic use of G-CSF as revealed by self-assessment questionnaires in which patients reported handling of the needle guard system and of the pre-filled syringes to be easy or very easy (97.7% and 97.8%, respectively and calculated on questionnaires evaluable). Disclosures: Tesch: Amgen, Astra Zeneca, Boehring Ingelheim, Celgene, GSK, Hexal, Janssen Cilag, Lilly, Merck, Novartis, Pfizer, Roche: Honoraria; Amgen, Astra Zeneca, Boehring Ingelheim, Celgene, GSK, Hexal, Janssen Cilag, Lilly, Merck, Novartis, Pfizer, Roche; Sanofi Aventis: Consultancy. Abenhardt:Hexal: Honoraria. Dietze:Hexal: Honoraria. Chang:Hexal: Employment. Ottillinger:Hexal, Sandoz: Consultancy, Honoraria.

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Specific prevention is one of the most effective methods for the control of infectious diseases causing considerable economic damage to commercial pig farms, among which is porcine pleuropneumonia. In order to improve the effectiveness of preventive vaccination, various immunomodulators that differ in their origin and mechanism of action are used. The paper presents the results of the study of the effect of such products as biferon-S and prostimul containing species-specific recombinant interferons on the immune status of piglets during specific prevention of porcine pleuropneumonia. Tests were carried out in clinically healthy 30–35-day-old piglets immunized with Ingelvac® APPX vaccine (Boehringer Ingelheim Vetmedica GmbH, Germany). It was found that the use of biferon-S and prostimul together with the vaccine administration is accompanied by immune status improvement in the animals, which is manifested as an increase, in comparison with vaccinated animals that received no interferon-containing products (base case), in serum levels of γ-globulins – by 34.6 and 53.7% (in case of prostimul and β-globulins – by 10.1%), total immunoglobulins – by 32.8 and 37.8%, large circulating immune complexes – by 37.5 and 52.6%, a less significant increase in the levels of small complexes and, as a result, pathogenicity coefficient reduction by 5.4 and 12.4%, respectively. Tests for post-vaccination immunity levels in piglets showed a 3.8-fold increase in the levels of specific antibodies against the antigen of porcine pleuropneumonia agent, and in case of the vaccine administration in combination with biferon-S and prostimul – a 4.0-fold and 4.9-fold increase, respectively. The use of prostimul was accompanied by a more considerable improvement of immune status in the piglets, and this is attributable to the fact that vitamins А, Е and С, which have antioxidant properties and improve the effectiveness of interferons, natural resistance and specific immunity, are included in its composition in addition to recombinant type 1 cytokine.

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Abstract Background and Objectives In the EINSTEIN PE study rivaroxaban (RX) was found to be as effective as warfarin in the treatment of acute pulmonary embolism (PE) with superior safety. However, study results need to be confirmed in unselected PE patients in daily care. Patients and Methods Using prospectively collected data from a large regional registry of patients treated with novel direct oral anticoagulants (NOAC) in the district of Saxony, Germany, we evaluated the rate of recurrent VTE, other cardiovascular complications and bleeding events in patients receiving rivaroxaban for acute PE. In this ongoing registry, a network of 239 physicians enrols up to 2500 daily care NOAC patients who receive central prospective follow up (FU) by the registry office at day 30 day and quarterly thereafter to collect efficacy and safety data. All outcome events are centrally adjudicated using standard scientific definitions. Results Until July 31th 2013, 2249 patients were enrolled. Of these, 72 patients received RX for acute PE treatment (demographic data in table 1). Registry patients were older than the EINSTEIN PE population (67.3 vs. 55.8 years), 55.6% were female and 23.6% were treated for a recurrent VTE. During follow-up, unplanned rivaroxaban discontinuation rates were low (around 5%; table 1). So far, only one recurrent VTE event occurred (1.7 events per 100 patient years). One patient experienced non-fatal ischaemic stroke within 4 weeks after PE diagnosis (1.7 events per 100 patient years). Bleeding complications were frequent but only 2 major bleeding (non-fatal vagin*l bleeds) occurred (3.3 events per 100 patient years). During follow-up three patients died of underlying diseases but none of these deaths were related to VTE or bleeding complications. Conclusion Acute PE treatment with rivaroxaban in daily care is effective, safe and well tolerated with low rates of unplanned treatment discontinuation. Thromboembolic and major bleeding complications are rare and seem to occur predominantly in the early phase of PE treatment. At ASH, updated results from our registry will be presented Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Pfizer: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Bayer Healthcare: Research Funding, Speakers Bureau.

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Background:Psoriasis (Pso) is one of the most common chronic inflammatory skin diseases in Europe. Psoriatic arthritis (PsA) is closely associated to Pso whereas the skin manifestation appears usually years before PsA-related symptoms emerge. Up to 30% of Pso patients develop PsA, but there is no clear correlation between disease duration of Pso and PsA development. In early PsA, changes in synovial vascularisation combined with increased expression of proangiogenic factors appear first. Therefore, imaging biomarkers for detection of changes in vascularisation might be useful for early detection of musculoskeletal disease. Fluorescence-optical imaging (FOI) is an indocyanine green (ICG) tailored method to detect microvascular changes in the hands using ICG kinetics over 360 sec. Different methods for assessment of FOI are available. It has not yet been demonstrated to what extent these methods can be used to differentiate psoriasis from psoriasis arthritis.Objectives:To evaluate different reader dependent assessment methods to evaluate FOI in psoriasis and psoriatic arthritis.Methods:FOI data (clinical PsA n=137, PsO without PsA n=202) from an observational prospective multicentre trial in Germany was used for manual assessment of the films using two different published assessment methods:(1) FOI activity score (FOIAS) and (2) individual characteristics of ICG kinetics. For (1) FOIAS, the levels of signal enhancement were scored using a scoring system from 0 to 3 (0=no enhancement, 3=strong enhancement) per joint as well as an assessment of the summation picture. (2) Kinetics were determined by joint-related signal enhancements as well as by ICG related flow-on and flow-off behaviour. Time to the first appearance of the signal, the time to the maximum enhancement and the time to the end of the signal were determined.Results:By use of (1) FOIAS, the maximum score (overall signals of all joints assessed by FOIAS) showed a significant difference (p=0.0075) between PsA (mean 4.76) and PsO (mean 3.84). (2) Time to global maximum showed no significant difference (PsA mean 91.1 sec vs PsO 92.6 sec). Moreover, the mean time to maximum and clearance of ICG did not differ between the two diseases. The duration of the 3 phases of kinetic (phase 1: flow-in, phase 2: stable, phase 3: clearance) was 52.4 sec, 180.2 sec and 119.8 sec for PsA and 57.6 sec, 186.0 sec and 130.5 sec for PsO with an earlier phase 2 and 3 for PsA by trend. The most frequently affected joints in PsA (affected > 10%): PIP 3 right and PIP 5 right.Conclusion:FOI is a sensitive method to detect changes in microvascularisation in the hands. The use of the manual FOIAS is able to differentiate significantly between PsA and PsO patients by comparison of the sum of scores over all joints (maximum score). The assessment of ICG kinetics is limited to discriminate between musculoskeletal and joint disease, differentiation of diseases is only seen by trend. Both methods characterize disease states differently. A combination of both methods might be useful to increase the potential of manual assessment of FOI signals.Figure 1.Maximum sum score of FOIAS in PsO and PsA patients (p=0.0075 in two-sided t-test).Disclosure of Interests:Luis Haan: None declared, Ulf Henkemeier: None declared, Ann Christina Foldenauer: None declared, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, Michaela Köhm Grant/research support from: Pfizer, Janssen, BMS, LEO, Consultant of: BMS, Pfizer, Speakers bureau: Pfizer, BMS, Janssen, Novartis

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Background:Psoriasis (Pso) is one of the most common chronic inflammatory skin diseases in Europe. Psoriatic arthritis (PsA) is closely associated to Pso whereas the skin manifestation appears usually years before PsA-related symptoms emerge. Up to 30% of Pso patients develop PsA, but there is no clear correlation between disease duration of Pso and PsA development. Therefore, biomarkers for its early detection are of major importance. In early PsA, changes in synovial vascularisation combined with increased expression of proangiogenic factors appear first. Therefore, imaging biomarkers for detection of changes in vascularisation might be useful for early detection of musculoskeletal disease. Fluorescence-optical imaging (FOI) is a new method to detect changes in microvascularisation of the hands.Objectives:To determine the number of positive PsA diagnosis within a 24 month follow-up period in PsO only patients with subclinical MSK-inflammation detected in FOI.Methods:Sensitivity of FOI for detection of subclinical signs of musculoskeletal inflammation as biomarker for early PsA was observed in a prospective, multicentre study (XCITING) including patients with dermatological confirmed skin psoriasis. 411 patients were included from dermatology care units across Germany without diagnosis of PsA but potential risk factors for its development (nail psoriasis and/or joint pain or swelling within the last 6 months). Clinical examination (CE; swollen (66) and tender (68) joint count, enthesitis, dactylitis assessment) and standardised ultrasound (US) assessment was performed by a qualified rheumatologist to assess musculoskeletal inflammation. FOI was performed additionally. Data was analysed in focus on increased vascularisation of musculoskeletal structures as inflammatory markers. In case of discrepant results (positive FOI and negative CE and US), MRI was performed to prove the findings. In case of MRI negativity, a follow-up period of 24-months was performed including FOI, CE, US and MRI assessment.Results:83 of the 411 patients of the cohort were negative in all assessments (Pso only), 136 of the 411 patients were classified as PsA by rheumatologic assessments. 119 patients showed subclinical signs of musculoskeletal inflammation in the central reading of FOI, whereas CE and US were negative. In 37,5% of those patients, subclinical inflammation was confirmed by MRI assessment. 22 patients of the cohort without MRI positivity were willing to be followed up until month 24. 5 (7.5%) patients developed a clinical PsA until month 24 whereas 7 (10.5%) patients converted to be FOI negative. In 5 patients an additional MRI examination was performed in which one patient showed positive signs for inflammation.Conclusion:FOI is an innovative method for measurement of changes in microvascularisation in the hands. 6/22 patients initial only positive in FOI (no clinical signs for PsA, negative US, negative MRI) developed either clinical evident PsA (n=5) or new inflammation in MRI (n=1) during follow-up of 24 months. Therefore, FOI positive signals in PsO patients increase the probability for PsA development.Figure 1.Flow Chart of the Follow-up period of the XCITING study.Disclosure of Interests:Michaela Köhm Grant/research support from: Pfizer, Janssen, BMS, LEO, Consultant of: BMS, Pfizer, Speakers bureau: Pfizer, BMS, Janssen, Novartis, Sarah Ohrndorf: None declared, Tanja Rossmanith Grant/research support from: Janssen, BMS, LEO, Pfizer, Marina Backhaus Grant/research support from: Pfizer, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Siegfried Wassenberg: None declared, Benjamin Köhler Grant/research support from: Pfizer, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai

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Background:Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory condition characterized by severe systemic and organ inflammation. In a phase 3 pivotal trial (CLUSTER study), TRAPS patients have been successfully treated with the interleukin-1β inhibitor canakinumab. 45% of patients reached clinical remission after 16 weeks (primary endpoint)1. Canakinumab has been approved and applied for the treatment of TRAPS patients since 20172.Objectives:The present study explores the long-term efficacy and safety of canakinumab under routine clinical practice conditions in pediatric (age ≥2 years) and adult TRAPS patients.Methods:RELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a 3-year follow-up period. Patients with clinically confirmed diagnoses of TRAPS, CAPS, FMF or HIDS/MKD who routinely receive canakinumab are enrolled in order to evaluate efficacy and safety of canakinumab under standard clinical practice conditions. Disease activity and remission by physician assessment, disease activity and fatigue by patient assessment, days absent from school/work due to study indication, inflammatory markers, and AIDAI (Auto-Inflammatory Diseases Activity Index) score were assessed at baseline and at 6-monthly intervals.Results:The interim analysis of TRAPS patients enrolled by December 2020 includes baseline (N=16, including 1 patient with atypical TRAPS) and preliminary 18-month data. Mean age in this cohort was 23 years (3−43 years) and the median duration of prior CAN treatment was 1.0 year (0−4 years).Physician assessment indicated 60-80% remission and laboratory parameters were within normal range. Disease control by patient assessment showed no major changes regarding the analyzed parameters (Table 1, Figure 1). Of the three serious adverse events reported none was classified as drug-related.Conclusion:Preliminary analysis of 18 month interim data of TRAPS patients treated with CAN available from the RELIANCE study indicate stable efficacy and safety of CAN long-term treatment.References:[1]De Benedetti F, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908–19.[2]Ilaris, INN-canakinumab (europa.eu)Table 1.Baseline characteristics and interim analysis data of patients with TRAPSBaseline6 months12 months18 monthsNumber of patients, N1613106Median age, years (min; max)23 (3; 43)17 (3; 43)16 (4; 38)25 (4; 43)Females (%)11 (69)9 (69)7 (70)3 (50)Median duration of prior CAN therapy at baseline, years (min; max)1.0 (0; 4)1.0 (0; 4)1.0 (0; 4)1.5 (0; 2)Number (%) of patients in disease remission (physician assessment)9 (60.0)9 (81.8)7 (77.8)4 (80.0)Physician Global Assessment, percentage of absent/mild-moderate/severe rating40 / 53 / 082 / 9 / 044 / 44 / 1180 / 20 / 0Patient assessment of current disease activity; 0–10, median (min; max)1.5 (0; 5)1.0 (0; 4)1.0 (0; 6)0.0 (0; 3)Patient assessment of current fatigue; 0–10, median (min; max)2.0 (0; 8)1.0 (0; 7)2,5 (0; 8)4.0 (0; 7)Number (%) of patients without impairment of social life by the disease4 (50)5 (63)2 (33)3 (60)Number (%) of patients with days absent from work/school during last 6 months8 (50)5 (39)5 (56)3 (50)CRP, median (mg/dl)0.10.10.10.0SAA, median (mg/dl)0.50.40.40.3ESR, median (mm/h)7.05.05.05.0SAENumber of eventsIncidence rate per 100 patient yearsTotal314.7Circulatory collapse (non fatal)14.9Dizziness14.9Headache14.9CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; SAA, serum amyloid A; SAE, serious adverse eventDisclosure of Interests:Norbert Blank Consultant of: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, Grant/research support from: Novartis, Sobi, Jörg Henes Consultant of: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, Grant/research support from: Novartis, Roche, Tilmann Kallinich Consultant of: Sobi, Novartis, Roche, Grant/research support from: Novartis, Prasad Oommen Grant/research support from: Novartis, Catharina Schuetz: None declared, Michael Borte Grant/research support from: Pfizer, Shire, Julia Weber-Arden Employee of: Novartis, J. B. Kuemmerle-Deschner Consultant of: Novartis, AbbVie, Sobi, Grant/research support from: Novartis, AbbVie, Sobi

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Background:There is few data available regarding differences in body composition and its possible changes in patients with ankylosing spondylitis (AS) treated with biological disease-modifying anti-rheumatic drugs (bDMARDs). An increase of body weight and lean mass in patients receiving TNF inhibitors, as well as a possible muscle wasting by high disease activity have been previously described. Bioelectrical impedance analysis (BIA) is a valid method to assess body composition and allows to distinguish between fat, fat-free mass and skeletal muscle mass.Objectives:To evaluate changes in body composition in patients with AS after 6 months of treatment with bDMARDs.Methods:Patients with a diagnosis of AS, fulfilling the modified New York criteria and starting a bDMARD therapy were included in the extension of the prospective German Spondyloarthritis Inception Cohort (GESPIC). All patients had high disease activity (BASDAI >=4 and/or ASDAS >=2.1) despite previous treatment with nonsteroidal anti-inflammatory drugs. Disease activity and body composition were assessed at baseline and after 6 months of bDMARD treatment. Body composition was assessed by the BIA with the seca© mBCA 515 device (SECA Deutschland GmbH, Hamburg/Germany) and included the following parameters: weight, body mass index (BMI), fat mass index (FMI), fat free mass index (FFMI), skeletal muscle mass value (SMM), and visceral adipose tissue value (VAT). Response to a bDMARD therapy was defined as achievement of clinically important improvement of ASDAS (>=1.1).Results:A total of 129 patients (66.7% male) with AS were recruited in this cohort extension between 2015 and 2019. The mean (mean ± SD) age was 36.2 ± 10.3 years, and symptom duration was 10.7 ± 9.1 years. HLA-B27 test was positive in 89.1% patients. BIA was assessed in 77 patients; the baseline characteristics of these patients were similar to those of the whole cohort. Of these, 75 patients were treated with TNF inhibitors and 2 patients were treated with an IL-17A inhibitor.After 6 months of a bDMARD treatment, body composition changed significantly with an increase of weight and BMI due to the gain of FMI but also of FFMI and SMM, while there was no increase of the visceral fat – table. In responders (improvement of ASDAS>=1.1 after 6 months) the results were similar to the whole group with a significantly gain (mean±SD) on BMI, FMI, FFMI and SMM (0.3 ± 1.4 kg/m2, 0.3 ± 1.0 kg/m2, 0.2 ±0.5 kg/m2, 0.5 ± 1.2 kg, p<0.05, respectively). In non-responders, there were no significant changes on the body composition after 6 months of treatment.Conclusion:Treatment with bDMARDs is associated with favorable changes of the body composition with increase of the muscle mass but not of the visceral fat. These changes were evident in treatment responders only.TABLE 1.Body composition parameter at baseline and after 6 months of treatment with a bDMARDs in patients with AS (n=77)Mean±SDDifference, mean±SD95% CIP*LowerUpperWeight at baseline, kg77.19±15.710.75±3.800.041.470.04Weight at 6 months, kg77.94±16.25BMI at baseline, kg/m225.03±4.320.30±1.290.060.550.02BMI at 6 months, kg/m225.33±4.43FMI at baseline, kg/m26.74±3.390.31±0.970.070.540.01FMI at 6 months, kg/m27.05±3.42FFMI at baseline, kg/m218.27±2.180.15±0.480.040.270.01FFMI at 6 months, kg/m218.42±2.27SMM at baseline, kg27.40±5.850.32±1.110.050.590.02SMM at 6 months, kg27.73±5.90VAT at baseline, liters1.94±1.62-0.12±0.63-0.270.040.14VAT at 6 months, liters1.82±1.56BMI: Body Mass Index; FMI: Fat Mass Index; FFMI: Free Fat Mass Index; SMM: Skeletal Muscle mass; VAT: Visceral Adipose Tissue.*Wilcoxon testAcknowledgments:GESPIC has been financially suported by ArthroMark and METARTHROS projectsDisclosure of Interests:Valeria Rios Rodriguez Consultant of: Abbvie, Novartis, Mikhail Protopopov Consultant of: Novartis, Fabian Proft Grant/research support from: Novartis Pharma GmbH, Consultant of: Consultancy / speaker fees from: Abbvie, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: Consultancy / speaker fees from: Abbvie, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, UCB, Judith Rademacher: None declared, Burkhard Muche: None declared, Anne Katrin Weber: None declared, Susanne Lüders: None declared, Hildrun Haibel Consultant of: Abbvie, Jansen, MSD, and Novartis, Speakers bureau: Abbvie, Jansen, MSD, and Novartis, Maryna Verba: None declared, Joachim Sieper Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Speakers bureau: AbbVie, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Novartis, Pfizer, Roche, and UCB Pharma, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB

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AbstractA prospective cohort study was designed to compare the effects of two different intrauterine antibiotic treatments for endometritis on fertility in a multi-farm trial during a 4 year-period. Product A contained 1.5 million I.E. of Procaine Penicilline-G and 500 mg of Neomycine sulfate in 20 ml of an oil in water suspension with a gas-driven applicator (Ubrocelan®, Boehringer-Ingelheim, Germany) and product B (positive control) contained 2g of Oxytetracycline and 500.000 I.E. Colistine in a 20 ml oil in water suspension (Colicycline® , A. U. V., Cuyk, The Netherlands). Diagnosis was by field veterinarians during routine monthly visits. Pyometra, vaginitis, toxic endometritis and post-insemination uterine treatments were excluded from the study. Only cases of non-toxic endometritis prior to first insemination in the period from 1- 150 days after calving were included. Cows were allocated to treatment group based on ear tag number (even/uneven) at the time of diagnosis by the veterinarian. Cows received only a single treatment. Cases were coded as censored at 150 days if not yet inseminated and at 180 days if not yet pregnant. A total of 623 cases of endometritis in first or later parity cows on 13 farms were used in the analysis. The distribution of treatments among farms was unequal ( chi-square = 0.167) , but no farm had more than 70% of one treatment and farm was included as a correction factorin all models. A larger number of controls than cases also had no effect on study outcome. The effect oftreament on the interval (days) from from treatment to conception or censoring was analyzed with a Cox proportional hazards model. Other variables included in the models were season, parity, herd and time of treatment (late/early) with respect to calving. There was no effect of treatment on the number of days to breeding or days open. Early/late ( cutoff = 40 days) endometritis was a significant factor for the interval from treatment to first insemination and conception rate to first breeding. Early/late metritis, however, was not a factor for the interval from treatment to pregnancy. This study suggests that there is an equal treatment efficacy for intrauterine therapy of endometritis between the two products tested. The authors discuss the growing trend away from intrauterine treatments and the suitability of survival analysis techniques for multi-farm field studies of this type.

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Trial designTwo randomised controlled vaccination trials with artificial challenges were carried out in addition to a serological survey of levels of maternally derived antibodies (MDA) to parainfluenza type 3 virus (PI3V) and bovine respiratory syncytial virus (BRSV) in European calves.ParticipantsTen-day-old calves with and without MDA were included in the two vaccine trials.InterventionsIntranasal administration of a bivalent modified live (PI3V/BRSV) vaccine followed by artificial challenge approximately three months post vaccination.ObjectiveThe study aimed to assess the efficacy of a modified live respiratory vaccine, Bovalto Respi Intranasal (Boehringer Ingelheim). In order to assess the interference of MDA, both seropositive and seronegative calves were used.RandomisationPI3V and BRSV serological status was determined seven days before vaccination; calves without maternal antibodies became the MDA− vaccinates. Calves with MDA were ranked according to individual titres and allocated alternately to MDA+ vaccinate and MDA+ control groups.BlindingTreatment was carried out by the unblinded study director. Animal care and veterinary examinations were conducted by personnel unaware of the treatments received. The serological survey used blood samples obtained from calves on commercial farms in five European countries, Germany, Spain, Italy, Ireland and the UK, to determine the levels of MDA to PI3V and BRSV in calves approximately two weeks of age.ResultsA total of 36 calves were included in the two challenge studies and 32 of these completed the challenge studies. Twenty-one calves were included in the PI3V challenge study, with six of six MDA− and six of seven MDA+ vaccinated calves and five of five MDA+ unvaccinated control calves being challenged with PI3V. Fifteen calves were included in the BRSV challenge study, with five of five MDA− and five of five MDA+ vaccinated calves and five of five MDA+ unvaccinated control calves being challenged with BRSV.OutcomeFor both challenges, clinical scores and nasal shedding were significantly higher in control animals compared with vaccinates (PI3V challenge: clinical scores P=0.001, nasal shedding P=0.001; BRSV challenge: clinical scores P=0.016, nasal shedding P=0.002) and not significantly different between MDA+ and MDA− vaccinated animals for both challenges (P>0.05). A total of 254 samples from six countries were tested in the serological survey of MDA.ConclusionThe results of the challenge studies demonstrated the efficacy of the vaccine in the presence of BRSV and PI3V MDA under laboratory conditions. The field assessment confirmed that the MDA titres in the MDA+ calves corresponded to those typically found on farms.

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Abstract Purpose/Background : Oral anticoagulation is recommended for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) and stroke risk factors, but discontinuation rates are high among those treated with vitamin K antagonists (VKA). After the first year of treatment, about half of patients permanently stop taking VKA therapy. We examined persistence to therapy with dabigatran etexilate (DE) in patients enrolled in the global, prospective GLORIA-AF Registry Program. Methods: GLORIA-AF collects data in three phases from routine clinical practice in 44 countries worldwide. Enrollment in Phase II was initiated following approval of DE, the first non-VKA oral anticoagulant (NOAC) available. During this phase, all patients with newly diagnosed NVAF at risk for stroke starting DE are followed for 2 years. This analysis is based on a pre-specified interim analysis once follow-up of the first 3000 DE patients was completed. Patients were recruited between November 2011 and December 2013 at nearly 1,000 sites worldwide, by cardiologists, neurologists and general practitioners. To reduce selection bias, patients were recruited consecutively, irrespective of antithrombotic therapy. Persistence was defined as time from initiation to discontinuation of therapy for >30 days or substitution of initial treatment by another oral anticoagulant. Persistence rates were analyzed on the basis of a time-to-event analysis using the Kaplan Meier method. Results: Among eligible patients, 2,937 were prescribed DE; 823 (27.4%) in North America, 1,503 (50.1%) in Europe, 194 (6.5%) in Latin America, 54 (1.8%) in Africa/Middle East and 363 (12.1%) in Asia. Overall, 55.3% were male, the median age was 71.0 (range 23-98) years; 36.7% were ≥75 years old. The CHA2DS2VASc score was ≥2 in 88.2%, 78.9% had hypertension, 22.7% diabetes mellitus, 10.1% prior stoke and 24.9% heart failure. All but 5 eligible patients took at least one dose of DE. The probability of remaining on DE treatment was 76.6% at 1 year and 69.2% at 2 years (based on Kaplan-Meier method). At the 2 years visit, half of the permanently discontinued patients (418 out of 828) had switched to another oral anticoagulant. Characteristics of patients discontinuing vs. sustaining therapy and relationships to stroke risk and geographical region will be presented. Conclusions: In this global, prospective, cohort of patients newly diagnosed with NVAF and treated with DE, persistence on therapy was high through 2 years of treatment, with an estimated probability of remaining on treatment of about 77% after 1 year and 70% after 2 years. The detailed results will provide a global perspective on the factors that influence treatment persistence in patients prescribed a NOAC for stroke prophylaxis. Disclosures Teutsch: Boehringer Ingelheim: Employment. Huisman:Boehringer Ingelheim Pharma GmbH & Co.KG: Other: Grant support; GlaxoSmithKline: Other: Grant support; Bayer HealthCare: Other: Grant support; Pfizer: Other: Grant support; Actelion: Other: Grant support. Lip:Bayer, BMS/Pfizer, Boehringer Ingelheim and Sanofi Aventis: Speakers Bureau; Bayer, Astellas, Merck, Sanofi, Bristol-Myers Squibb (BMS)/Pfizer, Daiichi-Sankyo, Biotronik, Portola and Boehringer Ingelheim: Consultancy. Diener:AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Novartis, Sanofi Aventis, Syngis and Talecris: Research Funding; Abbott, Allergan, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daiichi-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Medtronic, MindFrame, MSD, Neurobiological Technologies: Honoraria; The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, National Institutes of Health, Bertelsmann Foundation and Heinz: Research Funding. Dubner:steering committee member for Boehringer Ingelheim: Consultancy; St Jude Medical: Research Funding. Changsheng:steering committee member for Boehringer Ingelheim: Consultancy. Rothman:RTI Health Solutions: Employment. Zint:Boehringer Ingelheim: Employment. Elsaesser:Boehringer Ingelheim: Employment. Paquette:Boehringer Ingelheim: Employment. Bartels:Boehringer Ingelheim: Employment. Halperin:Bayer HealthCare: Consultancy; Boehringer Ingelheim: Consultancy.

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Background:Rheumatoid Arthritis (RA) is a chronic inflammatory joint disease. Strategies for its early detection and diagnosis are of high importance as prompt treatment improves clinical and structural outcome. Autoantibodies against cyclic citrullinated proteins (anti-CCP) have been associated with RA-development. Non-specific musculoskeletal (nsMSK) symptoms are often described prior to RA development. Majority of patients with nsMSK symptoms present to their general practice (GP) first. Studies of early arthritis cohorts have shown that many early arthritis patients cannot be accurately diagnosed at their first visit and are often referred as undifferentiated arthritis patients.Objectives:To evaluate the incidence of anti-CCP positivity in patients with new onset of nsMSK symptoms and the incidence of RA in these patients over a 3-year follow-up period compared to anti-CPP negative patients.Methods:In this prospective study (PANORA), 978 patients with new onset of nsMSK symptoms were included in 77 GP sites in Germany. Patients with a positive anti-CCP rapid-test (CCPoint®) were referred to Rheumatology Department (RD) for rheumatological assessment, RA-evaluation and an anti-CCP validation test (ELISA). ELISA anti-CCP positive patients without RA were monitored every 6 months for a total follow-up of 36 months or until RA-diagnosis. Patients with a negative anti-CPP result (CCPoint® or ELISA) are followed up with a questionnaire after 1 and 3 y.Results:From 978 included patients, 105 (10.7%) were CCPoint® positive. 96 were tested with ELISA and 27 (28.1%) were confirmed anti-CCP positive. 9 (33.3%) were diagnosed with RA at the first RD visit (study visit 2); 4 further patients were diagnosed with RA during the follow-up (FU) period so far. Overall, 48.1% of ELISA-positive (ELISA+) patients were diagnosed with RA up to now; 11 ELISA+ patients are still in the FU period of the study. Of the 868 CCPoint® negative patients, currently, 282 have filled out a 1-year FU questionnaire; 3.5% of those reported a RA diagnosis (Table 1). As expected, clinical parameters at V2 (e.g. CRP, swollen and tender joint count) were worse in the ELISA+/RA+ group compared to the ELISA-/RA- group, but no obvious differences were detected between ELISA+ patients who were diagnosed with RA during the FU period (after V2) and ELISA-/RA- patientsTable 1.Number and percentage of patients with a RA diagnosisAnti-CCP statusVisit 2Follow-up*TotalPoint-of-Care Test --3.5% (10 of 282)#3.5% (10 of 282)#Point-of-Care Test + / ELISA -2.9% (2 of 69)0% (0 of 34)#2.9% (2 of 69)Point-of-Care Test + / ELISA +33.3% (9 of 27)14.8% (4 of 27)48.1% (13 of 27)$* 1 year-questionnaire for Point-of-Care Test and ELISA negative patients or every 6 months follow-up for ELISA positive patients;#Patient-reported;$11 patients are still in the follow-up phase of the studyConclusion:Currently, 48.1% of anti-CCP+ (ELISA) patients have received a RA diagnosis, whereas 3.5% of the anti-CCP- (CCPoint®) received a RA diagnosis (patient reported), which underlines, that anti-CCP can be used as a marker to identify high-risk patients in GP setting. While clinical parameters are correlated with the diagnosis of RA, they are not suited for predicting future RA development alone. Anti-CCP, possibly in combination with additional parameters imaging, might increase the likelihood to early diagnose or predict RA development.Figure 1.Study overview: Patient distribution depending on anti-CCP results and RA diagnosis.Disclosure of Interests:Stephanie Dauth Grant/research support from: BMS, Michaela Köhm Grant/research support from: Pfizer, Janssen, BMS, LEO, Consultant of: BMS, Pfizer, Speakers bureau: Pfizer, BMS, Janssen, Novartis, Timm Oberwahrenbrock Grant/research support from: BMS, Ulf Henkemeier: None declared, Tanja Rossmanith Grant/research support from: Janssen, BMS, LEO, Pfizer, Karola Mergenthal Grant/research support from: BMS, Juliana J. Petersen Grant/research support from: BMS, Harald Burkhardt Grant/research support from: Pfizer, Roche, Abbvie, Consultant of: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Speakers bureau: Sanofi, Pfizer, Roche, Abbvie, Boehringer Ingelheim, UCB, Eli Lilly, Chugai, Bristol Myer Scripps, Janssen, and Novartis, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai

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Background:Autoinflammatory periodic fever syndromes characterized by excessive interleukin(IL)-1b release and severe systemic and organ inflammation have been successfully treated with the anti-IL-1 inhibitor canakinumab (CAN). In clinical trial situations and real life, rapid remission of symptoms and normalization of laboratory parameters were observed in most patients.1-3Objectives:The present study explores long-term effectiveness and safety of CAN under routine clinical practice conditions in pediatric and adult patients with CAPS (cryopyrin-associated periodic syndromes), FMF (familial Mediterranean fever), TRAPS (tumor necrosis factor receptor-associated periodic syndrome) and HIDS/MKD (hyperimmunoglobulinemia D syndrome/mevalonate kinase deficiency).Methods:RELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a 3-year follow-up period. Pediatric (age ≥2 years) and adult patients with clinically confirmed diagnoses of CAPS, FMF, TRAPS and HIDS/MKD that routinely receive CAN are enrolled in order to evaluate effectiveness and safety of CAN in clinical routine.Results:This first interim analysis of patient subgroups diagnosed with FMF, HIDS and TRAPS includes baseline data of 41 patients (10 TRAPS, 2 HIDS, 29 FMF), including preliminary 6-month data of a FMF-subset (N=16).Evaluation of disease activity and fatigue by patients’ assessment, days absent from school/work, inflammatory markers and physician global assessment (PGA) was performed at baseline and will be further assessed at 6-monthly intervals within the 3-year observation period. Preliminary results of a first subset of 16 patients diagnosed with FMF are available and indicate stable remission and disease control upon long-term CAN treatment: within the first study interval, no major changes were observed regarding the analyzed parameters (table 1).Table 1.Baseline characteristics of the TRAPS/HIDS/FMF-subgroups and preliminary 6-month data of FMF subset.TRAPSHIDSFMFBaselineBaselineBaselineall FMF patientsBaselineFMF subset6 monthsFMF subsetNumber of patients, N102291616Mean age, years (SD)22 (4; 43)11 (5; 18)26 (5; 56)16 (5; 47)16 (5; 47)Female (%), N=9 (1 missing)5 (56)1 (50)15 (52)7 (44)7 (44)Mean duration of prior canakinumab treatment, years (min; max)1 (0; 2)3 (2; 4)n. a.2.2 (0; 6)2.2 (0; 6)Patient’s assessment of disease activity 0-10, mean (min; max)2.1 (0; 5)0 (0; 0)3 (0; 10)2.8 (0; 8)2.2 (0; 7)Patient’s assessment of fatigue 0-103.4 (0; 8)0 (0; 0)4.4 (0; 9)4.6 (0; 9)3.9 (0; 8)Number (%) of patients with days absent from school/work due to study indication during last 6 months4 (44)2 (100)5 (17)2 (13)5 (31)Inflammatory markers, CRP/SAA, mean (mg/dL)2.07.90.10.60.95.30.52.40.62.4PGA of disease activity: no/mild to moderate/severe; N (%)*1 (11)6 (67)0 (0)2 (100)0 (0)0 (0)10 (35)8 (28)2 (7)5 (31)7 (44)1 (6)6 (38)7 (44)0 (0)SAE, N (%)0 (0)0 (0)2 (6.9)n. a.2 (12.5)Conclusion:Baseline characteristics of all subgroups and first interim data of FMF patients are available from the RELIANCE study, the longest running real-life CAN registry. Further interval data will be analyzed to assess efficacy and safety of long-term CAN-treatment in patients with autoinflammatory periodic fever syndromes.References:[1]Lachmann et al. N Engl J Med. 2009;360(23):2416-25[2]Kuemmerle-Deschner et al. Rheumatology (Oxford). 2016;55(4):689-96[3]De Benedetti et al. N Engl J Med. 2018;378(20):1908-1919Disclosure of Interests:Jörg Henes Grant/research support from: Novartis, Roche-Chugai, Consultant of: Novartis, Roche, Celgene, Pfizer, Abbvie, Sanofi, Boehringer-Ingelheim,, J. B. Kuemmerle-Deschner Grant/research support from: Novartis, AbbVie, Sobi, Consultant of: Novartis, AbbVie, Sobi, Michael Borte Grant/research support from: Pfizer, Shire, Ivan Foeldvari Consultant of: Novartis, Gerd Horneff Grant/research support from: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Speakers bureau: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Tilmann Kallinich Grant/research support from: Novartis, Consultant of: Sobi, Roche, Novartis, Birgit Kortus-Goetze Consultant of: Novartis, Frank Weller-Heinemann: None declared, Julia Weber-Arden Employee of: I am employed by Novartis, Norbert Blank Grant/research support from: Novartis, Sobi, Consultant of: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche

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Background:Systemic sclerosis (SSc) is characterized by inflammation, vasculopathy and progressive fibrosis. Pulmonary Hypertension (PH) is one of the leading causes of death in SSc (1). Currently, most patients with SSc are screened for the presence of PH, and focus lies on early detection and early treatment. Recent literature describes potential for both nailfoldcapillaroscopy (NCM) and several biomarkers to serve as non-invasive tools to identify SSc patients at risk for developing PH (2). Ideally this could attribute to further improvement of risk stratification in SSc and PH screenings algorithms.Objectives:To explore NCM characteristics and plasma levels of selected candidate biomarkers in a cross-sectional cohort of SSc patients with and without different forms of PH.Methods:From 02-2018 until 02-2019 we included 40 consecutive SSc patients with associated PH (30 (75%) were female, 32 (80%) LcSSc, median age 72 years (IQR 69-77), median SSc duration 10.7 years (IQR 4.3-17.8), median PH duration 3.9 years (IQR 1.5-7.06)) and 40 without PH (28 (70%) were female, 26 (65%) had a LcSSc, median age 59 years (IQR 51-71), median SSc duration 6 years (IQR 3.1-8.6). In each group NCM characteristics (both quantitative and qualitative) and plasma levels of IL4, IL6, IL8, IL13, PDGFAA, PDGFAB-BB, 6Ckine, sTRAIL, MMP1, MMP7, sICAM1, sVCAM, CCL19/MIP3b, Endostatin, sVEGFR1, sVEGFR2, sVEGFR3, CXCL4, Endothelin1, FGF1, FGF2, VEGF-A, VEGF-C, and VEGF-D using Luminex kits, and vascular auto-antibodies AT1R and ETAR using ELISA (Celltrend GmbH, Luckenwalde, Germany) were determined. NCM characteristics were compared using t-tests, biomarker levels were compared by using Mann-Whitney U tests.Results:We observed no differences in mean capillary density, number of abnormally shaped capillaries, number of fingers with density <3 capillaries/mm and in overall NCM pattern between patients with and without PH. Plasma levels showing significant differences between the two groups are presented in table 1.Conclusion:We found significant differences in several of the selected biomarkers in SSc patients with and without PH, but not in NCM characteristics between the groups. However, we did observe a tendency toward more morphologic abnormalities and an overall late pattern in the SSc-PH group. Future longitudinal research should explore the added value of these NCM parameters and biomarkers in personalized risk stratification for the development of PH.References:[1]Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017;76(11):1897-905.[2]Guillén-Del-Castillo A, Simeón-Aznar CP, Callejas-Moraga EL, Tolosa-Vilella C, Alonso-Vila S, Fonollosa-Pla V, et al. Quantitative videocapillaroscopy correlates with functional respiratory parameters: a clue for vasculopathy as a pathogenic mechanism for lung injury in systemic sclerosis. Arthritis Res Ther. 2018;20(1):281.Table 1.NCMSSc PH(n=40)SSc noPH(n=38, 2 missing)P valueMean capillary density/mm (±SD)5.0 (±1.4)5.4 (±1.6)0.39Mean number of fingers with density <3 (±SD)2.3 (±1.9)1.7 (±2.1)0.20Mean abnormally shaped capillaries/ mm (±SD)1.2 (±0.46)0.99 (±0.53)0.07NCM pattern (n)0.103Normal/aspecific13early03active47late3425Not interpretable12Biomarkers*SSc PH(n=33, 7 missing) (median, IQR)SSc noPH(n=40)(median, IQR)P valueIL6 pg/ml4.8 (1.7-8.2)2.5 (1.3-5.6)0.047PDGF-AB-BB pg/ml29535 (24777-33458)32221 (29409-37549)0.0034sTRAIL pg/ml36.6 (20,4 -50,6)60.8 (40.7 -82.4)<0.0001sVCAM1 ng/ml311 (254-374,)265 (228 - 323)0.0236Endostatin ng/ml53.8 (41.9- 72.6)39 (28.6 - 46)<0.0001sVEGFR2 pg/ml10388 (7276- 13323)13736 (10282 -16554)0.0006CXCL4 ng/ml3347 (2546-4708)5309 (4089-6322)<0.0001VEGF-A pg/ml672 (248 - 955)346 (175-703)0.0424VEGF-D pg/ml671 (421-1012)515 (262-734)0.0296* only significant values with a p<0.05 are shownDisclosure of Interests:Jacqueline Lemmers: None declared, C.H.M. van den Ende: None declared, R. Smeets: None declared, Brigit Kersten: None declared, Arjan van Caam: None declared, Sander van Leuven: None declared, Jolanda van Haren-Willems: None declared, Arie van Dijk Speakers bureau: Actelion(Janssen), Consultant of: Actelion(Janssen), Grant/research support from: Unrestricted educational Grant for PhD student from Actelion (Janssen), Madelon Vonk Speakers bureau: Actelion(Janssen), Boehringer Ingelheim, Roche, Consultant of: Advisory Board from Actelion(Janssen) and Boehringer Ingelheim, Grant/research support from: Unrestricted Educational Grant and research support from Actelion(Janssen), research support from Ferrer

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Abstract Abstract 2317 Introduction: Heparin and low molecular weight heparins such as enoxaparin and dlateparin are widely used in the management of thrombosis and cardiovascular disorders. However these anticoagulants are capable of producing the generation of HIT antibodies and their use is not recommended in patients with previous history of HIT. More recently several new oral anticoagulants have been approved around the world. These include the oral anti-Xa agents namely, Apixaban (Bristol-Myers Squibb), Rivaroxaban(Bayer Healthcare) and anti-IIa agents, dabigatran (Boehringer-Ingelheim). All of these represent synthetic low molecular weight compounds. Apixaban and Rivaroxaban are active agents where as Dabigatran requires endogenous activation. The purpose of this investigation was to determine the relative effects of the newer anticoagulants and enoxaparin on HIT antibody mediated platelet aggregation and other interactions with platelets. Materials: Rivaroxaban was obtained in powdered form from Bayer Healthcare (Wuppertal, Germany) Apixaban and Dabigatran were of synthetic origin. Enoxaparin was obtained from Sanofi-Aventis (paris, France). All drugs were dissolved in appropriate solutions and a working solution of 100 ug/ml was prepared in buffered saline. Pooled HIT sera was prepared by pooling clinically symptomatic HIT patients with high titers of anti-heparin platelet factor 4 antibodies. Method: Whole blood samples drawn from normal healthy volunteers were supplemented with each of these agents at a graded concentration of 0–100 ug/ml for 60 minutes to determine the relative release of platelet factor 4. To test the interaction of HIT antibody with each of these agents 50 ul of PRP samples were mixed with 150 ul HIT positive heat inactivated sera/plasma or plasmapheresis fliud (collected from symptomatic HIT patients). Graded amounts of each of these new anticoagulants at 0.1, 1.0 and 10 ug/ml were added to test the platelet aggregation response at a period of 60 minutes. Results: In contrast to enoxaparin which produced an increase in the platelet factor 4 release upon 60 minute incubation 25.6+3.1 ng/ml), none of the new oral anticoagulants produced an increase in the PF4 <15.0 ng/ml. Enoxaparin also produced a strong HIT antibody mediated response, whereas none of these newer oral agents produced any aggregation responses. Conclusion: These studies demonstrate that –enoxaparin the newer oral anticoagulant drugs do not interact with HIT antibody to mediate plarelet aggregation responses. Moreover, these newer agents do not promote platelet factor 4 release. Thus, these agents can be used in the long term anticoagulant management of heparin compromised patients. Disclosures: No relevant conflicts of interest to declare.

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Abstract Objectives: To determine the support of physicians for the recently published ASCO evidence-based clinical practice guidelines for venous thromboembolism (VTE) prophylaxis and treatment in patients with cancer (J Clin Oncol. 2015;33:654-6). Methods: ASCO key recommendations were presented as part of three CME seminars to physicians not specialized in hem/onc or hemostasis. In addition two specialists in the field discussed a list of arguments for and against each of the recommendations considering (1) quality of scientific evidence underlying each recommendation, (2) feasibility in daily practice including sensitivity to patients preferences, and (3) medicolegal implications and reimbursem*nt aspects. After each presentation attendees were asked to fill out a questionnaire on how much they supported the ASCO recommendations and each of the pro&con arguments. Results: A total of 89 physicians attended the three meetings. 56 questionnaires were returned. The ASCO recommendations with the highest degree of support were: ‒ Patients undergoing major cancer surgery should receive prophylaxis for 7-10 days and even 4 weeks after major abdominal or pelvic surgery with high-risk features (84% pro) ‒ LMWH should be given for the initial treatment as well as for long-term secondary prophylaxis (80% pro). The recommendations with the lowest degree of support were: ‒ Patients with cancer should be educated about signs and symptoms of VTE. They should be periodically assessed for VTE (59% pro). ‒ Anticoagulation should not be used to extend survival of patients with cancer in the absence of other indications (56% pro). Conclusion: After presenting ASCO recommendations as part of CME training the degree of physicians' support was still at best moderate and sometimes even close to neutrality. In daily medical practice scientific evidence has no priority to clinical practicability, patients preferences, medicolegal aspects and cost-restrictions. Guideline authors should complement their recommendations with advice from their own practice on how to implement guidelines in daily care and how they manage financial and medicolegal restrictions. In addition there is an unmet need for more education on VTE prophylaxis and treatment among physicians not specialized in hem/onc or hemostasis who are caring for cancer patients. Disclosures Matzdorff: AMGEN - e. Honoraria: Honoraria; Aspen Germany: Honoraria; Bayer: Equity Ownership; Boehringer Ingelheim: Honoraria; Behring: Honoraria; Bristol Myers Squibb: Honoraria; GlaxoSmithKline: Honoraria; LEO Pharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Equity Ownership, Honoraria. Schwindel:LEO Pharma GmbH: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Honoraria; Nordic Pharma: Honoraria. Hutt:LEO Pharma GmbH: Employment.

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Abstract Background The most common side effect of oral anticoagulants are bleeding complications. In large trials, novel direct oral anticoagulants (NOAC) have been shown to reduce the risk of major bleeding compared to warfarin. However, little is known about the distribution pattern, management and outcome of NOAC-related bleeding complications in daily care. Patients and methods Using data from a large regional registry of patients treated with novel direct oral anticoagulants (NOAC) in the district of Saxony, Germany, we evaluated pattern and management of NOAC-related bleeding complications in daily care. In this ongoing registry, a network of 239 physicians enrols up to 2500 daily care NOAC patients who receive central prospective follow up (FU) by the registry office at day 30 day and quarterly thereafter to collect efficacy and safety data. All outcome events are centrally adjudicated using standard scientific definitions. Results Until July 31th 2013, 2249 patients were enrolled into the registry. Of these, 1738 (77.3%) patients received rivaroxaban, 356 (15.8%) received dabigatran and 155 (6.9%) received apixaban. During follow-up (2674.0 patient years), a total of 825 patients reported 1137 bleeding complications (59.1% minor, 33.9% non-major, clinically relevant (NMCR) and 6.9% major bleeding according to ISTH definition). For non-major bleedings, mucosal and skin bleeding were the most common bleeding sites (67.9% of all bleedings), followed by genitourinary (10.9%) and gastrointestinal bleeding (10.9%). For major bleeding, gastrointestinal bleeding was the most common manifestation (2.8%), followed by genito-urinary (0.6%) bleeding. In 93% of all bleeding events, treatment was not necessary or consisted of conservative treatment with compression, tamponade or red blood transfusion. Surgical or interventional treatment was reqired in 7.0% of all bleedings (0.0% of minor, 13.0% of NMCR and 38.0% of major bleedings). Prothrombin complex concentrate was used in 1.3% (24% of all major bleedings). No patient received recombinant factor VII. Bleeding-associated mortality was 0.5% for all and 7.5% for major bleeding. Of the six fatal bleedings observed, three were intracranial bleedings. Conclusion Bleeding complications are common in daily care NOAC patients and are usually managed conservatively. Only 7% of all observed bleedings fulfil the ISTH criteria of major bleeding (mainly for RBC transfusion criterion) and are managed using interventions, FFP or PCC. Overall, only few NOAC-associated bleeding complications in daily care are fatal, indicating that available management strategies are sufficient. For presentation at ASH, updated results including risk assessments will be reported. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

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Abstract Abstract 2267 Background: In the EINSTEIN-EXT trial, rivaroxaban (RX) has been found to be at least as effective and safe as warfarin in extended venous thromboembolism (VTE) treatment, which lead to approval in many countries. However, patients in RCT‘s present a selected population treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of new oral anticoagulants (NOAC) need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of rivaroxaban anticoagulation for extended VTE treatment in daily care. Patients and methods: In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data. Results: Until July 31th 2012, 938 patients were registered. Of these, 126 patients received RX for extended VTE treatment (demographic data in table 1). In our registry, the population receiving extended VTE treatment is older than in EINSTEIN-EXT (65.0 vs. 58.2 years). Indication for prolonged treatment is proximal deep vein thrombosis or pulmonary embolism (93.3%). Most patients received 20 mg OD, but a quarter of patients received 15 mg OD due to impaired renal function. Until July 31th, completed FU cumulate to 44.2 patient years. The results of 1-, 3- and 6-months FU are shown in table 2. Until now, no recurrent VTE or VTE-related death occurred. Two patients experienced major vascular events (1 ACS, 1 TIA). Bleeding events were frequent (24.6%) but only 2 patients (1.6%) experienced major bleeding events, none of which were fatal. Two patients died due to underlying diseases. At 3 and 6 month, 94% resp. 85% of patients were still taking RX. Conclusion: In unselected patients in daily care, extended VTE treatment with RX is effective and safe with low rates of events or treatment discontinuation in the first 180 days of treatment. Long-term data will be reported. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

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Abstract Background: In Western Europe most patients with haemophilia (PWH) have the opportunity to get regular prophylaxis and can life normal lives due to the availability and funding of factor concentrates. The majority of haemophilia patients have to inject themselves every other day or three times a week.The need of frequent injections may impact negatively patients' treatment adherence which might result in increased annual bleeding rate and impaired quality of life. Therefore there is a need for half-life extended (EHL) products which will be launched in the next years in Europe for treatment of haemophilia A and B and are expected to improve patients' quality of life. However, little is known about patients' perspectives on the use of these new EHL products and their willingness to switch to these products. Aim: National Member Organisations (NMO) of haemophilia patients from the DACH Region (D=Germany, A=Austria, CH=Switzerland) were interested to better understand PWH's expectations and concerns towards these new EHL products in order to adapt haemophilia treatment to real patients' needs. Methods: A systematic postal survey was sent out to 2,644 patients and parents of children with haemophilia A or B in Germany (2015), Switzerland (2016) and Austria (2016). The postal survey included questions concerning demographic and clinical data of the patient, knowledge about half-life of actual factor concentrates (FC) and attitudes towards FC in terms of satisfaction with actual factor concentrate, expectation towards new EHL products, willingness to switch to new EHL products, required information for decision making, preferred information sources and facilitation of therapy in general. Results: In total 1,013 questionnaires were sent back (38.3%); 2 patients had to be excluded from further analysis since these patients had VWD. 747 adult haemophilia patients and 262 parents of haemophilic children participated, 2 respondents could not be classified. The majority of patients had haemophilia A (84.1%), were severely affected (73%), received prophylaxis (56.6%), mostly three times a week (40.9%) and used recombinant products (59.4%). 14% had a history of an inhibitor (past, actual). Most of the patients and parents did not know the correct half-life of the actual FC [FVIII: 30%, FIX: 75%]. In general they were satisfied (M=4.4±0.8) with their actual FC; only 4.1% were unsatisfied, mainly with difficult manageability and short half-life of FC. They expected from the new products to provide less frequent injections, better efficacy and safety/no side effects. 59.6% would be willing to switch to new products if they have a prolonged half-life and have the same safety of the actual FC. Reasons for not willing to switch were fear of inhibitor development and no side effects of actual FC. They had almost no information about the new up-coming products, wish more information about half-life, possible side-effects and efficacy and would consider changing product if the prolongation of the half-life is at least double as high as the actual FC. 20.6% would switch already with a half-life prolongation of 1.2-1.5 times longer; 3.3% would not switch at all. The majority wanted to receive information about new products from their haemophilia treater (77.1%), newsletter of their NMO (73.4%) and information letter from their HTC/NMO (35.7%). They would wish smaller packages, different mode of administration and better manageability of the product in order to facilitate their therapy. There was a significant difference across countries regarding treatment regimen (p<.0001) and used product category (p<.0001); in Germany more patients were on prophylaxis (71.3%) and in Switzerland more patients used recombinant products (75.8%). No differences were found for the satisfaction with their actual product, their willingness to switch to new EHL products in general and the time of required half-life prolongation. In Switzerland more patients required information on costs of the new EHL products for an adequate decision making process for switching (p<.0001). Conclusions: In this representative survey among patients and parents of children with haemophilia of the DACH Region it could be shown that even though they were generally satisfied with their actual FC the majority would be willing to switch from their actual FC to the new up-coming EHL products assuming the half-life is prolonged and has the same safety of the actual FC. Disclosures von Mackensen: Shire: Research Funding; SOBI: Research Funding. Kalnins:SOBI: Research Funding. Lino:SOBI: Research Funding. Joerg:SOBI: Research Funding. Albisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Weiss:Shire: Research Funding.

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Background:Average life spans of patients with rheumatoid arthritis (RA) are approaching those of the general population. This results in a large proportion of RA patients being elderly at some point and underlines effective RA treatments needed for this population. Pivotal clinical trials have demonstrated the efficacy of tocilizumab (TCZ) for the treatment of RA. However, real-world studies that explore the effectiveness of TCZ especially in the elderly are lacking. ICHIBAN was a large, observational study that followed patients with RA treated with TCZ under real-world conditions in Germany for up to 2 years.Objectives:In this analysis of ICHIBAN, we examined the safety and effectiveness of long-term TCZ treatment according to patient baseline (BL) age (<50, 50–65, >65 years).Methods:ICHIBAN (NCT01194401) was a prospective, non-interventional study that observed adult patients with active moderate to severe RA in German rheumatology clinics and practices. Patients were treated with TCZ according to the local label. The safety analyses set (SAF) included all patients who received at least one dose of TCZ. The effectiveness set (EFF) included all patients from the SAF who had no prior TCZ therapy. Patient-reported outcomes (PROs) were assessed using the visual analogue scale. Last observation carried forward was used to substitute for missing values.Results:At baseline (BL), 3,164 patients were included in the SAF: 29.2% <50 years, 47.3% 50–65 years, and 23.5% >65 years old (1.2% ≥80 years). Patients >65 years old were not only the most likely to have comorbidities such as hypertension, anaemia, renal insufficiency, osteoporosis, diabetes, and coronary heart disease, but also had the highest BL disease activity according to Disease Activity Score-28 erythrocyte sedimentation rate (DAS28-ESR) and Clinical Disease Activity Index (CDAI) (Table 1).Proportions of patients with adverse events (AEs) considered related to treatment were similar in patients <50 (22.3%), 50–65 (21.9%) and >65 years (22.2%). More patients >65 years (20.2%) and 50–65 years (14.4%) experienced serious AEs (SAEs) than patients <50 years (11.5%). Slightly more patients >65 years old experienced infectious SAEs (4.8%) than younger patients (<50 years, 3.2% and 50–65 years, 3.1%). Yet, similar proportions of patients across all age groups discontinued TCZ due to AE (7.0% <50 years; 9.6% 50–65 years; 7.8% >65 years).2,902 patients were included in the EFF. Patients <50 years experienced DAS28-ESR remission at least once during the treatment period (65.4%) more often than patients aged 50–65 years (59.8%) or >65 years (59.5%). However, patients >65 years had numerically greater improvements in DAS28-ESR (Table 1). Patients <50 years had the best physical functioning at BL and the greatest reduction in Health Assessment Questionnaire Disease Index (HAQ-DI) score (Figure 1A). All age groups had similar improvements in PROs such as fatigue, strength of pain, and sleep disturbances (Figure 1B).Table 1.Model summary for prediction of DAS28CRP using time and etanercept originator (relative to biosimilar)<50 years50–65 years>65 yearsDAS28-ESR, mean ± SDn*7771237617BL4.9 ± 1.45.3 ± 1.35.4 ± 1.3Last visit2.8 ± 1.73.1 ± 1.73.2 ± 1.7Change from BL-2.0 ± 1.7-2.2 ± 1.7-2.2 ± 1.8CDAI, mean ± SDn*7681217590BL25.7 ± 12.828.4 ± 13.328.8 ± 12.8Last visit13.3 ± 12.814.6 ± 13.214.5 ± 12.8Change from BL-12.5 ± 13.6-13.8 ± 14.0-14.3 ± 13.8*271 patients with missing data at BL**327 patients with missing data at BLConclusion:Although elderly patients experienced a higher rate of infections, the proportion of patients withdrawing due to AE was not higher than in the other age groups. Starting with higher baseline disease activity, patients >65 years had similar benefits to disease activity and PROs when compared with younger patients. Overall, these results indicate that long-term TCZ treatment of elderly patients is effective and has an acceptable safety profile.Disclosure of Interests:Christof Specker Speakers bureau: AbbVie, Celgene, Chugai, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Chugai, Lilly, Novartis, Sobi, and UCB, Grant/research support from: Boehringer, Chugai, GSK, and Roche, Martin Aringer Speakers bureau: Roche and Chugai, Consultant of: Roche and Chugai, Grant/research support from: Roche, Gerd Rüdiger Burmester Consultant of: Lilly, Pfizer, Sanofi, and Roche, Grant/research support from: Roche, Marvin Peters Employee of: Roche Pharma AG, Michael W. Hofmann Employee of: Chugai Pharma Germany GmbH, Herbert Kellner Consultant of: Roche, Grant/research support from: Roche, Frank Moosig Grant/research support from: Roche, Hans-Peter Tony Speakers bureau: Roche, Abbvie, BMS, Chugai, Janssen, Novartis, Sanofi, and Lilly, Consultant of: Roche, Abbvie, BMS, Chugai, Janssen, Novartis, Sanofi, and Lilly, Grant/research support from: Roche, Gerhard Fliedner Grant/research support from: Roche, Chugai, Abbvie, and Lilly

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Abstract Introduction Direct factor Xa and thrombin inhibitors (apixaban, Bristol-Myers Squibb, Princeton, NJ; rivaroxaban, Bayer Healthcare, Leverkusen, Germany; dabigatran, Boehringer Ingelheim, Ridgefield, CT) have shown favorable efficacy profiles in comparison to standard therapy in a variety of clinical conditions including the prevention of stroke in patients with non-valvular atrial fibrillation. Although clinical trials have shown that the safety of these new drugs in terms of the incidence of major hemorrhage is similar or better than with conventional therapies, there remains concern over the ability to reverse their anticoagulant effects in cases of overdose or medical emergency. Prothrombin complex concentrates (PCCs) have been used to reverse the effect of warfarin and in cases of significant bleeding in patients with coagulopathy. PCCs may be useful in modulating hemorrhage caused by the new oral anticoagulant drugs. This study tested the ability of three PCCs to reverse bleeding induced by apixaban, rivaroxaban or dabigatran in a standardized rat model. Methods Following anesthesia with an IM injection of ketamine and xylazine, male Sprague-Dawley rats were anticoagulated by an IV injection of apixaban (100 or 300 µg/kg), rivaroxaban (100 or 300 µg/kg) or dabigatran (50 or 100 µg/kg). After 5 minutes, rats were treated with vehicle, a 3-factor PCC (Profilnine, Grifols Biologicals, Los Angeles, CA), a 4-factor PCC (Beriplex, CSL Behring, Marburg, Germany) or an activated 4-factor PCC (FEIBA, Baxter, Deerfield, IL). Five minutes after PCC administration, a standardized tail snip was performed and the time for bleeding to stop was measured. Upon cessation of bleeding, a blood sample was collected by cardiac puncture and the rat was humanely euthanized. Platelet poor plasma was prepared from the blood samples and was analyzed using PT, aPTT and PiCT assays. Results for individual treatment groups were compared using one-way ANOVA (SigmaPlot 12, Systat, San Jose, CA). Results While at a dose of 100 µg/kg, apixaban did not increase the bleeding time vs. saline (6.25 ± 0.8 vs. 6.0 ± 1.7 min), a dose of 300 µg/kg apixaban significantly prolonged the bleeding time (17.1 ± 5.6; p=0.024). Administration of Beriplex at doses up to 10 U/kg did not shorten the bleeding time. 10 U/kg Profilnine shortened bleeding time, but not completely to baseline (9.8 ± 4.2 min). The administration of FEIBA dose-dependently prolonged bleeding beyond that seen with apixaban alone (22.6 ± 11.4 and 37.5 ± 5.2 min for doses of 5 and 10 U/kg, respectively; p<0.001 apixaban + 10 U/kg FEIBA vs. apixaban alone). Doses of 100 and 300 µg/kg rivaroxaban prolonged bleeding time (20.8 ± 2.5, p=0.002 vs. saline; 25.0 ± 10.0 min, p<0.001 vs. saline, respectively). While 10 U/kg Beriplex or Profilnine shortened the bleeding time, Profilnine was more effective (9.7 ± 3.2 min; p=0.508 vs. saline). FEIBA at a dose of 5 U/kg did not reverse rivaroxaban-induced bleeding. Dabigatran caused a dose-dependent increase in bleeding time which could be prevented by the administration of Beriplex or Profilnine (10 U/kg). As with apixaban, the administration of FEIBA enhanced the bleeding seen with dabigatran (50.3 ± 8.3 vs. 15.9 ± 1.2 min; p<0.001). As it was hypothesized that the increased bleeding observed following FEIBA administration may be due to a Protein C mediated facilitation of fibrinolysis, additional groups of rats were anticoagulated with apixaban or rivaroxaban and then treated with FEIBA + 10 mg/kg epsilon aminocaproic acid. In these rats, the bleeding times were comparable to those in non-anticoagulated rats (6.7 ± 5.0 min with apixaban; 7.7 ± 6.4 min with rivaroxaban). Discussion PCCs appear useful for neutralizing bleeding induced by direct factor Xa and thrombin inhibitors. Owing to their different compositions, each PCC exhibits a distinct neutralization profile. Co-administration of a fibrinolytic inhibitor with a PCC may enhance the effectiveness of hemorrhage reversal. Disclosures: Jeske: Bristol-Myers Squibb: Research Funding.

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Abstract Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease in which BCR/ABL enhances growth and survival of leukemic cells. In most patients, the disease can be kept under control by the BCR/ABL tyrosine kinase inhibitor imatinib (STI571; Novartis Basel, Switzerland). However, resistance or intolerance against imatinib may occur during therapy. Therefore, current research is focusing on novel targets and targeted drugs in CML. Polo-like kinase 1 (Plk-1) is a serine/threonine kinase that plays an essential role in mitosis and is expressed in activated/phosphorylated form in various malignancies including acute myeloid leukemia (AML). BI 2536 (Boehringer Ingelheim GmbH, Germany) is a novel selective inhibitor of Plk-1, that is currently tested in AML-trials. In this study, we have evaluated expression and the potential role of Plk-1 as a novel target in CML cells. As assessed by PCR, Plk-1 mRNA was found to be expressed abundantly in primary CML cells and in the CML cell line K562, whereas normal peripheral blood cells did not express detectable levels of Plk-1 mRNA. The Plk-1 protein was detected in primary CML cells and K562 cells by immunocytochemistry. In consecutive experiments, we were able to show that CML cells display phosphorylated Plk-1. As assessed by 3H-thymidine-uptake experiments, BI 2536 was found to inhibit the proliferation of K562 cells in a dose-dependent manner (IC50 5–15 nM). Moreover, BI 2536 was found to inhibit the proliferation of both imatinib-naive (n=6) and imatinib-resistant (n=3) primary CML cells (IC50: 1–15 nM). The growth-inhibitory effect of BI 2536 on CML cells was found to be associated with mitotic arrest, a G2-M cell cycle arrest, and consecutive apoptosis. In normal bone marrow or peripheral blood mononuclear cells, neither mitotic cell arrest nor apoptosis were observed after exposure to BI 2536. In further experiments, primary CML cells were coincubated with BI 2536 plus imatinib or with BI 2536 plus nilotinib (AMN107; Novartis) at fixed ratio of drug concentrations. In these experiments, BI 2536 was found to synergize with both tyrosine kinase inhibitors in counteracting the proliferation of CML cells. In conclusion, our data show that Plk-1 is expressed in activated form in CML cells and plays a role in cell cycle progression and cell viability. Targeting Plk-1 with BI 2536 leads to mitotic arrest, growth inhibition, and apoptosis in imatinib-naive and imatinib-resistant leukemic cells. Moreover, BI 2536 synergizes with imatinib and nilotinib in counteracting the growth of neoplastic cells in CML. Targeting of Plk-1 may be a novel interesting pharmacologic approach to counteract growth of CML cells.

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Abstract Abstract 502 Background: In the RE-LY trial, dabigatran (DB) has been found to be at least as effective and safe as warfarin to prevent stroke in atrial fibrillation (AF), which lead to approval in many countries. However, patients in RCT‘s present a selected population treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of new oral anticoagulants (NOAC) need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of dabigatran anticoagulation in AF in daily care. Patients and methods: In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data. Results: Until July31th 2012, 938 patients were registered. Of these, 201 received DB for AF (table 1). The population in our registry is older than in RELY (74.2 vs. 71.5 years) and has a higher CHADS2-Score (2.7 vs. 2.1). Interestingly, 110 mg BID was the preferred dosage in DB patients (55.7%) despite the fact that these patients had higher CHADS2-scores than patients receiving 150 mg BID (2.3 vs. 2.9). Two third of patients were newly anticoagulated and one third was switched from Vitamin-K antagonists, mainly due to poor INR control or bleeding complications. Results of 30-day-, 3-month and 6-month FU are shown in table 2. Currently, FU data cumulate to 86.8 patient years. During FU, Three patients (1.5%) experienced major cardiovascular events (xyz) and another two patients (1.0%) minor cardiovascular events (syncope). Until now, no deaths occurred. Bleeding complications were frequent (14.9%) but major bleeding was rare (n=3; 1.5%) none of which was fatal. At 3 month, 93% of patients were still taking DB but switch to other anticoagulants increased between 3 and 6 month, mainly due to side effects or incompliance. Conclusion: In unselected patients in daily care, DB is effective and safe with low rates of cardiovascular or major bleeding events. However, within 6 month, about 20% of patients are switched to other anticoagulants. Long-term data will be reported. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

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Abstract Background: Dabigatran is approved for stroke prevention in atrial fibrillation (SPAF) in many countries. However, little is known about the effectiveness and safety of or the persistence with Dabigatran therapy in unselected patients in daily care. Objectives: To evaluate the effectiveness, safety and discontinuation rates of dabigatran anticoagulation in SPAF in daily care. Patients and methods: The prospective NOAC registry was initiated in November 2011. A network of more than 230 physicians in the district of Saxony, Germany, enroll up to 3000 patients in the registry, which are prospectively followed by the central registry office for up to 36 months. Persistence to dabigatran, rates of stroke/TIA/systemic embolism and of NMCR or major bleeding (ISTH definition) during or within 3 days after last intake of dabigatran were assessed using Kaplan-Meier time-to-first-event analysis. Results: Between November 2011 and February 2013, 341 SPAF patients were enrolled with dabigatran (133 with VKA pre-treatment and 208 newly anticoagulated patients). 158 received dabigatran 150 mg BID and 174 received 110 mg BID. Patients on 110 mg BID were significantly older (78 vs. 71 years), more often had diabetes, a history of stroke, a CHADS2 score ≥ 2 and HAS-BLED scores ≥2 (table 1). In the intention-to-treat analysis, stroke/TIA/systemic embolism occurred at a rate of 2.14/100 pt. years. In the valid-for safety analysis (all events during or within 3 days after last intake of dabigatran) stroke/TIA/systemic embolism occurred at a rate of 1.4/100 pt. years, which was numerically lower for patients receiving 150 compared to 110 mg BID (0.7 vs 2.1/100 pt. years; table 2). Major bleeding occurred at a rate of 1.7/100 pt. years and numerically more often in patients receiving 110 instead of 150 mg BID (2.0 vs 1.3/100 pt. years). Similarly, rates of NMCR bleeding (8.9/100 pt. years) were numerically higher in the 110 mg BI cohort (10.3/100 pt. years) compared to the 150 mg BID cohort (7.0/100 pt. years). Treatment discontinuation occurred in a total of 124 patients during follow up, which in a Kaplan-Meier analysis translated into a discontinuation rate of 23.8/100 pt. years. Documented reasons for treatment discontinuation were “side effects” (40/124; 32.3%), “no longer indicated” (13/124; 10.5%), “worsening of renal function” (12/124; 9.7%), “bleeding complications” (11/124; 8.9%), “costs” (4/124; 3.2%), “inconvenience” (13/124; 10.5%); “others” (31/124; 25%). Conclusion: In unselected patients in daily care, dabigatran is effective and safe with low rates of cardiovascular or major bleeding events. However, within 12 month, about 24.6% (84/341) of patients are switched to other anticoagulants. Disclosures Werth: Bayer: Honoraria. Köhler:Bayer: Honoraria. Beyer-Westendorf:Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding.

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Abstract Abstract 1156 Background: In the ROCKET-AF trial, rivaroxaban (RX) has been found to be at least as effective and safe as warfarin to prevent stroke in atrial fibrillation (AF) and is approved in many countries. However, patients in RCT‘s present a selected population which is treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of new oral anticoagulants (NOAC) need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of rivaroxaban anticoagulation in AF in daily care. Patients and methods: In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data. Results: Until July 31th 2012, 938 patients were registered. Of these, 504 patients received RX for atrial fibrillation (demographic data in table 1). Despite similar age (mean 75 years), our real world cohort has lower CHADS2-Scores compared to ROCKET-AF (2.4 vs. 3.5). The preferred dosage in most RX patients (68.8%) was 20mg, but these patients had lower CHADS2-scores than patients receiving 15 mg (2.2 vs. 2.8). Two third of patients were newly anticoagulated and one third was switched from Vitamin-K antagonists, mainly due to poor INR control or bleeding complications. Results of 30-day-, 3-month and 6-month FU are shown in table 2. Currently, FU data cumulate to 112.2 patient years. Five patients (1.0%) experienced major cardiovascular events (3 ACS, 1 ischemic stroke, 1 TIA). Another five patients experienced minor cardiovascular events (syncope). Three patients (0.6%) died within the first month of treatment (one due to sudden cardiac death, possibly related to ventricular fibrillation, two of underlying disease). Bleeding complications were frequent (15.2%) but major bleeding was rare (n=1; 0.2%). At 3 month, 95% of patients were still taking RX. Conclusion: In unselected patients in daily care, RX is effective and safe with low rates of cardiovascular or major bleeding events and low rates of treatment discontinuation in the first 180 days of treatment. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

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Abstract Abstract 1173 Background: Among other side effects, hair loss is a frequent complaint in patients receiving anticoagulant therapy with Vitamin-K antagonists (VKA) and sometimes also found in patients receiving low-molecular weight heparin (LMWH). Novel oral anticoagulants (NOAC) such as apixaban, dabigatran or rivaroxaban have been tested in large prospective phase-III trials including over 100.000 patients. Furthermore, after approval more than one million patients have been treated with these novel drugs in daily care. So far, hair loss has not been reported as a side effect of NOAC therapy. Using data from a large monocentric prospective NOAC registry, we evaluated incidence and risk profile of newly reported hair loss in patients receiving dabigatran or rivaroxaban therapy. Objectives: To evaluate the incidence of newly reported hair loss as a potential side effect of NOAC therapy in daily care. Patients and methods: In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data. Results: Until July 31th 2012, 938 patients were registered. Of these, 730 patients received rivaroxaban for atrial fibrillation (AF) or venous thromboembolism (demographic data in table 1) and 208 received dabigatran for AF. For these patients, current follow up data cumulate to 270.8 patient years of NOAC treatment. During follow-up visits, twelve patients spontaneously reported new hair loss (nine with rivaroxaban, 3 with dabigatran; demographic data in table 1). Therefore, total incidence of newly reported hair loss in our registry is 4.4 per 100 patient years. The mean time between start of NOAC and first report of hair loss was 68±76 days. Despite the fact that all twelve patients were female, uni- and multivariate analysis did not detect any correlation to baseline data including demographic data, co-morbidity or co-medication. Conclusion: In patients receiving long-term NOAC therapy, the incidence of hair loss as a spontaneously reported side effect is around 4.4 per 100 patient years. Before treatment initiation, patients should be informed about this potential side effect. Further data in larger cohorts are necessary to evaluate potential risk factors for hair loss with novel oral anticoagulants. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

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Background:Familial Mediterranean Fever (FMF) is characterized by recurrent attacks of fever and serositis as well as elevated inflammatory markers. FMF treatment goals according to EULAR are to control acute attacks and subclinical inflammation and to improve patients´ quality of life1. In a phase 3 pivotal study (CLUSTER study), FMF patients treated with the interleukin-1β inhibitor canakinumab met all these goals2.Objectives:The present study explores the long-term efficacy and safety of canakinumab (CAN) in routine clinical practice in pediatric (age ≥2 years) and adult FMF patients.Methods:RELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a three-year follow-up period. Patients with clinically confirmed diagnosis of FMF who routinely receive CAN were enrolled in order to evaluate effectiveness and safety of CAN under standard clinical practice conditions. Disease activity and remission by physicians´ assessment, disease activity, fatigue and impact on social life by patients’ assessment, inflammatory markers and AIDAI (Auto-Inflammatory Diseases Activity Index) score were recorded at baseline and were assessed at 6-monthly intervals within the three-year observation period of the study.Results:This interim analysis of FMF patients (N=54) enrolled by December 2020 includes baseline as well as 6-, 12- and 18-month data. Mean age in this cohort was 25 years (4−56 years) and the proportion of female patients was 46 % (N=25). At baseline, median duration of prior CAN treatment was 2.0 years (0−6 years).While physician ratings report around 62% of patients in disease remission, 52% with absent and 34% with mild-moderate disease activity, patient-reported disease activity decreased from moderate (PPA 3.0) to low (PPA 2.0) during the observation period. A decrease was observed regarding disease activity parameters, in particular in patients without prior CAN therapy (Table 1, Figure 1). A total of 11 serious adverse events was reported, of which one case of tonsillectomy was classified as drug-related.Conclusion:Interim data of FMF patients from the RELIANCE study, the longest running real-life CAN registry, confirm efficacy and safety of long-term CAN treatment.References:[1]Ozen S, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016;75:644–651. doi:10.1136/annrheumdis-2015-208690[2]De Benedetti F, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908–19.Table 1.Baseline characteristics and third interim analysis data of patients with FMFBaseline6 months12 months18 monthsAll patients | patients without prior CAN therapyNumber of patients, N5411357275163Number (%*) of patients in disease remission (physician assessment)18 (48.6)1 (20.0)19 (73.1)3 (75.0)13 (65.0)1 (50.0)8 (61.5)1 (100.0)Physician Global Assessment, percentage* of absent/mild-moderate/severe rating43/38/110/40/6065/27/050/50/055/35/00/50/046/46/00/100/0Patient assessment of current disease activity; 0–10, median (min; max)3.0 (0; 10)7.0 (0; 10)2.5 (0; 7)2.0 (0; 5)2.0 (0; 7)2.0 (0; 2)2.0 (0; 6)0.5 (0; 1)Patient assessment of current fatigue; 0–10, median (min; max)5.0 (0; 10)5.0 (0; 9)3.5 (0; 10)3.0 (1; 6)3.0 (0; 10)0.0 (0; 4)3.0 (0; 7)0.5 (0; 1)Number (%*) of patients without impairment of social life by the disease19 (46.3)3 (37.5)18 (66.7)3 (75.0)14 (66.7)4 (80.0)5 (55.6)2 (66.7)CRP, median (mg/dl)0.21.10.20.10.20.00.10.5SAA, median (mg/dl)0.76.80.80.40.80.60.60.7ESR, median (mm/h)9.018.56.05.05.54.08.05.0SAENumber of eventsIncidence rate per 100 patient yearsTotal1116.23Arthritis57.38SARS-CoV-2 infection22.95Familial Mediterranean Fever11.48Intestinal Hemorrhage11.48Pyrexia11.48Tonsillectomy (SADR)11.48*not reported for all patientsCRP, c-reactive protein; ESR, erythrocyte sedimentation rate; n. a., not annotated; SAA, serum amyloid A; SADR, serious adverse drug reaction; SAE, serious adverse eventDisclosure of Interests:Jörg Henes Consultant of: Novartis, AbbVie, Sobi, Roche, Janssen, Boehringer-Ingelheim, Grant/research support from: Novartis, Roche, J. B. Kuemmerle-Deschner Consultant of: Novartis, AbbVie, Sobi, Grant/research support from: Novartis, AbbVie, Sobi, Tilmann Kallinich Consultant of: Sobi, Novartis, Roche, Grant/research support from: Novartis, Frank Dressler Consultant of: Abbvie, Mylan, Novartis, Pfizer, Grant/research support from: Novartis, Frank Weller-Heinemann: None declared, Birgit Kortus-Goetze Consultant of: Novartis, Ivan Foeldvari Consultant of: Novartis, Gerd Horneff Speakers bureau: bbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Grant/research support from: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Markus Hufnagel Grant/research support from: Novartis, Florian Meier Speakers bureau: Novartis, Julia Weber-Arden Employee of: Novartis, Norbert Blank Consultant of: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, Grant/research support from: Novartis, Sobi

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Abstract Background and aim of the study. Telomerase inhibition is a novel promising anticancer strategy which has been pursued using antisense oligonucleotides and more recently pharmacological inhibitors. BIBR-1532 is a mixed-type non-competitive inhibitor of the catalytic subunit of telomerase (h-TERT). In solid tumor cell lines, BIBR-1532 successfully induced telomere shortening and growth inhibition (Damm K et al, The Embo J, 2001). The activity of BIBR-1532 has not been so far evaluated in hematological cancers. Aim of this study is to evaluate the activity of this compound in cell lines derived from B-cell lymphoid tumors. These neoplasms are an interesting model to investigate BIBR1532 since they show marked differences in their telomere lenght according to GC origin (i.e. GC-derived have long telomeres and extra GC-derived have short telomeres)(Ladetto et al Blood 2004). Methods. We employed two extra-GC derived cell lines (the multiple myeloma KMS-11 and the chronic lymphocytic leukemia JVM-2 provided respectively by M. Massaia MD and C Carlo Stella MD) and two GC-derived cell lines (the Burkitt’s Lymphoma CA46 and the follicular lymphoma cell line DHL16 provided by J.G. Gribben MD). All the four cell lines were h-TERT positive. BIBR-1532 (kindly provided by Klaus Damm MD and Jacques van Meel, PhD, Boehringer Ingelheim Pharma, Germany) was administrated thrice a week to the standard concentration of 10μM. Cells were cultured for at least 80 mitotic divisions both in presence and absence of the agent. Cell growth was assessed three times a week. Aliquots of cultured cells were taken approximately every 20 days for telomere length evaluation. Cells were also assessed using the propidium iodide assay to verify whether growth inhibition was due to apotosis or prolipherative arrest. Results. As expected based on their GC-status, the four cell lines had different baseline telomere length (CA46: 6500bp DHL 16: 7000bp KMS11 3200bp, JVM-2 3500). When cells were cultured without BIBR 1532 no significant telomere shortening occurred over the whole culture period. In the presence of BIBR-1532, cell lines approximately lost 32bp at each mitotic division. After 20 mitoses KMS-11 and JVM-2 underwent marked and progressive growth inhibition with a clear plateau effect after 50 to 55 mitoses. In contrast no growth inhibition was noticed in GC-derived cell lines despite a similar degree telomere erosion. Growth inhibition in cell lines responsive to BIBR-1532 was mostly associated with G1 arrest. Conclusions: These results are the first reported experience on the use of BIBR1532 on B-lymphoid cell lines and indicate that: a) BIBR1532 effectively induces telomere shortening in lymphoid tumors; b) in extra-GC telomere erosion quickly lead to pharmacologically-induced senescence with marked growth inhibition; c) GC-derived lymphoid cell lines are effectively protected from pharmacological senescence induced by BIBR 1532 due to their long telomeres. These results indicate that telomerase inhibitors require extensive evaluation as anti-cancer agents in extra-GC-derived lymphoid tumors.

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Abstract Systemic mastocytosis (SM) is a myeloid neoplasm characterized by abnormal growth and accumulation of mast cells (MC) in various internal organs. In most patients, the D816V-mutated variant of c-KIT, which mediates resistance against several tyrosine kinase (TK) inhibitors like imatinib, is found. In advanced SM, the response of neoplastic MC to conventional drugs is poor and the prognosis is grave. Therefore current research is attempting to identify novel targets in neoplastic MC. Polo-like kinase 1 (Plk-1) is a serine/threonine kinase that plays an essential role in mitosis and has recently been introduced as a new target in myeloid leukemias. In the present study, we analyzed expression and function of Plk-1 in neoplastic human MC, and asked whether Plk-1 can serve as a target of therapy in SM. As determined by immunohistochemistry, primary neoplastic MC were found to display activated/phosphorylated Plk-1 in all patients examined (n=5). The human MC leukemia cell line HMC-1 was also found to exhibit activated Plk-1. In addition, we found that primary neoplastic MC as well as HMC-1 cells express Plk-1 mRNA in RT-PCR experiments. As assessed by 3H-thymidine-uptake experiments, the Plk-1-targeting drug BI 2536 (Boehringer Ingelheim GmbH, Germany) was found to inhibit the proliferation of HMC-1 cells in a dose-dependent manner (IC50 5–15 nM). The effect of BI 2536 was seen in both subclones of HMC-1, i.e. in HMC-1.1 cells displaying KIT G560V (but not KIT D816V), and HMC-1.2 cells exhibiting both KIT G560V and KIT D816V, with comparable IC50 values. Moreover, BI 2536 was found to inhibit the proliferation of primary neoplastic cells, with IC50 values ranging between 5 and 50 nM. The growth-inhibitory effects of BI 2536 on HMC-1 cells were found to be associated with mitotic arrest and G2-M cell cycle arrest as well as consecutive apoptosis. In normal bone marrow or peripheral blood mononuclear cells, neither mitotic cell arrest nor apoptosis were observed after treatment with BI 2536. In a consecutive phase of the study, we asked whether combined targeting of KIT D816V and Plk-1 would lead to synergistic drug-interactions. For this purpose, HMC-1 cells and primary neoplastic MC were coincubated with BI 2536 and midostaurin (PKC412), a multitargeted kinase inhibitor that blocks KIT D816V TK activity. In these experiments, BI 2536 was found to synergize with midostaurin in counteracting the proliferation of HMC-1 cells and primary neoplastic MC. In conclusion, our data show that activated Plk-1 is detectable in MC neoplasms and plays a role in cell cycle progression and viability of neoplastic MC. Targeting of Plk-1 with BI 2536 leads to growth inhibition and apoptosis in neoplastic MC. Furthermore, BI 2536 synergizes with midostaurin in counteracting growth of neoplastic MC. Targeting of Plk-1 may be an attractive new pharmacologic concept in advanced SM.

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Abstract Background and Objective: No-VKA oral anticoagulants (NOAC) have been approved for acute and extended treatment of venous thromboembolism (VTE) or long-term anticoagulation in atrial fibrillation (AF). A major concern of physicians is the fear of uncontrolled bleeding or cardiovascular events during NOAC therapy resulting in fatal outcomes. We evaluated causes of death in a large cohort of NOAC registry patients. Methods: The prospective NOAC registry was initiated in November 2011. A network of more than 230 physicians in the district of Saxony, Germany, enrol up to 3000 patients in the registry, which are prospectively followed by the central registry office for up to 36 months. Every death was centrally adjudicated and categorized according to standard definitions. Results: Until June 30th 2014, 2667 patients were enrolled into the registry. Of these, 1818 (68.2%) patients received rivaroxaban, 348 (13.0%) received dabigatran and 501 (18.8%) received apixaban. NOAC indication was atrial fibrillation (AF) in 2025 (75.9%) cases, venous thromboembolism (VTE) in 609 (22.8%), and other indications in 33 (1.2%) cases. Patients had a mean age of 71.9 years (range 14–100y) and 1415 (53.1%) patients were male. At present, 18396 completed FU correlate to 9087.9 patient years. During follow-up, 173 patients died (1.9 per 100 patient years). Causes of death are presented in table 1. Cardiovascular death was the most common cause of death but mainly consisted of sudden cardiac death and chronic heart failure and rarely consisted of acute thromboembolic events. Fatal bleeding accounted for 7.5% of all fatalities. More than 34% of deaths could be attributed to acute infections or terminal malignant disease. Conclusion: In patients receiving NOAC therapy, mortality mainly relates to age, sudden cardiac death, malignant disease or acute infections. Thromboembolic events and fatal bleeding together account for only 13.2% of all fatalities, indicating the road therapeutic window for NOACs even in terminally ill patients. Table 1: causes of death in all patients and in actively anticoagulated patients in the Dresden NOAC registry Cause of death All deathsn=173 deaths during anticoagulant treatment (NOAC and other anticoagulation)n= 125 fatal cardiovascular event sudden cardiac death 32/173 (18.5) 22/125 (17.6) stroke 4/173 (2.3) 3/125 (2.4) ACS 3/173 (1.7) 2/125 (1.6) VTE 3/173 (1.7) 2/125 (1.6) Other fatal CV (e.g. chronic heart failure) 31/173 (17.9) 23/125 (18.4) fatal bleed 13/173 (7.5) 12/125 (9.6) terminal malignant disease 29/173 (16.8) 20/125 (16.0) age related death 19/173 (11.0) 12/125 (9.6) infection/sepsis 31/173 (17.9) 22/125 (17.6) other 8/173 (4.6) 7/125 (5.6) Figure 1: causes of death in all patients (1a) and more detailed analysis of the type of cardiovascular death (1b) Figure 1:. causes of death in all patients (1a) and more detailed analysis of the type of cardiovascular death (1b) Figure 2 Figure 2. Disclosures Werth: Bayer: Honoraria. Köhler:Bayer: Honoraria. Beyer-Westendorf:Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding.

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Abstract Background: Glycogen-storage disease 1b (GSD 1b) is characterized by neutropenia, hepatomegaly, hypoglycemia, enterocolitis and recurrent severe infections. For more than 25 years, many GSD 1b patients worldwide have been treated with granulocyte colony-stimulating factor (G-CSF). Methods: The Severe Chronic Neutropenia International Registry (SCNIR) enrolls and prospectively follows GSD 1b patients with both severe (ANC&lt; 0.5 x 109/L) and mild or moderate neutropenia (ANC&lt; 1.5 x 109/L). For this report we analyzed records for 83 patients enrolled through the SCNIR offices in Seattle, Washington and Hannover, Germany. Findings - Clinical outcomes: Overall most patients and parents report very favorable outcomes with increases in neutrophils, reduced infections, reduced symptoms of enterocolitis and improved quality of life. Neutropenia: Because splenomegaly may increase markedly with G-CSF treatment, clinical experience dictates that the G-CSF dose should be carefully monitored to maintain the ANC at 1.0 to 2.0 x 109/L. Summary data for treatment of 83 patients are shown in Table 1. Myeloid malignancies: We assessed the risk of GSD 1b patients developing myeloid malignancies from review of the medical literature and patients prospectively followed through the SCNIR. We identified 1 case of AML prior to availability of G-CSF and 6 cases of AML in G-CSF treated patients, 4 from the cohort followed prospectively by the SCNIR. Table 2 shows detailed data for the 7 patients with GSD1b who have developed AML. Conclusions: In the 83 SCNIR patients followed for a mean (median) of 12.2 (11.0) years there are 4 cases (4/83, 4.8%) of AML, or 1 case/253 years of G-CSF treatment. This is lower than the estimated risk of evolution to AML in the major genetic subgroups of severe congenital neutropenia treated with G-CSF, e.g., harboring ELANE, HAX1, SDS mutations . The numbers of patients in other genetic subgroups, such as G6PC3, JAGN1, TCIRG1, etc. are too small to make any reliable comparison about the risk of developing leukemia. (Skokowa J et al. Nat Rev Dis Primers. 2017 Jun 8. doi: 10.1038/nrdp.2017.32. [Epub ahead of print]). Disclosures Dale: Amgen: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Editor, Current Opinions in Hematology, Honoraria; Cellerant: Membership on an entity's Board of Directors or advisory committees; Genzyme (now owned by Sanofi-Aventis): Consultancy, Patents & Royalties, Research Funding; Genkyotex: Other: DSMB (work completed 6/2015); Hospira: Consultancy; Prolong: Consultancy; Boheringer-Ingelheim: Consultancy; Coherus: Consultancy; Omeros: Other: DSMB; Shire: Other: Independent Review Board; X4Pharma: Research Funding; Philips: Research Funding; Wolter Kluwer: Other: Editor, Current Opinions in Hematology; WedMD/Medscape: Membership on an entity's Board of Directors or advisory committees; National Institutes of Health: Research Funding; University of Washington: Employment, Research Funding; American College of Physicians: Other: Editor and author; GlaxoSmithKline: Equity Ownership; Johnson&Johnson: Equity Ownership. Weinstein: Vitaflo: Research Funding; Dimension Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Background:Gastroesophageal reflux (GER) is common in SSc and thus treatment with anti-acid therapy (AAT) is frequent. An association between GER and the development / progression of SSc-ILD has been hypothesized. However, outcomes of AAT on disease progression in SSc-ILD has only sparsely been studied.Objectives:Methods:The German Network for Systemic Scleroderma (DNSS), which includes SSc pts. prospectively, was analyzed for SSc-ILD. Those without progression at ILD 1stdiagnosis were categorized in AAT vs. no-AAT users and disease outcome was assessed.Results:SSc-ILD was reported in 1165 (28.2%) out of 4131 pts. 712 of SSc-ILD pts had no disease progression at ILD 1stdiagnosis. 567 used AAT while 145 did not. Baseline characteristics were similar between groups with regards to age (mean 54.7 years), BMI, time since SSc diagnosis and immunosuppressant use. Significant differences in no-AAT vs. AAT were found for gender (male 18% vs. 25%, p=0.05), SSc subtype (p=0.002, diffuse more common in AAT), lung function (DLCO 66% vs. 58%, p=0.001; FVC 86% vs. 77%, p=0.001), mRSS (8 vs. 11.5, p<0.01), esophageal involvement (32% vs. 56%, p<0.01) and steroid use (30% vs. 43%, p=0.005). While mortality did not differ between groups (3.9%, p= 0.59), disease progression was more common in the AAT group than in no-AAT users (24.5% vs. 13%, p=0.03). Furthermore, there was a significant difference in decline of FVC≥10% with 30% in the AAT compared to 14% in no-AAT (p=0.018); a decline in DLCO≥15% was more common in the AAT group by trend (23% vs. 14%, p=0.087).Conclusion:While results may have partially been biased by differences in baseline characteristics, this current analysis disfavors the approach of AAT use for SSc-ILD.Disclosure of Interests:Michael Kreuter Grant/research support from: Roche, Boehringer, Consultant of: Roche, Boehringer, Speakers bureau: Boehringer, Roche, Francesco Bonella Grant/research support from: Boehringer, Consultant of: Boehringer, Roche, Bristol MS, Galapagos, Speakers bureau: Boehringer, Roche, Gabriela Riemekasten Consultant of: Cell Trend GmbH, Janssen, Actelion, Boehringer Ingelheim, Speakers bureau: Actelion, Novartis, Janssen, Roche, GlaxoSmithKline, Boehringer Ingelheim, Pfizer, Ulf Müller-Ladner Speakers bureau: Biogen, Jörg Henes Grant/research support from: Novartis, Roche-Chugai, Consultant of: Novartis, Roche, Celgene, Pfizer, Abbvie, Sanofi, Boehringer-Ingelheim,, Elise Siegert Grant/research support from: Actelion, Consultant of: AEC, Speakers bureau: NA, Claudia Guenther: None declared, Ina Koetter Grant/research support from: Novartis, Roche, Speakers bureau: Abbvie, Actelion, Celgene, MSD, UCB, Sanofi, Lilly, Pfizer, Novartis, Chugai, Roche, Boehringer, Norbert Blank Speakers bureau: Actelion, Roche, Boehringer, Pfizer, Chugai, Christiane Pfeiffer: None declared, Marc Schmalzing: None declared, Gabriele Zeidler: None declared, PETER KORSTEN Grant/research support from: Novartis, Juarms GmbH, Consultant of: Abbvie, Pfizer, Lilly, BMS, Speakers bureau: Abbvie, Pfizer, chugai, BMS, Lilly, Sanofi aventis, Laura Susok: None declared, Aaron Juche: None declared, Margitta Worm Consultant of: Mylan Gemany, Bencard Allergie, BBV Technologies S.A., Novartis, Biotest, Sanofi, Aimmune Therapies, Regeneron, Speakers bureau: ALK-Abello, Novartis, Sanofi, Biotest, Mylan, Actelion, HAL Allergie, Aimmune Bencard Allergie, Ilona Jandova: None declared, Jan Ehrchen: None declared, Cord Sunderkoetter: None declared, Gernot Keyszer: None declared, Andreas Ramming Grant/research support from: Pfizer, Novartis, Consultant of: Boehringer Ingelheim, Novartis, Gilead, Pfizer, Speakers bureau: Boehringer Ingelheim, Roche, Janssen, Tim Schmeiser Speakers bureau: Actelion, UCB, Pfizer, Alexander Kreuter Speakers bureau: Sanofi, Abbvie, Merck Sharp&Dohme, Boehringer, Kathrin Kuhr: None declared, Hanns-Martin Lorenz Grant/research support from: Consultancy and/or speaker fees and/or travel reimbursem*nts: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly. Scientific support and/or educational seminars and/or clinical studies: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly, Baxter, SOBI, Biogen, Actelion, Bayer Vital, Shire, Octapharm, Sanofi, Hexal, Mundipharm, Thermo Fisher., Consultant of: see above, Pia Moinzadeh: None declared, Nicolas Hunzelmann Speakers bureau: Actelion, Boehringer

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Abstract Introduction Tissue factor (TF) is a protein expressed by perivascular cells including pericytes (PCs) where it is responsible for initiation of blood coagulation. Many conditions have been associated with increased cellular TF expression, including inflammation, malignant transformation and tumor angiogenesis. However, our previous studies have shown that TF expression in PCs paradoxically decreases during wound healing.{McDonald:2008fy} To date, no studies have demonstrated the mechanism responsible for the downregulation of TF expression in any cell type. Because angiogenesis is a critical occurrence during wound healing, pro-angiogenic cytokines are likely candidates responsible for the downregulation of TF expression in PCs. Therefore, several well-characterized pro-angiogenic cytokines were studied for their effects on TF expression and activity in PCs. Materials and Methods PCs (PromoCell, Heidielberg, Germany) were treated directly with each of five individual angiogenic factors: angiopoietin 2 (ANG2, 1-1000ng/mL), basic fibroblast growth factor (bFGF, 0.1-10 ng/mL), platelet derived growth factor (PDGF, 1-1000ng/mL), transforming growth factor beta (TGFB 0.2-200 ng/mL), and vascular endothelial growth factor (VEGF, 1-1000ng/mL). Serum rich media was used for all experiments and all treatments lasted 24 hours. PCs were assessed for TF activity using a coagulation factor X (FX) activation assay. In addition to direct treatment, PCs were assayed for TF protein expression following treatment in a co-culture model. Briefly, PCs were plated in a standard tissue culture treated plate. Human Dermal Microvessel Endothelial Cells (ECs) were placed inside a 0.4um polyester membrane transwell insert, which was placed into the well containing the PCs. This allowed for communication via soluble factors through the membrane, but not direct contact between the two cell types. Co-cultured ECs were treated with angiogenic factors as described above. Additionally, ECs cells were cultured for 24 hours with bFGF and the conditioned media was collected, cleared of cells, and applied to cultured pericytes. Following treatment PCs were lysed and whole cell lysate was separated by polyacrylamide gel electrophoresis and Western blot (WB). WB membranes were probed with anti-TF antibody for total protein determination. Actin was used as a loading control for all blots. Results Following direct stimulation for 24 hours, none of the angiogenic growth factors assayed produced a reduction in TF activity or antigen, even at supraphysiological concentrations. Following treatment of ECs in a co-culture model neither ANG2, PDGF, TGFB, nor VEGF produced a change in TF expression in pericytes. However, treatment of ECs with bFGF for 24 hours produced a marked decrease in total TF protein expression in co-cultured PCs. Four independent experiments confirmed the decreased expression of TF under these conditions. In contrast, bFGF conditioned EC media applied to PCs for 24 hours resulted in no change in TF protein expression. Conclusions The observation that bFGF stimulation of co-cultured ECs, but not direct stimulation, causes a decrease in TF protein expression in PCs suggests that a soluble mediator is responsible for the effect. The finding that a decrease in TF expression was not observed in PCs treated with bFGF-conditioned ECs media suggests that a labile mediator may be responsible. Disclosures: Hoffman: Novo Nordisk: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Boehringer Ingelheim: Research Funding.