Value through Innovation18 September 2014

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

49 publications regarding Clinical Studies
  • Author:
    Knudsen S; Jensen T; Hansen A; Mazin W; Lindemann J; Kuter I; Laing N; Anderson E
    Title:
    Development and validation of a gene expression score that predicts response to fulvestrant in breast cancer patients
    Source:
    PLoS ONE 9 (2) atr.no. e87415 (2014)
    Abstract:
    Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = -0.63, P = 0.003). The predictor was applied to tumor biopies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced, estrogen-receptor-positive breast cancer most likely to respond to fulvestrant. © 2014 Knudsen et al.
  • Author:
    Gallagher AM; Van Staa TP; Murray-Thomas T; Schoof N; Clemens A; Ackermann D; Bartels DB
    Title:
    Population-based cohort study of warfarin-treated patients with atrial fibrillation: Incidence of cardiovascular and bleeding outcomes
    Source:
    BMJ Open art.no.e003839 (2014)
    Abstract:
    Objectives: Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice. Design: Pharmacoepidemiological cohort study using observational data. Methods/setting: This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and oters. The main focus of the study was on outcome events requiring hospitalisation using the HES data. Results: The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal. Conclusions: This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective.
  • Author:
    Mück T
    Title:
    Useful combination in cold symptoms? Study on acetylsalicylic acid plus pseudoephedrine [Sinnvolle kombination bei erkältungssymptomen? Studie zu acetylsalicylsäure plus pseudoephedrin]
    Source:
    Dtsch Apoth Ztg 153 (38), 44-45 (2013)
    Abstract:
    no abstract available
  • Author:
    Roden M; Weng J; Eilbracht J; Delafont B; Kim G; Woerle HJ; Broedl UC
    Title:
    Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial
    Source:
    Lancet Diabetes Endocrinol Article in press (2013)
    Abstract:
    Background: We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. Methods: In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged .18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. Findings: Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0.74% (95% CI -0.88 to -0.59; p<0.0001) for empagliflozin 10 mg, -0.85% (-0.99 to -0.71; p<0.0001) for empagliflozin 25 mg, and -0.73% (-0.88 to -0.59; p<0.0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). Interpretation: Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. Funding: Boehringer Ingelheim and Eli Lilly. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Hijazi Z; Oldgren J; Wallentin L; Andersson U; Connolly SJ; Yusuf S; Ezekowitz MD; Hohnloser SH; Reilly PA; Vinereanu D; Siegbahn A
    Title:
    Response to Ietter regarding article, "cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: A randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy"
  • Author:
    Lang I; Köhne C-H; Folprecht G; Rougier P; Curran D; Hitre E; Sartorius U; Griebsch 1; Van Cutsem E
    Title:
    Quality of life analysis in patients with KRAS wild-type metastatic colorectal cancer treated first-line with cetuximab plus irinotecan, fluorauraeil and leucovorin
    Source:
    Eur J Cancer 49 (2), 439-448 (2013)
    Abstract:
    Background: ln the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (Qol)was assessed, and associations with tumour response and survival were investigated. Patients and methods: The European Organization for Research and Treatment of Cancer Qoql uestionnaire­ core 30 was used, focusing on global health status (GHS)/Qoal nd social functioning scales. Radiological responsewas assessed by an independent review committee. Results: Qowl as evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/Qo(lP = 0.12) and social functioning scores (P = 0.43) between the treatment arms. ln additional analyses: early skin reactions in patients receiving cetuximab Background: ln the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (Qol)was assessed, and associations with tumour response and survival were investigated. Patients and methods: The European Organization for Research and Treatment of Cancer Qoql uestionnaire­ core 30 was used, focusing on global health status (GHS)/Qoal nd social functioning scales. Radiological responsewas assessed by an independent review committee. Results: Qowl as evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/Qo(lP = 0.12) and social functioning scores (P = 0.43) between the treatment arms. ln additional analyses: early skin reactions in patients receiving cetuximab did not significantly affect these Qosl cales, and tumour response was more common (58% versus 40%, P = 0.0002) and survivallonger (Hazard ratio 1.68, P < 0.0001) in asymptomatic compared with symptomatic patients at baseline. Adding cetuximab to FOLFIRI was associated with significantly higher tumour response irrespective of patient baseline symptomatic status, and enhanced symptom relieffrom baseline in those whose tumours had responded. Conclusion: Adding cetuximab to FOLFIRI improved response rate and survival without either improving or negatively impacting on GHS/QoL and social functioning. © 2012 Elsevier Ud. All rights reserved.
  • Author:
    Lacy BE; Wang F; Bhowal S; Schaefer E
    Title:
    On-demand hyoscine butylbromide for the treatment of self-reported functional cramping abdominal pain
    Source:
    Scand J Gastroenterol 48 (8), 926-935 (2013)
    Abstract:
    Objective. Hyoscine butylbromide (HBB) has been used for 60 years to treat cramping abdominal pain, but scientific evidence to support on-demand use is limited. The aim of this study was to identify a meaningful efficacy end point that differentiates between the effects of HBB (20-100 mg/day) and placebo when used on demand. Materials & methods. 175 patients were treated in a randomized, double-blind, placebo-controlled, two-arm parallel group study. After a 4-week run-in period, patients used HBB to treat 2 distinct episodes of abdominal pain associated with cramping (APC). Patients entered data into an electronic diary for up to 4 h/episode. Pain intensity was assessed using an 11-point numerical pain rating scale (NPRS). Patients were allowed to self-medicate with up to 4 additional doses of HBB every 30 min. Results. The adjusted mean difference for the change from baseline during the 4-h observation period for a reduction in abdominal pain was -0.7 (95% confidence interval (CI) -1.3, -0.1, p = 0.016) for episode 1 and -0.6 (95% CI -1.2, 0.0, p = 0.051) for episode 2. Patients in the HBB group recorded a clinically relevant reduction of at least 2 points on the NPRS (approximately 30% pain relief) earlier than patients in the placebo group (HBB: 45 min, placebo: 60 min). Reported adverse events were infrequent in both groups (10.2% and 10.3%). Conclusions. HBB is effective in the treatment of recurrent APC and is safe and well tolerated when used on demand. The change from baseline in the intensity of APC using the 11-point NPRS distinguished HBB from placebo. © 2013 Informa Healthcare.
  • Author:
    Sulkowski MS; Bourlière M; Bronowicki J-P; Asselah T; Pawlotsky J-M; Shafran SD; Pol S; Mauss S; Larrey D; Datsenko Y; Stern JO; Kukolj G; Scherer J; Nehmiz G; Steinmann GG; Böcher WO
    Title:
    Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial
    Source:
    Hepatology 57 (6), 2155-2163 (2013)
    Abstract:
    Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (&lt;1 log10 viral load [VL] drop at any time on treatment) or partial response (?1 log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI. Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL &lt;25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. In the 240 mg QD/LI group, a significantly higher proportion of mRVR patients rerandomized to 48 weeks' treatment achieved SVR compared with those assigned to 24 weeks treatment (72% versus 43%; P = 0.035). Rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were increased at 240 mg BID compared with the 240 mg QD dose. Faldaprevir discontinuations owing to adverse events occurred in 6%, 4%, and 23% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. Conclusion: Faldaprevir 240 mg QD with PegIFN/RBV was safe and tolerable and produced substantial SVR rates in prior null and partial responders. The 240 mg QD dose is currently undergoing phase 3 evaluation. © 2013 American Association for the Study of Liver Diseases.
  • Author:
    Sulkowski MS; Asselah T; Lalezari J; Ferenci P; Fainboim H; Leggett B; Bessone F; Mauss S; Heo J; Datsenko Y; Stern JO; Kukolj G; Scherer J; Nehmiz G; Steinmann GG; Böcher WO
    Title:
    Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial
    Source:
    Hepatology 57 (6), 2143-2154 (2013)
    Abstract:
    Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. © 2013 American Association for the Study of Liver Diseases.
  • Author:
    Kjeldsen SE; Schumacher H; Neldam S; Guthrie RM
    Title:
    Telmisartan/Hydrochlorothiazide Combination Therapy for the Treatment of Hypertension: A Pooled Analysis in Older and Younger Patients
    Source:
    J Clin Hypertens 15 (6), 380-388 (2013)
    Abstract:
    Older patients frequently receive angiotensin II receptor blocker/diuretic combinations to control blood pressure (BP), although there have been relatively few trials specifically examining this patient population. A pooled analysis was performed of data from 7 randomized trials of telmisartan/hydrochlorothiazide combinations or telmisartan monotherapy in older (65 years and older) and younger (younger than 65 years) patients to better understand the response of older patients to a telmisartan/hydrochlorothiazide combination. Telmisartan doses were 40 mg and 80 mg (T40 and T80). Hydrochlorothiazide doses were 12.5 mg and 25 mg (H12.5 and H25). A total of 3654 patients were included and the mean treatment duration was approximately 8 weeks. BP reductions with telmisartan/hydrochlorothiazide combinations were broadly similar in older and younger patients. In older patients, mean BP reductions from baseline were -30.1/-19.0 mm Hg with the T80/H25 combination and -21.7/-13.0 mm Hg with T80 monotherapy. Tolerability was similar regardless of age, and the incidence of adverse events in both older and younger patients was similar to placebo. The telmisartan/hydrochlorothiazide combination, particularly high-dose T80/H25, is effective and well tolerated in patients 65 years and older as well as in younger patients. © 2013 Wiley Periodicals, Inc.
  • Author:
    Bezemer I D; Roemer W H; Penning-van Beest F J A; van Eekelen E; Kramer M H H
    Title:
    INR control calculation: Comparison of Dutch and international methods
    Source:
    Neth J Med 71 (4), 194-198 (2013)
    Abstract:
    Results of trials with new oral anticoagulant drugs and vitamin K antagonists (VKA) might not be directly applicable to Dutch clinical practice due to the high level of control of anticoagulation in the Netherlands. In addition, the Dutch method for assessing anticoagulation control uses cross-sectional international normalised ratio (INR) test results while the method used in the trials is based on person-time. To enable comparisons, the two calculation methods were applied to INR data of a cohort of 5422 atrial fibrillation patients treated with VKA. Overall, 74% of test results and 77% of person-time were in the therapeutic range [2.0-3.5]. For the narrower target INR interval [2.5-3.5], 59% of test results and 61% of person-time were in range. It was only between two and six months after the start of treatment that the percentage of person-time in range was lower than the percentage of test results in range. Control of anticoagulation, expressed as a percentage of person-time spent in range, in this Dutch dataset was similar to recent trials with new oral anticoagulants, although it should be noted that the Dutch INR target is higher than the target in these trials. INR control as estimated by the two calculation methods (cross-sectional and longitudinal) was similar. © Van Zuiden Communications B.V. All rights reserved.
  • Author:
    Roskell NS; Samuel M; Noack H; Monz BU
    Title:
    Major bleeding in patients with atrial fibrillation receiving vitamin K antagonists: A systematic review of randomized and observational studies
    Source:
    Europace 15 (6), 787-797 Cited 1 time (2013)
    Abstract:
    Aims Clinical trials have shown that anticoagulation with vitamin K antagonists (VKAs), e.g. warfarin, decreases the risk of stroke in patients with atrial fibrillation (AF); however, increased bleeding risk is one of the safety concerns. The primary objective was to conduct a systematic review of the published literature, assessing the risk of major bleeding and mortality in patients with AF treated with VKAs. Methods and resultsOnline searches of MEDLINE, EMBASE, BIOSIS, and the Cochrane Library were performed to a pre-specified protocol from 1960 to March 2012 for randomized controlled trials (RCTs) and from January 1990 to March 2012 for observational studies. A total of 47 studies (16 RCTs and 31 observational studies) were included. Cumulative follow-up was 61 563 patient-years for RCTs and 484 241 patient-years for observational studies. The overall median incidence of major bleeding was 2.1 per 100 patient-years (range, 0.9-3.4 per 100 patient-years) for RCTs and 2.0 per 100 patient-years (range, 0.2-7.6 per 100 patient-years) for observational studies. With study year as a proxy for changing management patterns, some evidence of bleeding rates and/or their reporting increasing over time was noted. Mortality rates from observational studies were inadequately reported to allow comparison with those from RCT data. Conclusion The median rate of major bleeding in observational studies and RCTs is similar. The larger heterogeneity in bleeding rates observed in a real-life setting could reflect a high variability in standard of care of patients on VKAs and/or methodological differences between observational studies and/or variability in data sources. © 2012 The Author.
  • Author:
    Hu S; Zhan L; Liu B; Gao Y; Li Y; Tong R; Wu L; Yu B; Gao S
    Title:
    Economic burden of individual suffering from atrial fibrillation-related stroke in China
    Source:
    Value Health Reg Issues 2 (1), 135-140 (2013)
    Abstract:
    Objective: Atrial fibrillation (AF) is an important risk factor for stroke. The primary purpose of this study was to estimate the 1-year direct and indirect costs of ischemic stroke in Chinese patients with AF. Method: A total of 300 charts were selected and reviewed in 18 hospitals from neurology departments in six major cities of China nationwide. Patients with primary diagnosis of ischemic stroke and secondary diagnosis of AF were selected for review. A total of 63 patients were selected from the chart review pool and followed up for 1 year to record their resource utilization and absenteeism from work following discharge. Results: The mean±SD age of the cohort was 70.2±11.8 years, with an average hospitalization duration of stay of 17.9 days. The mean total direct cost for AF-related stroke was estimated at 30,438.3 China Yuan (CNY) per patient-year. The major cost driver for direct cost was stroke's acute hospitalization expense, which accounted for 61.5% (CNY 18,706.1). Among the seven patients not reaching the legal retirement age, the indirect cost per person-year totaled 16,838.9 CNY, most of which (63.0%) was a result of early retirement. The analysis also suggested that higher hospital ranking (based on the tier system), longer hospital stay, higher modified Rankin Scale score, taking surgery during hospitalization, receiving thrombolysis therapy, and incidence of complications such as pneumonia or cerebral edema predicted higher inpatient costs. Conclusions: Hospital costs due to strokes among patients with AF are the predominant contributor to the total direct cost, which is consistent with current hospital-centered treatment pattern in China. However, literature suggested that AF-induced strokes are highly preventable with drugs and clinical procedures, which highlights the importance of optimal clinical management of stroke prevention in patients with AF. © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
  • Author:
    Gelez H; Greggain-Mohr J; Pfaus J G; Allers K A; Giuliano F
    Title:
    Flibanserin treatment increases appetitive sexual motivation in the female rat
    Source:
    J Sex Med 10 (5), 1231-1239 (2013)
    Abstract:
    Introduction.: Flibanserin is a mixed 5-HT1A agonist/5-HT2A antagonist that has been developed for the treatment of hypoactive sexual desire disorder in women. Aim.: To assess the acute and chronic dose-response effects of flibanserin on measures of sexual desire and copulation in ovariectomized rats primed with estradiol benzoate (EB) alone or in combination with progesterone (P). Methods.: In Experiment 1, sexually experienced ovariectomized (OVX) rats at one testing site were rendered fully sexually receptive with EB+P priming and tested weekly with a sexually active male in bi-level pacing chambers following daily flibanserin treatment for 28 days. In Experiment 2, sexually experienced OVX rats at a different testing site received EB alone and were tested weekly with sexually active males following daily flibanserin treatment. Main Outcome Measures.: Female appetitive behaviors (solicitations, hops and darts, anogenital investigations), defensive behaviors, pacing, lordosis, and male copulatory responses (intromissions and ejaculations) were measured during each 30-minute copulation test. Results.: Acute flibanserin or 1 week of chronic flibanserin treatment did not modify sexual responses in fully (EB+P) or partially (EB-alone) primed females. After 2 weeks of chronic treatment, fully primed females displayed significantly more solicitations than the three other groups. After 3 weeks of chronic treatment, a significant increase in female solicitations was observed in both hormone-treatment groups. Conclusion.: This study shows the first evidence that chronic, but not acute, flibanserin treatment augments appetitive sexual behaviors in OVX female rats primed with EB+P or EB alone. Given the positive effect of flibanserin in clinical trials, these results confirm previous reports that solicitations in the female rat are a predictive animal model of human female sexual desire. © 2013 International Society for Sexual Medicine.
  • Author:
    Ring A; Rathgen K; Stangier J; Reilly P; Clemens A; Friedman J
    Title:
    Dabigatran does not prolong the QT interval with supratherapeutic exposure: A thorough qt study in healthy subjects
    Source:
    Clin Drug Invest 33 (5), 333-342 (2013)
    Abstract:
    Background: Dabigatran etexilate is a pro-drug of the oral reversible direct thrombin inhibitor dabigatran that interacts with the active site in the catalytic domain of the thrombin molecule. Objective: To assess the electrophysiological effects of therapeutic and supratherapeutic doses of dabigatran etexilate in healthy subjects, a thorough QT study was performed. Methods: In this single-centre, blinded, placebo- and active-controlled, four-period, crossover study, 40 healthy Caucasian subjects (20 women and 20 men) received single oral doses of dabigatran etexilate (150 mg and 600 mg), moxifloxacin 400 mg (positive control) or placebo, in a randomized order. Electrocardiogram (ECG) profiles were recorded at baseline and during the randomized study treatment in each period. The individually heart-rate-corrected QT interval (QTcI) was the primary parameter. The primary endpoint was the mean of these QTcI values obtained at 1.5, 2 and 3 h following study drug administration minus the mean of the time-matched QTcI values obtained at baseline day -1. The hypothesis tested was that the difference between each of the two doses of dabigatran etexilate (150 mg and 600 mg) and placebo, for the mean time-matched change from baseline (CfB) of QTcI between 1.5 and 3 h (the primary endpoint), was greater than or equal to 10 ms. Secondary endpoints were the time-matched CfB of QTcI between 0.5 and 24 h post-dose. Results: All subjects completed the study without premature discontinuation and all treatments were well tolerated. Following dabigatran etexilate administration, the mean values of the placebo-adjusted time-matched CfB of QTcI between 1.5 and 3 h post-dose were close to 0; the upper bound of the two-sided 90 % confidence interval (CI) was 1.4 ms for dabigatran etexilate 150 mg and 1.3 ms for dabigatran etexilate 600 mg. The placebo-adjusted time-matched CfB of QTcI remained close to 0 at all time points, and all 90 % CIs were between -5 ms and 5 ms, well below the pre-defined non-inferiority margin of 10 ms. Conclusion: This thorough QT study demonstrated that therapeutic and fourfold supratherapeutic doses of dabigatran etexilate do not prolong QT intervals. © 2013 The Author(s).
  • Author:
    Esperester A; Schütt T; Ottilinger B
    Title:
    The evidence of the clinical effectiveness of edema-protective agents and their pitfalls [Der Nachweis der klinischen Wirksamkeit von Ödemprotektiva und seine Tücken]
    Source:
    Med Monatsschr Pharm 36 (2) (2013)
    Abstract:
    no Abstract available
  • Author:
    Johnson B H; Smoyer-Tomic K E; Siu K; Walker D R; Sander S; Huse D; Smith D M; Song X; Amin A
    Title:
    Readmission among hospitalized patients with nonvalvular atrial fibrillation
    Source:
    Am J Health-Syst Pharm 70 (5), 414-422 (2013)
    Abstract:
    Purpose: Hospital readmission rates for patients with nonvalvular atrial fibrillation (NVAF), as well as reasons and risk factors for rehospitalization, were investigated. Methods: Demographic, clinical, and prescription claims data on patients hospitalized for atrial fibrillation (AF) over a five-year period were extracted from insurance claims databases; from that data set, a subset of adults with NVAF on whom continuous data were available before and after the index admission (n = 6439) was identified, and their 30-day readmission rate was examined. Results: The overall 30-day readmission rate was 18.0%. The five most common readmission diagnoses (grouped per International Classification of Diseases codes) were general and other nonspecific symptoms (12.8% of readmitted patients), AF (10.2%), ischemic heart disease (7.2%), heart failure (7.1%) and cerebrovascular disease (6.0%). Controlling for demographic and clinical variables, index admission factors associated with an increased risk of readmission included a longer hospital length of stay, higher Charlson Comorbidity Index scores, and admission through the emergency room (p ? 0.01 for all). For the subset of patients discharged from the index admission to home self-care (n = 1161), no individual follow-up care measure evaluated (a physician or other medical office visit, International Normalized Ratio testing, filling an anticoagulant prescription) taken within 7 days of discharge correlated with reduced readmission risk during postdischarge days 8-30. Conclusion: The 30-day readmission rate for patients hospitalized with NVAF was comparable to rates previously documented among patients with other cardiac conditions. Symptoms, AF, ischemic heart disease, heart failure, and cerebrovascular disease were the most common reasons for readmission. Copyright © 2013, American Society of Health-System Pharmacists, Inc. All rights reserved.
  • Author:
    Araki E; Kawamori R; Inagaki N; Watada H; Hayashi N; Horie Y; Sarashina A; Thiemann S; von Eynatten M; Dugi K; Woerle H-J
    Title:
    Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes
    Source:
    Diabetes Obes Metab 15 (4), 364-371 (2013)
    Abstract:
    Aims: In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), linagliptin 5 and 10mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of linagliptin over 52weeks. Methods: Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to linagliptin 5 or 10mg, while the linagliptin groups maintained dosage. Results: In all, 540 patients received at least one dose of linagliptin 5 or 10mg and 494 completed the extension. Long-term treatment with linagliptin was well tolerated; adverse events (AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with linagliptin 5 and 10mg. Conclusions: These findings provide evidence for the safety and tolerability of oral linagliptin at either 5 or 10mg for up to 52weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain. © 2012 Blackwell Publishing Ltd.
  • Author:
    Lee S; Monz B U; Clemens A; Brueckmann M; Lip G Y H
    Title:
    Representativeness of the dabigatran, apixaban and rivaroxaban clinical trial populations to real-world atrial fibrillation patients in the United Kingdom: A cross-sectional analysis using the General Practice Research Database
    Source:
    BMJ Open 2 (6) (2012)
    Abstract:
    Objective: Three oral anticoagulants have reported study results for stroke prevention in patients with atrial fibrillation (AF) (dabigatran etexilate, rivaroxaban and apixaban); all demonstrated superiority or non-inferiority compared with warfarin (RE-LY, ARISTOTLE and ROCKET-AF). This study aimed to assess the representativeness for the real-world AF population, particularly the population eligible for anticoagulants. Design: A cross-sectional database analysis. Setting: Dataset derived from the General Practice Research Database (GPRD). Primary and secondary outcomes measure: The proportion of real-world patients with AF who met the inclusion/exclusion criteria for RE-LY, ARISTOTLE and ROCKET-AF were compared. The results were then stratified by risk of stroke using CHADS2 and CHA2DS2-VASc. Results: 83 898 patients with AF were identified in the GPRD. For the population at intermediate or high risk of stroke and eligible for anticoagulant treatment (CHA 2DS2-VASc ?1; n=78 783 (94%)), the proportion eligible for inclusion into RE-LY (dabigatran etexilate) was 68% (95% CI 67.7% to 68.3%; n=53 640), compared with 65% (95% CI 64.7% to 65.3%; n=51 163) eligible for ARISTOTLE (apixaban) and 51% (95% CI 50.7% to 51.4%; n=39 892) eligible for ROCKET-AF (rivaroxaban). Using the CHADS2 method of risk stratification, for the population at intermediate or high risk of stroke and eligible for anticoagulation treatment (CHADS2 ?1; n=71 493 (85%)), the proportion eligible for inclusion into RE-LY was 74% (95% CI 73.7% to 74.3%; n=52 783), compared with 72% (95% CI 71.7% to 72.3%; n=51 415) for ARISTOTLE and 56% (95% CI 55.6% to 56.4%; n=39 892) for ROCKET-AF. Conclusions: Patients enrolled within RE-LY and ARISTOTLE were more reflective of the 'real-world' AF population in the UK, in contrast with patients enrolled within ROCKET-AF who were a more narrowly defined group of patients at higher risk of stroke. Differences between trials should be taken into account when considering the applicability of findings from randomised clinical trials. However, assessing representativeness is not a substitute for assessing generalisibility, that is, how well clinical trial results would translate into effectiveness and safety in everyday routine care.
  • Author:
    Nalysnyk L; Cid-Ruzafa J; Rotella P; Esser D
    Title:
    Incidence and prevalence of idiopathic pulmonary fibrosis: Review of the literature.
    Source:
    Eur Respir Rev 21 (126), 355-361 (2012)
    Abstract:
    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown aetiology.. lt is a rare disease, and its incidence and prevalence are not clear. Therefore, we sought to review the published evidence on the global epidemiology of IPF. A comprehensive review of English language literature was performed by searching Medline and EMBASE for studies on IPF epidemiology published between January 1990 and August 2011. Studies providing quantitative data on IPF incidence and/or prevalence were identified and key data collected. 15 studies reporting on the incidence and/or prevalence of IPF were identified and summarised. IPF prevalence estimates in the USA varied between 14 and 27.9 cases per 100,000 population using narrow case definitions, and 42.7 and 63 per 100,000 population using broad case definitions. In Europe, IPF prevalence ranged from 1.25 to 23.4 cases per 100,000 population. The annual incidence of IPF in the USA was estimated at 6.8-8.8 per 100,000 population using narrow case definitions and 16.3-17.4 per 100,000 population using broad case definitions. In Europe, the annual incidence ranged between 0.22 and 7.4 per 100,000 population. IPF prevalence and incidence increase with age, are higher among males and appear to be on the increase in recent years. IPF is an orphan disease that affects a potentially increasing number of people in Europe and the USA. The observed variability in IPF incidence and prevalence may be explained by the differences in diagnostic criteria used, case definition, study population and study design. © 2012
  • Author:
    Azoulay L; Assimes TL; Yin H; Bartels DB; Schiffrin EL; Suissa S
    Title:
    Long-term use of angiotensin receptor blockers and the risk of cancer.
    Source:
    PLoS ONE 7 (12) art.no.50893 (2012)
  • Author:
    Dahl OE; Kurth AA; Rosencher N; Noack H; Clemens A; Eriksson BI
    Title:
    Erratum to: Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip relacement surgery. (International Orthopaedics (DOI: 10.1007/s00264-011-1393-5).
    Source:
    Int Orthop 36 (5), 1113 (2012)
  • Author:
    Zhu DL; Bays H; Gao P; Mattheus M; Voelker B; Ruilope LM
    Title:
    Efficacy and tolerability of initial therapy with single-pill combination telmisartan/hydrochlorothiazide 80/25 mg in patients with grade 2 or 3 hypertension: A multinational, randomized, double-blind, active-controlled trial.
    Source:
    Clin Ther 34 (7), 1613-1624 (2012)
    Abstract:
    Background: Patients with grade 2 or 3 hypertension may require high-dose combination therapy to achieve blood pressure (BP) targets in a timely manner. Objectives: This study compared the effectiveness and tolerability of a single-pill combination (SPC) of telmisartan/hydrochlorothiazide 80/25 mg (T80/H25) with T80 monotherapy. Methods: In a Phase IV, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-group trial, 894 patients with mean seated trough cuff systolic BP [SBP] =160 mm Hg and diastolic BP [DBP] =100 mm Hg were randomly assigned in a 2:1 ratio to receive T40/H12.5 SPC or telmisartan 40 mg monotherapy for 1 week before the dose was uptitrated to T80/H25 SPC or T80, respectively, administered for 6 weeks. The primary efficacy measure was the change from baseline in mean seated cuff trough SBP. Adverse events (AEs) were recorded. Results: A total of 888 patients received treatment (294 and 594 patients in the T80/H25 and T80 groups, respectively) (mean age, 57.0 years; age =65 years, 25.7%; male, 53.8%; white, 68.0%); 61 patients prematurely discontinued. Mean baseline SBP/DBP values were 172.3/104.3 mm Hg (T80/H25) and 173.3/104.5 mm Hg (T80). After 7 weeks, SBP was changed by -37.0 and -28.5 mm Hg in the T80/H25 and T80 groups (P < 0.0001); DBP was changed by -18.6 and -15.4 mm Hg respectively (P < 0.0001). These differences were significant after 2 weeks at the higher dosage (P < 0.0001). BP target (SBP/DBP <140/<90 mm Hg) was achieved in 55.5% and 34.7% of patients in the T80/H25 and T80 groups (P < 0.0001). T80/H25 SPC and T80 had a similar frequency of overall AEs (16.0% vs 17.0%). The prevalences of treatment-related AEs with T80/H25 SPC and T80 were low (4.6% and 2.8%), as were the rates of AEs that led to discontinuation (1.0% and 2.8%). Conclusions: In these patients with grade 2 or 3 hypertension, initial therapy with T80/H25 was associated with a significantly greater reduction in mean seated cuff trough SBP compared with T80 alone, as well as with improved hypertension goal attainment rates. Both treatments appeared to be well tolerated. ClinicalTrials.gov identifier: NCT00926289
  • Author:
    Mross K; Dittrich C; Aulizky WE; Strumberg D; Schutte J; Schmid RM; Hollerbach S; Merger M; Munzert G; Fleischer F; Scheulen ME
    Title:
    A randomised phase II trial of the polo-like kinase inhibitor BI 2536 in chemo-nave patients with unresectable exocrine adenocarcinoma of the pancreas-a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.
    Source:
    Br J Cancer 107 (2), 280-286 (2012)
    Abstract:
    Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating =2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control =12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population
  • Author:
    Healey JS; Eikelboom J; Douketis J; Wallentin L; Oldgren J; Yang S; Themeles E; Heidbuchle H; Avezum A; Reilly P; Connolly SJ; Yusuf S; Ezekowitz M
    Title:
    Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: Results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial.
    Source:
    Circulation 126 (3), 343-348 (2012)
    Abstract:
    Background-Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. Methods and Results-The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received dabigatran 110 mg, 25.4% received dabigatran 150 mg, and 25.9% received warfarin, P=0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either dabigatran dose, the last dose of study drug was given 49 (35-85) hours before the procedure on comparison with 114 (87-144) hours in patients receiving warfarin, P<0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44. Conclusions- Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600
  • Author:
    Gomis R; Owens DR; Taskinen M-R; Del Prato S; Patel S; Pivovarova A; Schlosser A; Woerle H-J
    Title:
    Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: Up to 2 years exposure in 24-week phase II trials followed by a 78-week open-label extension.
    Source:
    Int J Clin Pract 66 (8), 731-740 (2012)
    Abstract:
    Aim: The aim of this study was to evaluate the long-term safety, tolerability and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin given either alone or in combination with other oral glucose-lowering agents in persons with type 2 diabetes. Methods: A 78-week open-label extension study evaluated subjects who participated in one of four preceding 24-week, randomised, double-blind, placebo-controlled parent trials and who received linagliptin, linagliptin + metformin, linagliptin + metformin + a sulphonylurea or linagliptin + pioglitazone (all with linagliptin administered orally once daily). Individuals receiving one of these treatments during a previous trial continued the same treatment (n = 1532) for up to a total of 102 weeks, whereas those previously receiving placebo were switched to linagliptin (n = 589). All 2121 participants received at least one dose of the trial medication and were included in the primary safety analysis. Results: In subjects previously receiving active treatment, the glycosylated haemoglobin A 1c reduction achieved during the 24-week parent trials was sustained through the 78-week extension period (change from baseline to week 102: -0.8%). Drug-related adverse events were experienced by 14.3% of participants. Hypoglycaemia occurred in 13.9% of participants and was similar between those previously receiving treatment (13.6%) and those switching from placebo to linagliptin (14.6%). Hypoglycaemia occurred most frequently with the use of metformin + a sulphonylurea background therapy (11%). Overall, no clinically relevant changes in body weight were observed. Conclusion: Long-term treatment with linagliptin was well tolerated with no change in the safety profile observed during the extension study. Sustained long-term glycaemic control was maintained for up to 102 weeks with either linagliptin monotherapy or linagliptin in combination with other oral glucose-lowering agents
  • Author:
    Eriksson BI; Smith JJ; Caprini J; Hantel S; Clemens A; Feuring M; Schnee J; Barsness GW
    Title:
    Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery: Findings from four phase 3 trials.
    Source:
    Thromb Res 130 (3), 396-402 (2012)
    Abstract:
    Introduction: Several anticoagulants have been associated with a 'rebound effect' that potentially increases the risk of thrombosis and cardiovascular events following discontinuation. Four Phase 3 trials of dabigatran etexilate in major orthopedic surgery incorporated measures to assess the risk of acute coronary syndrome (ACS) events during and after treatment. Materials and methods: Patients in RE-MOBILIZE®, RE-MODEL™, RE-NOVATE®, and RENOVATE® II were randomized to dabigatran etexilate (150 mg or 220 mg once daily) or enoxaparin for 6-35 days, and followed for up to 90 days. ACS data were tabulated from investigator-reported serious adverse events using ACS-specific Medical Dictionary for Regulatory Authorities (MedDRA) lower-level terms. To ensure that all ACS events were identified in the initial three studies, RE-MOBILIZE®, RE-MODEL™, and RE-NOVATE®, a broader list of MedDRA terms was prespecified that would trigger treatment-blinded adjudication. Results: When pooling the four trials, patients receiving dabigatran etexilate 220 mg had the fewest treatment-emergent, investigator-reported ACS events (6 [0.16%] vs 14 [0.51%] for dabigatran 150 mg and 13 [0.35%] for enoxaparin). Corresponding post-treatment rates were 2 (0.06%), 1 (0.04%), and 4 (0.11%). Similarly, treatment-emergent centrally adjudicated definite or likely ACS events in the first three trials were fewer in patients on dabigatran 220 mg (16 [0.60%]) than dabigatran 150 mg (26 [0.95%]) and enoxaparin (20 [0.74%]). The corresponding numbers post treatment were 2, 2, and 7. None of these between-group differences were statistically significant. Conclusion: No increased ACS signal was detected with dabigatran etexilate compared with enoxaparin during or after treatment
  • Author:
    Aicher B; Peil H; Peil B; Diener H C
    Title:
    Responsiveness of efficacy endpoints in clinical trials with over the counter analgesics for headache
    Source:
    Cephalalgia 32 (13), 953-962 (2012)
    Abstract:
    Aim: To quantify and compare the responsiveness within the meaning of clinical relevance of efficacy endpoints in a clinical trial with over the counter (OTC) analgesics for headache. Efficacy endpoints and observed differences in clinical trials need to be clinically meaningful and mirror the change in the clinical status of a patient. This must be demonstrated for the specific disease indication and the particular patient population based on the application of treatments with proven efficacy. Methods: Patient's global efficacy assessment during two study phases (pre-phase and treatment phase) was used to classify patients as satisfied or non-satisfied with the efficacy of their medication. The analysis is based on 1734 patients included in the efficacy analysis of a randomized, placebo-controlled, double-blind, multi-centre parallel group trial with six treatment arms. Based on this classification and the pain intensity recorded by the patients on a 100mm visual analogue scale, group differences by assessment categories and receiver operating characteristic (ROC) curve methods were used to quantify responsiveness of the efficacy endpoints 'time to 50% pain relief', 'time until reduction of pain intensity to 10 mm', 'weighted sum of pain intensity difference' (%SPIDweighted), 'pain intensity difference (PID) relative to baseline at 2 hours', and 'pain-free at 2 hours'. Results: Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed for all efficacy endpoints. Patients with the highest rating of efficacy had the fastest and strongest pain relief. In comparison, patients assessing efficacy as 'less good' reached a 50% pain relief on average nearly an hour later than those scoring efficacy as at least 'good'. Simultaneously, their extent of pain relief was only half as great 2 hours after medication intake. Patients scoring efficacy as 'poor' experienced practically no pain relief within the 4 hour observation interval. ROC curve calculations confirmed an adequate responsiveness for all continuous endpoints. The following cut-off points for differentiating between satisfied and non-satisfied patients were deduced from the data in the pre- and treatment phase, respectively: 'time to 50% pain relief' 1:10 and 1:31 h:min, 'time until reduction of pain intensity to 10 mm' 2:40 and 3:00 h:min, '%SPIDweighted' 68 and 64%, 'PID at 2 hours' 35 and 35 mm. The sensitivity and specificity based on these cut-off points ranged from 70 to 79%. The binary endpoint 'pain-free at 2 hours' showed a clearly higher specificity (80 and 87%) than sensitivity (65 and 61%) in the pre- and treatment phase, respectively. Conclusions: When global assessment of efficacy by the patient was used as external criterion, ROC curve calculations confirmed a high responsiveness for all efficacy endpoints included in this study. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed. The endpoint '%SPIDweighted' proved slightly but consistently superior to the other endpoints. SPID and %SPIDweighted are not easy to interpret and the time course of pain reduction is of high importance for the patients in the treatment of acute pain, including headache. The endpoint 'pain-free at 2 hours' showed the expected high specificity, but at the cost of a concurrently low sensitivity and clearly makes less use of the available information than the endpoint 'time to 50% pain reduction', which combines the highly relevant aspects of time course and extent of pain reduction. Responsiveness, the ability of an outcome measure to detect clinically important changes in a specific condition of a patient, should be added in future revisions of IHS guidelines for clinical trials in headache disorders. © 2012 International Headache Society.
  • Author:
    van de Werf F; Brueckmann M; Connolly SJ; Friedman J; Granger CB; Haertter S; Harper R; Kappetein AP; Lehr T; Mack MJ; Noack H; Eickelboom JW
    Title:
    A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt (RE-ALIGN)
    Source:
    Am Heart J 163 (6), 931-937.e1 (2012)
    Abstract:
    Background: Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. Objective: This study aims to test a new dosing regimen for dabigatran etexilate in patients with a mechanical bileaflet valve. Methods: Patients aged =18 years and =75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels =50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. Conclusions: RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study. © 2012 Mosby, Inc.
  • Author:
    Wagner C L; Visvanathan S; Elashoff M; Mcinnes I B; Mease P J; Krueger G G; Murphy F T; Papp K; Gomez-Reino JJ; Mack M; Beutler A; Gladman D; Kavanaugh A
    Title:
    Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
    Source:
    Ann Rheum Dis 72 (1), 83-88 (2013)
    Abstract:
    Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results: Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1?) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor ?). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions: This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment. Copyright Article author (or their employer) 2012.
  • Author:
    Miller VA; Hirsh V; Cadranel J; Chen Y-M; Park K; Kim S-W; Zhou C; Su W-C; Wang M; Sun Y; Heo DS; Crino L; Tan E-H; Chao T-Y; Shahidi M; Cong XJ; Lorence RM; Yang JCH
    Title:
    Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial.
    Source:
    Lancet Oncol 13 (5), 528-538 (2012)
    Abstract:
    Background: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. Methods: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136. Findings: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. Interpretation: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd. |
  • Author:
    Yang JCH; Shih J-Y; Su W-C; Hsia T-C; Tsai C-M; Ou SHI; Yu C-J; Chang G-C; Ho C-L; Sequist LV; Dudek AZ; Shahidi M; Cong XJ; Lorence RM; Yang P-C; Miller VA
    Title:
    Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): A phase 2 trial.
    Source:
    Lancet Oncol 13 (5), 539-548 (2012)
    Abstract:
    Background: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. Methods: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. Findings: 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Interpretation: Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd
  • Author:
    Hart R G; Diener H-C; Yang S; Connolly S J; Wallentin L; Reilly P A; Ezekowitz M D; Yusuf S
    Title:
    Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: The RE-LY trial.
    Source:
    Stroke 43 (6), 1511-1517 (2012)
    Abstract:
    Background and Purpose-: Intracranial hemorrhage is the most devastating complication of anticoagulation. Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined. Methods-: Analysis of 18 113 participants with atrial fibrillation in the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial assigned to adjusted-dose warfarin (target international normalized ratio, 2-3) or dabigatran (150 mg or 110 mg, both twice daily). Results-: During a mean of 2.0 years of follow-up, 154 intracranial hemorrhages occurred in 153 participants: 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, and 0.23% per year among those assigned to warfarin, dabigatran 150 mg, and dabigatran 110 mg, respectively (P<0.001 for either dabigatran dose versus warfarin). Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (n=13 and n=11, respectively) versus warfarin (n=32; P<0.01 for both). Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients; P<0.05 for both dabigatran doses versus warfarin). Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), age (relative risk, 1.1 per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). Conclusions-: The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran. Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage. © 2012 American Heart Association, Inc
  • Author:
    Mancia G; Schumacher H
    Title:
    Incidence of adverse events with telmisartan compared with ACE inhibitors. Evidence from a pooled analysis of clinical trials.
  • Author:
    Lin NU; Winer EP; Wheatley D; Carey LA; Houston S; Mendelson D; Munster P; Frakes L; Kelly S; Garcia AA; Cleator S; Uttenreuther-Fischer M; Jones H; Wind S; Vinisko R; Hickish T
    Title:
    A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab.
    Source:
    Breast Cancer Res Treat 133 (3), 1057-1065 (2012)
    Abstract:
    Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-compe-tent ErbB family members. This phase II, open-label, singlearm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0-15) and 68.3% had received trastuzumab for >1 year.Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1-16.7); median overall survival was 61.0 weeks (95% CI: 56.7-not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.
  • Author:
    Dullweber F; Riedel A; Boehler S
    Title:
    Evaluation of paediartric study applications - Experiences of the members of the German Association of Research-Based Pharmaceutical Companies (vfa).
    Source:
    Monatsschr Kinderheilkd 160 (7), 6621-668 (2012)
    Abstract:
    The applications for paediatric clinical trials have to fulfil the high demands imposed by the legal requirements. A survey was sent to the members of the German Association of Research-Based Pharmaceutical Companies (vfa) to investigate the type and quantity of objections raised by Ethics Committees and the competent regulatory authorities. Most objections refer to the patient information and consent document, followed by objections to the trial protocol. Nearly 47% of all objections referred to special paediatric questions. The analysis of those objections was used to derive recommendations for the improvement of the applications: description of risk threshold and degree of distress as well as the concept of minimal risk and minimal burden with regard to the application; consideration of the pubertal maturity when describing types of contraception; design of consent documents for children in an age-appropriate language to enable the minor participants to take part in the decision-making process; addressing the principle of subsidiarity based on the approved paediatric investigation plan (PIP).
  • Author:
    Neldam S; Edwards C; Lang M; Jones R
    Title:
    Long-term tolerability and efficacy of single-pill combinations of telmisartan 40-80 mg plus amlodipine 5 or 10 mg in patients whose blood pressure was not initially controlled by amlodipine 5-10 mg: Open-label, long-term follow-ups of the TEAMSTA-5 and TEAMSTA-10 studies.
    Source:
    Curr Ther Res 73 (1-2), 65-84 (2012)
    Abstract:
    Background: Two 8-week, randomized, double-blind, controlled studies previously evaluated the efficacy and tolerability of single-pill combinations of telmisartan 40-80 mg/amlodipine 5-10 mg (T40-80/A5-10) in patients with hypertension not at diastolic blood pressure (DBP) goal (DBP <90 mm Hg) after 6 weeks of amlodipine 5 mg monotherapy (A5) (TEAMSTA-5) or amlodipine 10 mg monotherapy (A10) (TEAMSTA-10). The long-term (=6 months) tolerability and efficacy of single-pill combinations of T40-T80/A5-A10 have now been evaluated in 2 open-label studies in patients who had successfully completed either TEAMSTA-5 or TEAMSTA-10 (TEAMSTA-5 and TEAMSTA-10 Follow-Ups). Methods: In the TEAMSTA-5 Follow-Up, 976 patients whose blood pressure was not initially controlled by taking A5 received T40/A5 for 4 or 8 weeks, with consecutive uptitration to T80/A5 if DBP was =90 mm Hg. In TEAMSTA-10 Follow-Up, 838 patients not initially achieving blood pressure control using A10 received T40/A10 for 4 weeks before randomization to T40/A10 or T80/A10; after 4 weeks, patients randomized to T40/A10 with DBP =90 mm Hg were uptitrated to T80/A10. In both studies, add-on antihypertensive medication was allowed if DBP was not at goal. Results: Treatment compliance in both follow-up studies was =98.4%. Single-pill combinations of T40-T80/A5-A10 resulted in additional clinically relevant blood pressure reductions and 67% to 93% of patients achieved DBP goal (<90 mm Hg); only 1% to 19% of patients received additional medication for hypertension, of whom 29% to 76% achieved DBP goal. Long-term treatment with T40-T80/A5-A10 was well tolerated, with comparable adverse event profiles for all telmisartan/amlodipine combinations. The most common drug-related adverse events were peripheral edema (1.9%-3.9%) and dizziness (1.5% in the T80/A5 group only); these were consistent with the known tolerability profiles of telmisartan/amlodipine combinations. Overall treatment discontinuation rates due to adverse events were low (0.7%-1.5%). Conclusions: In patients not achieving DBP goal with either A5 or A10 monotherapy, the vast majority achieved DBP goal with single-pill combinations of T40-T80/A5-A10. Long-term treatment was well tolerated with high compliance, promoting treatment adherence regardless of telmisartan/amlodipine dose. . ClinicalTrials.gov identifiers: . NCT00614380 (TEAMSTA-5 Follow-up) and . NCT00624052 (TEAMSTA-10 Follow-up).
  • Author:
    Sharma AM; Bakris G; Neutel JM; Littlejohn TW; Kobe M; Ting N; Ley L
    Title:
    Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients. An 8-week randomized parallel-group, double-blind trial.
    Source:
    Clin Ther 34 (3), 537-551 (2012)
    Abstract:
    Background: Hypertensive patients with diabetes often require combination therapy to achieve a blood pressure (BP) goal, and evidence suggests that time to BP goal is crucial to decrease cardiovascular risk. Objective: The aim of the study was to investigate whether the single-pill combination of telmisartan and amlodipine was superior to amlodipine alone as initial antihypertensive therapy in patients with diabetes and hypertension. Methods: An 8-week, randomized, parallel-group, double-blind international trial comparing the once-daily single-pill combination of telmisartan 80 mg and amlodipine 10 mg (T/A; n = 352) with once-daily amlodipine 10 mg (A; n = 354) in patients with type 2 diabetes mellitus and stage 1 or 2 hypertension (systolic BP [SBP] >150 mm Hg). Results: Patient demographics were similar between treatment groups, with an mean (SD) age of 60.5 (10.1) years; 51.7% were male, the mean (SD) body mass index was 32.0 (6.1) and the mean (SD) duration of hypertension was 8.8 (7.9) years. After 8 weeks (primary end point) as well as after 1, 2, and 4 weeks (key secondary end points), significantly greater decreases in the in-clinic mean seated trough cuff SBP with T/A versus A were achieved (-29.0 mm Hg vs -22.9 mm Hg at 8 weeks; P < 0.0001). After 8 weeks, 71.4% versus 53.8% of patients achieved the BP goal (<140/90 mm Hg) with T/A versus A, with mean SBPs of 131.9 and 137.9 mm Hg, respectively. Similar results were observed in the obese (metabolic syndrome) subpopulation. The more stringent goal (<130/80 mm Hg) was achieved by 36.4% and 17.9% patients in the T/A and A groups, respectively. The most common adverse events were peripheral edema, headache, and dizziness. Conclusions: In this selected population of patients with diabetes and hypertension, T/A provided prompt and greater BP decreases compared with A monotherapy, with the majority of patients achieving the BP goal (<140/90 mm Hg).
  • Author:
    Neutel JM; Mancia G; Black HR; Dahloef B; Defeo H; Ley L; Vinisko R; Donova T; Gotcheva N; Milanov S; Mincheva V; Pencheva G; Zlatareva N; Raev D; Stoimenov S; Petranov S; Homy I; Jerabek O; Karen I; Kuchar JC; Krumlov Lorenc Z; Nagel J; Petenka M; Zidkova E; Barucq F; Queguiner A; Robin F; Touzet P; Bismuth M; Bourgoin M; Giraldi C; Breton M; Combet R; Venturini G; Causse P; Henriot F; Khennouf A; Lecaignard D; Cayron P; Chalaux P; Chaleon A; Chalvignac A; Forestier BD; Deme JC; Fivel C; Depoisier M; Dimon B; Flosi M; MacAgno A; Ripoll M; Geronimi O; Michalak B; Geoffray B; Hannoush E; Jacquet J-P; Jappy L; Jordan E; Lacoin F; Lefort D; Lemarie B; Martocq G; Michellier P; Nabedian E; Percheron C-A; Perrin B; Pouget M; Roger J-J; Rouviere G; Sacareau D; Taminau D; Vuong M-H; Zimmermann D; Andras V; Livia T; Ferenc P; Gabriella N; Laszloe I; Ibolya P; Judit S; Karoly Z; Judit R; Benedek I; Cristea M; Tatu-Chitoiu GP; Dragulescu S; Gaita D; Georgescu CA; Minescu B; Manitiu I; Matei A; Salajan M; Tyurina T; Vishnevsky A; Baek S-H; Kang S-M; Kwon H-M; Park C-G; Kim M-H; Lee M-Y; Yang JY; Gonsorcik J; Hojenova S; Hranai M; Kolikova V; Ruffini L; Zareczky P; Gil-Extremera B; Munoz J; Olivan J; Pont F; Tovar J-L; Faynyk A; Goloborodko B; Shatilo V; Sirenko Y; Svyshchenko Y; Vykhovanyuk I; Yena L; Karpenko O; Kononenko L; Zehnder B; Portnoy EB; Punzi HA; Ricci DR; Samson MB; Slabic S; Struble R; Tidman RE; Wayne J; Webster DE; Winer N; Jagminas L; Kanna B; Khronusova Y; Lane´PJ; Lewinson L; Marple R; Mello CJ; Patel NR; Paltron A; Pool JL; Korzh O; Kraiz I; Bittar N; Cheung DG; Crump K; Diaz JL; Eddy PL; Eyzaguirre RD; Graf RJ; Hill JM; Jack DB
    Title:
    Single-pill combination of telmisartan/amlodipine in patients with serve hypertension: Results from the TEAMSTA serve HTN study.
    Source:
    J Clin Hypertens 14 (4), 206-215 (2012)
    Abstract:
    Despite the well documented benefits conferred by adequate control of hypertension, the majority of hypertensive patients display suboptimal control and few patients achieve blood pressure (BP) levels <14090mmHg. As a consequence, combination therapy will be required in the majority of patients to achieve target BP. Fixed-dose combinations of antihypertensives not only simplify treatment regimens, contributing to enhanced patient adherence, they provide superior BP-lowering efficacy and an improved tolerability profile. Fixed-dose combinations have become the strategy of choice in high-risk patients or those with stage 23 hypertension. The combination of a renin-angiotensin system inhibitor (RASI) with a calcium channel blocker (CCB) is a first-line combination that, in addition to its antihypertensive efficacy, reduces oedema, the main adverse effect of the dihydropyridine CCB and the main factor limiting their use. In morbiditymortality studies, this fixed-dose combination has also demonstrated superiority over a RASI combined with a diuretic. The single-pill combination of telmisartan and amlodipine has been shown to produce a dose-dependent BP-lowering effect significantly greater than that of either agent administered as monotherapy. These findings have been confirmed by ambulatory BP monitoring in patients with stage 1 and 2 hypertension, which demonstrated that single-pill telmisartanamlodipine provides substantial 24-hour BP-lowering efficacy. A higher proportion of patients achieved 24-hour BP goals of <13080mmHg on combination therapy. The superior efficacy of combination therapy has been demonstrated across a broad range of patients, including those with moderate-to-severe hypertension, diabetes mellitus and obesity. Moreover, combined use of telmisartan and amlodipine reduces the incidence of amlodipine-induced oedema, making it a preferred combination for the treatment of hypertension. © 2011 Adis Data Information BV. All rights reserved
  • Author:
    Hijazi Z; Oldgren J; Andersson U; Connolly SJ; Ezekowitz MD; Hohnloser SH; Reilly PA; Vinereanu D; Siegbahn A; Yusuf S; Wallentin L
    Title:
    Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: A randomized evaluation of long-termn anticoagulation therapy (RE-LY) substudy.
    Source:
    Circulation 125 (13), 1605-1616 (2012)
  • Author:
    Hohnloser SH; Oldgren J; Yang S; Wallentin L; Ezekowitz M; Reilly P; Eikelboom J; Brueckmann M; Yusuf S; Connolly SJ
    Title:
    Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized evaluation of long-term anticoagulation therapy) trial.
    Source:
    Circulation 125 (5), 669-676 (2012)
    Abstract:
    Background-There is a modest risk of myocardial infarction (MI) and myocardial ischemic events in patients with atrial fibrillation. Methods and Results-Data from the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy) were used to report rates of MI, unstable angina, cardiac arrest, and cardiac death and the prespecified net clinical benefit and treatment effects of dabigatran versus warfarin. MI occurred at annual rates of 0.82% and 0.81% with dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96-1.75, P=0.09 for dabigatran 110 mg; HR 1.27, 95% CI 0.94-1.71, P=0.12 for dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with dabigatran 110 mg, 3.33% per year with dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80-1.06, P=0.28 for dabigatran 110 mg and HR 0.98, 95% CI 0.85-1.12, P=0.77 for dabigatran 150 mg). Events prespecified as "net clinical benefit" (all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death) occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% per year with dabigatran 150 mg, and 7.91% per year with warfarin (HR 0.92, 95% CI 0.84-1.01, P=0.09 for dabigatran 110 mg and HR 0.90, 95% CI 0.82-0.99, P=0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on myocardial ischemic events were consistent in patients with or without a baseline history of MI or coronary artery disease. Conclusions-There was a nonsignificant increase in MI with dabigatran compared with warfarin, but other myocardial ischemic events were not increased. Treatment effects of dabigatran were consistent in patients at higher and lower risk of myocardial ischemic events. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00262600.
  • Author:
    Frost A; Mross K; Steinbild S; Hedborn S; Unger C; Kaiser R; Trommeshauser D; Munzert G
    Title:
    Phase I study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumors.
    Source:
    Curr Oncol 19 (1), 28-35 (2012)
    Abstract:
    Background This open-label phase i study with an accelerated titration design was performed to determine the maximum tolerated dose of BI 2536, a potent, highly selective small-molecule polo-like kinase 1 (Plk1) inhibitor. Methods Patients with advanced solid tumours received a single 60-minute intravenous infusion of BI 2536 (50-70 mg) on days 1-3 of each 21-day treatment course. Recipients without disease progression or untenable toxicity could receive additional treatment courses. The maximum tolerated dose was determined based on dose-limiting toxicities. Other assessments included safety, pharmacokinetic profile, and antitumour activity according to the Response Evaluation Criteria in Solid Tumors. Results The study enrolled 21 patients. The maximum tolerated dose for BI 2536 was determined to be 60 mg for the study schedule. Dose-limiting toxicities included hematologic events, hypertension, elevated liver enzymes, and fatigue. The most frequently reported drug-related adverse events were mild-to-moderate fatigue, leukopenia, constipation, nausea, mucosal inflammation, anorexia, and alopecia. The pharmacokinetics of BI 2536 were linear within the dose range tested. Plasma concentration profiles exhibited multi compartmental pharmacokinetic behaviour, with a terminal elimination half-life of 20-30 hours. Conclusions In the present study, BI 2536 showed an acceptable safety profile warranting further investigation of Plk1 inhibitors in this patient population.
  • Author:
    Eikelboom JW; Connoly SJ; Healey JS; Yang s; Yusuf S; Wallentin L; Oldgren J; Ezekowitz M; Alings M; Kaatz S; Hohnloser SH; Diener H-C; Franzosi MG; Huber K; Reilly P; Varrone J
    Title:
    Reply to letters regarding article. "risk of bleeding with 2 doses of daigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term therapy (RE-LY) trial.
    Source:
    Circulation 125 (3), e293-e294 (2012)
    Abstract:
    no Abstract
  • Author:
    Derogatis LR; Komer L; Katz M; Moreau M; Kimura T; Garcia Jr. M; Wunderlich G; Pyke R
    Title:
    Treatment of hypoactive sexual desire disorder in premenopausal woman: Efficacy of flibanserin in the VIOLET study.
    Source:
    J Sex Med 9 (4), 1074-1085 (2012)
  • Author:
    Glomb P; Ring A
    Title:
    Delayed effects in the exposure-response analysis of clinical QTC trials.
    Source:
    J Biopharm Stat 22 (2), 387-400 (2012)
    Abstract:
    In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientific attention. A direct concentration-QTc relationship is usually assumed with this pharmacokinetics (PK) QT analysis. Consequently, unconsidered effect delays might lead to severe bias in estimation. Although literature and the Food and Drug Administration (FDA) recommend checking for hysteresis, little guidance is given for evaluating the presence of lagged effects. Based on simulated delay scenarios, we derive a metric that allows for the detection of relevant effect delays. With this, the necessity for refined modeling of lag times can be easily recognized.
  • Author:
    Thorp J; Simon J; Dattani D; Taylor L; Kimura T; Garcia Jr. M; Lesko L; Pyke R
    Title:
    Treatment of hypoactive sexual desire disorder in premenopausal women: Efficacy of flibanserin in the DAISY study.
    Source:
    J Sex Med 9 (3), 793-804 (2012)
    Abstract:
    Introduction. Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty. Aim. To assess the efficacy and tolerability of flibanserin, a postsynaptic 5-HT1A agonist/5-HT2A antagonist, in the treatment of premenopausal women with HSDD. Methods. North American premenopausal women with HSDD (mean age 35years) were randomized to 24weeks' treatment with flibanserin 25mg twice daily (N=396), 50mg twice daily (N=392), 100mg once daily at bedtime (N=395), or placebo (N=398). Main Outcome Measures. Co-primary endpoints were changed from baseline to study end in number of satisfying sexual events (SSE) and sexual desire score, measured daily using an eDiary. Secondary endpoints included change in Female Sexual Distress Scale-Revised (FSDS-R) total score and Item 13 score (distress due to low sexual desire), Female Sexual Function Index (FSFI) total and desire domain scores, and Patient's Global Impression of Improvement. Results. Flibanserin 100mg once daily was associated with an increase in SSE (P<0.01 vs. placebo) but the 25mg and 50mg twice daily doses were not. No group showed a significant increase in eDiary desire score vs. placebo. All flibanserin regimens improved FSDS-R total, FSDS-R Item 13, FSFI total, and FSFI desire domain scores vs. placebo (P<0.05, for all). More women receiving flibanserin 50mg twice daily and 100mg once daily considered their HSDD to have improved than women receiving placebo (44.1% and 47.0% vs. 30.3%, respectively) (P<0.000, 1 vs. placebo). The most frequently reported adverse events in women receiving flibanserin were somnolence (11.8%), dizziness (10.5%), and fatigue (10.3%). Conclusion. In premenopausal women with HSDD, flibanserin 100mg once daily was well tolerated and associated with statistically significant improvements in SSE, sexual desire (FSFI desire domain score but not eDiary desire score), sexual function, and decrease in sexual distress vs. placebo.
  • Author:
    Dahl OE; Kurth AA; Rosencher N; Noack H; Clemens A; Eriksson BI
    Title:
    Thromboprophylaxis with dabigatran etexilate in patients over seventy-five years of age with moderate renal impairment undergoing or knee replacement.
    Source:
    Int Orthop 36 (4), 741-748 (2012)
    Abstract:
    Purpose: Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation. Methods: We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran. Results: Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin. Conclusion: For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.
  • Author:
    Stopfer P; Marzin K; Narjes H; Gansser D; Shahidi M; Uttenreuther-Fischer M; Ebner T
    Title:
    Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers.
    Source:
    Cancer Chemother Pharmacol 69 (4), 1051-1061 (2012)
    Abstract:
    Purpose: To investigate the pharmacokinetics, metabolism and tolerability of afatinib (BIBW 2992), an oral irreversible ErbB family blocker, in healthy male volunteers. Methods: In this open-label, single-center study, 8 healthy male volunteers received a single oral dose of 15 mg [14C]-radiolabeled afatinib (equivalent to 22.2 mg of the dimaleinate salt) as a solution. Blood, urine and fecal samples were collected for at least 96 hours (h) after dosing. Plasma and urine concentrations of afatinib were analyzed using high-performance liquid chromatography-tandem mass spectrometry. [14C]-radioactivity levels in plasma, whole blood, urine and feces were measured by liquid scintillation counting methods. Metabolite patterns were assessed by high-performance liquid chromatography. Results: [14C]-radioactivity was mainly excreted via feces (85.4%). Overall recovery of [14C]-radioactivity was 89.5%, indicative of a complete mass balance. Afatinib was slowly absorbed, with maximum plasma concentrations achieved at a median of 6 h after dosing, declining thereafter in a biexponential manner. The geometric mean terminal half-life of afatinib was 33.9 h in plasma and longer for [14C]-radioactivity in plasma and whole blood. Apparent total body clearance for afatinib was high (geometric mean 1,530 mL/min). The high volume of distribution (4,500 L) in plasma may indicate a high tissue distribution. Afatinib was metabolized to only a minor extent, with the main metabolite afatinib covalently bound to plasma proteins. Oxidative metabolism mediated via cytochrome P-450 was of negligible importance for the elimination of afatinib. Afatinib was well tolerated. Conclusions: Afatinib displayed a complete mass balance with the main route of excretion via feces. Afatinib undergoes minimal metabolism.
  • Author:
    Redon J; Mancia G; Sleight P; Schumacher H; Gao P; Pogue J; Fagard R; Verdecchia P; Weber M; Boehm M; Williams B; Yusoff K; Teo K; Yusuf S
    Title:
    Safety and efficacy of low blood pressures among patients with diabetes. Subgroup analyses from the ontarget (ongoing telmisartan alone and in combination with ramipril global trial endpoint).
    Source:
    J Am Coll Cardiol 59 (1), 74-83 (2012)
    Abstract:
    We sought to determine whether the blood pressure (BP) levels at which cardiovascular (CV) protection is achieved differ between diabetic and nondiabetic patients from the ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial). Greater absolute benefits of BP reductions have been claimed for diabetic as compared with nondiabetic patients. A total of 25,584 patients (9,603 diabetic), older than 55 years, at high CV risk were randomized to ramipril, telmisartan, or both and observed for 4.6 years. We pooled the treatment arms to examine the relationships between BP and the primary composite outcome (CV death, nonfatal myocardial infarction or stroke, or hospitalized heart failure) and its components. The primary outcome occurred in 1,938 (20.2%) diabetic patients and in 2,276 (14.2%) nondiabetic patients. Compared with nondiabetic patients, diabetic patients had a significantly higher risk for the primary endpoint (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.38 to 1.57) and CV death (HR: 1.56; 95% CI: 1.42 to 1.71); myocardial infarction (HR: 1.30 (95% CI: 1.17 to 1.46); stroke (HR: 1.39; 95% CI: 1.23 to 1.56); and congestive heart failure hospitalization (HR: 2.06; 95% CI: 1.82 to 2.32). The CV risk was significantly higher in diabetic than in nondiabetic patients regardless of the systolic BP changes during treatment. In both diabetic and nondiabetic patients, progressively greater systolic BP reductions were accompanied by reduced risk for the primary outcome only if baseline systolic BP levels ranged from 143 to 155 mm Hg; except for stroke, there was no benefit in fatal or nonfatal CV outcomes by reducing systolic BP below 130 mm Hg. The relationship between BP and overall CV risk had a similar pattern in diabetic and nondiabetic patients over a wide range of baseline and in-treatment BP values although, for the same systolic BP, a higher risk is observed in diabetic patients. (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial [ONTARGET]; NCT00153101)