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PubMed | Shanghai Eastern Hepatobiliary Surgery Hospital, Bayer AG, University of Verona, Sungkyunkwan University and 10 more.
Type: Clinical Trial, Phase II | Journal: Journal of hepatology | Year: 2016

Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead; DEB-TACE) is effective in patients with Barcelona clinic liver cancer stage B hepatocellular carcinoma (HCC). The multikinase inhibitor sorafenib enhances overall survival (OS) and time-to-tumor progression (TTP) in patients with advanced HCC. This exploratory phase II trial tested the efficacy and safety of DEB-TACE plus sorafenib in patients with intermediate stage HCC.Patients with intermediate stage multinodular HCC without macrovascular invasion (MVI) or extrahepatic spread (EHS) were randomized 1:1 to DEB-TACE (150 mg doxorubicin) plus sorafenib 400 mg twice daily or placebo. The primary endpoint was TTP by blinded central review. Secondary endpoints included time to MVI/EHS, OS, overall response rate (ORR) using modified response evaluation criteria in solid tumors, disease control rate (DCR), time to unTACEable progression (TTUP), and safety.Of 307 patients randomized, 154 received sorafenib and 153 received placebo. Median TTP for subjects receiving sorafenib plus DEB-TACE or placebo plus DEB-TACE was similar (169 vs. 166 days, respectively; hazard ratio (HR) 0.797, p=0.072). Median time to MVI/EHS (HR 0.621, p=0.076) and OS (HR 0.898, p=0.29) had not been reached. The ORRs for patients in the sorafenib and placebo groups with post-baseline scans were 55.9% and 41.3%, respectively, and the DCRs were 89.2% and 76.1%, respectively. TTUP was lower with sorafenib than with placebo (HR 1.586; 95% confidence intervals, 1.200-2.096; median 95 vs. 224 days). No unexpected adverse events related to sorafenib were observed.Sorafenib plus DEB-TACE was technically feasible, but the combination did not improve TTP in a clinically meaningful manner compared with DEB-TACE alone.


PubMed | University of Michigan, M.A.R.C.O. GmbH & Co. KG, Monash University, Northwestern University and 9 more.
Type: Journal Article | Journal: European heart journal | Year: 2016

To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7-10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.55, 510, 7.515, 1020, and 1520 mg finerenone groups, respectively (P = 0.42-0.88). Except for the 2.55 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 1020 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to 5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups.Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 1020 mg group should be further explored in a large outcomes trial.


Ryttberg L.,Örebro University | Diamantopoulos A.,Symmetron Ltd | Forster F.,IMS Health | Lees M.,Bayer Plc | And 2 more authors.
Expert Review of Pharmacoeconomics and Outcomes Research | Year: 2011

Aims: The objective of this study was to evaluate the cost-effectiveness of rivaroxaban versus the low-molecular-weight heparins (LMWH) enoxaparin and dalteparin for the prevention of venous thromboembolism (VTE) after total hip replacement and total knee replacement in Sweden. Methods: The model included acute venous thromboembolic events and long-term complications over a 5-year time horizon represented by an acute and a chronic phase with 1-year cycles. Transition probabilities were derived from the Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism (RECORD) clinical trials. Results: In patients undergoing total hip replacement, the incremental cost per additional quality-adjusted life-year of extended prophylaxis for 35 days with rivaroxaban versus 14 days of prophylaxis with enoxaparin or dalteparin was SEK29,400 and SEK35,400, respectively. In total knee replacement patients, 14 days of rivaroxaban dominated 14 days of LMWH as prophylaxis for VTE. Conclusion: The results of the economic model consistently showed that, over a 5-year period, rivaroxaban is a cost-effective alternative to 14 days of LMWH for VTE prophylaxis in Sweden. © 2011 Expert Reviews Ltd.


McDonald H.,Bayer AG | Diamantopoulos A.,Symmetron Ltd | Wells P.,University of Ottawa | Lees M.,Bayer Plc | And 3 more authors.
Journal of Medical Economics | Year: 2012

Objectives: A cost-effectiveness model for rivaroxaban evaluated the cost-effectiveness of prophylaxis with rivaroxaban (a once-daily, orally administered Factor Xa inhibitor) vs enoxaparin in the prevention of venous thromboembolism (VTE) after total hip replacement (THR) and total knee replacement (TKR). This Canadian analysis was conducted using the Ontario Ministry of Health perspective over a 5-year time horizon. The model combined clinical data and builds upon existing economic models. Methods: The model included both acute VTE (represented as a decision tree) and long-term complications (represented as a Markov process with 1-year cycles) phases. The model allowed VTE event rates, quality-Adjusted life expectancy and direct medical costs to be estimated over a 5-year time horizon, based on current approved practice patterns in Canada. A number of one-way sensitivity analyses were performed on the baseline assumptions, including a comparison of rivaroxaban with dalteparin, and probabilistic sensitivity analyses were performed to address any uncertainty concerning model inputs. Results: When comparing equal durations of therapy, rivaroxaban dominated enoxaparin in the prevention of VTE events in patients undergoing THR and TKR, providing more benefit at a lower cost. Rivaroxaban was cost-effective when comparing 35 days' prophylaxis with 14 days' prophylaxis with enoxaparin following THR. One-way and probabilistic sensitivity analyses demonstrated that the results of the economic analysis were robust to variations in key inputs. Rivaroxaban remained dominant during one-way sensitivity analyses comparing rivaroxaban with dalteparin after THR or TKR. Limitations: Although clinical trial data were used in the prophylaxis module, assumptions and values used in the post-prophylaxis and long-term complication (LTC) modules were based on several different literature sources; it was not always possible to source Canadian data. Conclusions: This economic analysis suggests that the use of rivaroxaban for the prophylaxis of VTE after THR or TKR in Canada was cost-effective. © 2012 Informa UK Ltd.


Bakris G.L.,University of Chicago | Agarwal R.,Indiana University | Chan J.C.,Chinese University of Hong Kong | Cooper M.E.,Baker IDI Heart and Diabetes Institute | And 13 more authors.
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE: Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events. OBJECTIVE: To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug. INTERVENTIONS: Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days. MAIN OUTCOMES AND MEASURES: The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate. RESULTS: The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P<.001]; for 20 mg/d, 0.62 [90% CI, 0.54-0.72; P < .001]). The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%, respectively. There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups. CONCLUSIONS AND RELEVANCE: Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT1874431. Copyright 2015 American Medical Association. All rights reserved.


PubMed | Baker IDI Heart and Diabetes Institute, Hannover Medical School, University Medical Center Groeningen, University of Chicago and 9 more.
Type: Clinical Trial, Phase II | Journal: JAMA | Year: 2015

Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events.To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug.Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n=96; 2.5 mg/d, n=92; 5 mg/d, n=100; 7.5 mg/d, n=97; 10 mg/d, n=98; 15 mg/d, n=125; and 25 mg/d, n=119) or matching placebo (n=94) for 90 days.The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate.The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR 300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P=.004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P=.001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P<.001]; for 20 mg/d, 0.62 [90% CI, 0.54-0.72; P<.001]). The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%, respectively. There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups.Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications.clinicaltrials.gov Identifier: NCT1874431.


PubMed | Bayer AG, Peking Union Medical College, Guangdong General Hospital and Guangdong Cardiovascular Institute, Bayer plc and 2 more.
Type: Journal Article | Journal: Heart Asia | Year: 2016

PATENT-1 and CHEST-1 were pivotal, international phase III trials assessing riociguat for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Here we compare Chinese patients from these studies with the overall populations, and report the clinical effect and safety of riociguat in Chinese patients with PAH and CTEPH.PATENT-1 was a 12-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5mg three times daily or 1.5mg three times daily (exploratory) in patients with PAH. CHEST-1 was a 16-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5mg three times daily) in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. The primary endpoint in each study was change from baseline to study end in 6min walking distance (6MWD). Secondary endpoints included pulmonary vascular resistance (PVR), N-terminal prohormone of brain natriuretic peptide, WHO functional class (FC), and time to clinical worsening.Chinese patients in PATENT-1 (n=77) and CHEST-1 (n=32) were younger and had better baseline 6MWD and WHO FC versus the overall population. Riociguat increased 6MWD versus placebo in Chinese patients in PATENT-1 and CHEST-1, with a greater increase observed in CHEST-1 (least-squares mean differences +46m and +102m in PATENT-1 and CHEST-1, respectively). Riociguat also improved several secondary endpoints in both studies, and was well tolerated.Chinese patients displayed differences in baseline characteristics versus the overall populations in PATENT-1 and CHEST-1. Riociguat improved 6MWD, PVR, WHO FC, and other clinical outcomes in Chinese patients with PAH or CTEPH.PATENT-1: NCT00810693, Results; CHEST-1 NCT00855465, Results.


Stevenson V.L.,National Hospital for Neurology and Neurosurgery | Gras A.,Market Access Health | Bardos J.I.,Costello Medical Consulting | Broughton J.,Bayer Plc.
Multiple Sclerosis Journal | Year: 2015

Background: Spasticity is an extremely common, distressing and disabling symptom of multiple sclerosis. Limited data suggest the associated health care costs correlate with increasing severity and place a high economic burden on individuals, health care systems and society. Objective: The aim of this study was to quantify the impact of multiple sclerosis spasticity on health care resources and the associated costs at different levels of severity in people with multiple sclerosis in the United Kingdom. Methods: An online survey was carried out to understand the resources used in the management of spasticity in multiple sclerosis. The questionnaire asked health care specialists to estimate their involvement and the resource use associated with different levels of spasticity, and the survey outputs were used to derive the resource costs. Results: The level and cost of care substantially increased with the degree of spasticity. Key factors contributing to high annual costs per patient were home care, hospital admissions and high-cost items, such as hospital beds. Conclusions: Based on the survey results, it can be assumed that managing spasticity early and effectively could result in substantial cost savings, in addition to the improvements in health-related quality of life. © The Author(s), 2015.


Stevenson V.L.,National Hospital for Neurology and Neurosurgery | Gras A.,Market Access Health | Bardos J.I.,Costello Medical Consulting | Broughton J.,Bayer plc
Multiple Sclerosis | Year: 2015

Background: Spasticity is an extremely common, distressing and disabling symptom of multiple sclerosis. Limited data suggest the associated health care costs correlate with increasing severity and place a high economic burden on individuals, health care systems and society. Objective: The aim of this study was to quantify the impact of multiple sclerosis spasticity on health care resources and the associated costs at different levels of severity in people with multiple sclerosis in the United Kingdom. Methods: An online survey was carried out to understand the resources used in the management of spasticity in multiple sclerosis. The questionnaire asked health care specialists to estimate their involvement and the resource use associated with different levels of spasticity, and the survey outputs were used to derive the resource costs. Results: The level and cost of care substantially increased with the degree of spasticity. Key factors contributing to high annual costs per patient were home care, hospital admissions and high-cost items, such as hospital beds. Conclusions: Based on the survey results, it can be assumed that managing spasticity early and effectively could result in substantial cost savings, in addition to the improvements in health-related quality of life. © SAGE Publications.


PubMed | a GfK and Bayer plc
Type: Journal Article | Journal: Expert review of pharmacoeconomics & outcomes research | Year: 2016

Severity of spasticity in multiple sclerosis (MS) directly correlates with the level and cost of care required. This study assessed whether a tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray for treatment of moderate-severe MS spasticity is a cost-effective use of healthcare resources in Wales.A Markov model was developed to compare THC/CBD plus standard of care (SoC) treatments with SoC alone.At 30 years, total incremental cost for THC/CBD plus SoC treatment was estimated at 3,836/patient (ICER: 10,891/quality-adjusted life year [QALY]). Hospital admission costs had the greatest effect on the base case ICER. Inclusion of carer cost led to incremental cost of -33,609/patient (ICER: -95,423/QALY).The THC/CBD spray was found to be cost-effective for the treatment of spasticity in MS, and dominant, if home carer costs were included. Use of THC/CBD has the potential to generate cost savings by significantly improving the symptoms of moderate to severe MS spasticity.

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