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Forns X.,Hospital Clinic | Lawitz E.,University of Texas Health Science Center at San Antonio | Zeuzem S.,Goethe University Frankfurt | Gane E.,Auckland Hospital Clinical Studies Unit | And 12 more authors.
Gastroenterology | Year: 2014

Background & Aims Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy. Methods Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group). Results Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6-53.0; P <.001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir. Conclusions In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. number: NCT01281839. © 2014 by the AGA Institute.

Cure S.,The Cricket | Bianic F.,The Cricket | Gavart S.,Janssen Pharmaceutical | Curtis S.,Janssen Pty Ltd | And 2 more authors.
Journal of Medical Economics | Year: 2014

Background: Telaprevir (T, TVR) is a direct-acting antiviral (DAA) used for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection. The sustained virological response (SVR) rates, i.e., undetectable HCV RNA levels 24 weeks after the end of treatment, is what differentiate treatments. This analysis evaluated the cost-effectiveness of TVR combined with pegylated interferon (Peg-IFN) alfa-2a plus ribavirin (RBV), with Peg-IFN and RBV (PR) alone or with boceprevir (B, BOC) plus Peg-IFN alfa-2b and RBV, in naïve patients. Methods: A Markov cohort model of chronic HCV disease progression reflected the pathway of naïve patients initiating anti-HCV therapy. SVR rates were derived from a mixed-treatment comparison including results from Phase II and III trials of TVR and BOC, and trials comparing both PR regimens. SVR has significant impact on survival, quality-of-life, and costs. Incremental cost per life year (LY) gained and quality-adjusted-life-year (QALY) gained were computed at lifetime, adopting the (National Health Service) NHS perspective. Cost and health outcomes were discounted at 3.5%. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses. Sub-group analyses were also performed by interleukin (IL)-28B genotype and fibrosis stage. Results: Higher costs and improved outcomes were associated with T/PR relative to PR alone, resulting in an ICER of £12,733 per QALY gained. T/PR retained a significant SVR advantage over PR alone and was cost-effective regardless of IL-28B genotype and fibrosis stages. T/PR regimen 'dominated' B/PR, generating 0.2 additional QALYs and reducing lifetime cost by £2758. Sensitivity analyses consistently resulted in ICERs less than £30,000/QALY for the T/PR regimen over PR alone. Limitations: No head-to-head trial provides direct evidence of better efficacy of T/PR vs B/PR. Conclusion: The introduction of TVR-based therapy for genotype 1 HCV patients is cost-effective for naïve patients at the £30,000 willingness-to-pay threshold, regardless of IL-28B genotype or fibrosis stage. © 2014 Informa UK Ltd.

Alphs L.,Janssen Scientific Affairs LLC | Mao L.,Jansen R and D LLC | Rodriguez S.C.,Janssen Scientific Affairs LLC | Hulihan J.,Janssen Global Services LLC | Starr H.L.,Janssen Scientific Affairs LLC
Journal of Clinical Psychiatry | Year: 2014

Background: Public health considerations require that clinical trials address the complex "real-world" needs of patients with chronic illnesses. This is particularly true for persons with schizophrenia, whose management is frequently complicated by factors such as comorbid substance abuse, homelessness, and contact with the criminal justice system. In addition, barriers to obtaining health care in the United States often prevent successful community reentry and optimal patient management. Further, nonadherence to treatment is common, and this reinforces cycles of relapse and recidivism. Long-acting injectable antipsychotic therapy may facilitate continuity of treatment and support better outcomes, particularly in patients who face these challenges. Clinical trials with classical explanatory designs may not be the best approaches for evaluating these considerations. We describe the design and rationale of a novel trial that combines both explanatory and pragmatic design features and studies persons with schizophrenia who face these challenges. Design and Rationale: The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study is a prospective, open-label, randomized, 15-month study conducted between May 5, 2010, and December 9, 2013, comparing long-acting injectable paliperidone palmitate and oral antipsychotic medications in subjects with schizophrenia (according to DSM-IV criteria). Investigators and subjects had broad flexibility for treatment decision-making, thus making it a model that better reflects real-world practice. The primary end point was time to treatment failure, defined as arrest/incarceration psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. This end point was adjudicated by a blinded event monitoring board. Patients were followed to the 15-month end point, regardless of whether they were maintained on their initial randomized treatment. This article provides some of the reasoning behind the authors' choices when combining features from both explanatory and pragmatic approaches to this trial's design. Conclusions: The PRIDE study incorporates real-world design features in a novel, prospective, comparative study of long-acting injectable and oral antipsychotics in persons with schizophrenia who have had recent contact with the criminal justice system. Insights provided should help the reader to better understand the need for more real-world approaches for clinical studies and how a broader approach can better aid clinical treatment and public health decision-making. Trial Registration: identifier: NCT01157351. © Copyright 2014 Physicians Postgraduate Press, Inc.

Zeuzem S.,Goethe University Frankfurt | Demasi R.,Janssen Research and Development LLC | Baldini A.,Janssen | Coate B.,Janssen Research and Development LLC | And 3 more authors.
Journal of Hepatology | Year: 2014

Background & Aims Anemia is a common adverse event associated with telaprevir-based triple therapy of chronic, genotype 1 hepatitis C. Identification of patients at risk of developing anemia could allow evaluation of suitability for therapy, and aid in determining frequency of anemia monitoring and treatment management. Methods This post-hoc analysis utilized data from the no lead-in telaprevir, peginterferon and ribavirin arm of the REALIZE study. Anemia was defined as a single occurrence of hemoglobin <10 g/dl at any point during treatment. Pre-treatment factors with potential to act as prognostic indicators of anemia including age, sex, BMI, and baseline hemoglobin were analysed by univariate and multivariate logistic regression analyses. Nomograms (graphical representations of risk factors) were developed to predict the likelihood of developing anemia. Results Among the 265 patients, 102 (38%) had anemia, with 78/102 (77%) developing anemia on or before week 12. Most patients developed anemia after week 2 and an inverse correlation was found between week 2 hemoglobin and the likelihood of developing anemia. Overall, 60% of patients (60/100) with week 2 hemoglobin <13 g/dl subsequently developed anemia. The multivariate analysis revealed older age (>45 years), lower BMI (≤25 mg/m2) and baseline hemoglobin (continuous variable) were significantly associated with the probability of developing anemia during telaprevir treatment. Conclusions These analyses indicate the potential of using predictive risk factors such as low baseline and on-treatment hemoglobin to identify patients at risk of developing anemia on telaprevir-based triple therapy, which may increase the potential for treatment success by careful patient monitoring. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Bamber L.,Bayer AG | Wang M.Y.,Bayer AG | Prins M.H.,Maastricht University | Ciniglio C.,Janssen Global Services LLC | And 3 more authors.
Thrombosis and Haemostasis | Year: 2013

Rivaroxaban, an oral, direct factor Xa inhibitor, has been approved for the treatment of deep-vein thrombosis (DVT) and pulmonary embolism (PE) and the prevention of recurrent DVT and PE as a fixed-dose, single-drug regimen that does not require initial heparinisation, routine coagulation monitoring or dose adjustment. This study evaluated patient-reported treatment satisfaction in EINSTEIN DVT - a large, open-label, randomised study that compared rivaroxaban with enoxaparin/ vitamin K antagonist (VKA) therapy in patients with acute symptomatic DVT without PE. As part of EINSTEIN DVT, a total of 1,472 patients in seven countries were asked to complete a new, validated measure of treatment satisfaction - the Anti-Clot Treatment Scale (ACTS) - at scheduled visits throughout 12 months of treatment. ACTS scores were compared between study groups in the intentionto-treat population. Patients reported greater satisfaction in the rivaroxaban group compared with the enoxaparin/VKA group, with higher mean ACTS scores across visits. Mean ACTS Burdens scores were 55.2 vs 52.6 (p<0.0001) in favour of rivaroxaban, equivalent to a moderate effect size of 0.42. The treatment effect was consistent over time, with the mean score difference ranging from 2.18 (month 2) to 3.18 (month 12). Overall mean ACTS Benefits scores were 11.7 vs 11.5 in favour of rivaroxaban (p=0.006). This was associated with a small overall effect size of 0.12. The improvement in ACTS Benefits for rivaroxaban became apparent at month 2 and subsequent visits. Rivaroxaban results in improved treatment satisfaction compared with enoxaparin/VKA among patients with DVT, particularly in reducing patient-reported anticoagulation burden. © Schattauer 2013.

Type 2 diabetes mellitus (T2DM) is primarily a self-managed disease in which selfcare behaviors play an important role in achieving optimal outcomes. Because self-care does not result in immediate tangible or noticeable benefits, adherence to such a regimen can be confusing, difficult, and frustrating. People are more likely to adhere to treatment regimens that offer benefits from the patient perspective, such as convenience, avoidance of hypoglycemic episodes, and weight loss, compared with regimens that do not. In this study, we explored the impact of the average weight loss amount demonstrated with canagliflozin treatment on improvement in 3 patient-relevant outcomes that have been linked to performance of healthy behaviors and better outcomes in T2DM: weight-related quality of life, as measured by the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, and satisfaction with physical health and emotional health, as measured by the Current Health Satisfaction Questionnaire (CHES-Q), using data from a previously reported study. Weight loss of an amount demonstrated in clinical trials of canagliflozin was associated with improvements in weight-related quality of life and satisfaction with physical and emotional health, concepts shown to be important to the persistent and consistent performance of healthy behaviors. © Postgraduate Medicine.

Mehra M.,Janssen Global Services LLC | Hill K.,Janssen Global Services LLC | Nicholl D.,Janssen Global Services LLC | Schadrack J.,Janssen Global Services LLC
Journal of Medical Economics | Year: 2012

Background: This research addresses the need for population-based studies on the burden of chronic low back pain (CLBP) by examining healthcare service use and costs for patients with and without neuropathic components in the US population. Methods: Data were analyzed from PharMetrics IMS LifeLink™ US Claims Database (20062008). Patients (≥18 years) with 36 months continuous enrollment, ICD-9 code for low back pain, and claims in 3 out of 4 consecutive months in the 12-month prospective period were included and classified with CLBP. Patients were further classified with a neuropathic component (wNP) and without a neuropathic component (woNP) based on ICD-9 codes. Healthcare resources, physical therapy, prescription medication use, and associated costs were assessed for the period January 1December 31, 2008. Results: A number of patients (39,425) were identified with CLBP (90.4% wNP). Patients wNP included more women, were older and more likely to have clinically diagnosed depression, and made significantly greater use of any prescription medication at index event, opioids (particularly schedule II), and healthcare resources. Total direct costs of CLBP-related resource use were ∼US$96 million over a 12-month follow-up. CLBP wNP accounted for 96% of total costs and mean annual cost of care/patient was ∼160% higher than CLBP patients woNP (US$ 2577 vs US$ 1007, p<0.0001). Limitations: This study was descriptive and was not designed to demonstrate causality between diagnosis, treatment, and outcomes. Resource use and costs for reasons other than LBP were not included. Patients with neuropathic pain are more likely to seek treatment; therefore CLBP patients with a non-neuropathic component may be under-represented. Conclusions: The disproportionately high share of interventional resource use in CLBP wNP suggests greater need for new treatment options that more comprehensively manage the range of pain symptoms and signaling mechanisms involved, to help improve patient outcomes and reduce the burden on healthcare systems. © 2012 Informa UK Ltd.

Cepeda M.S.,Janssen Research and Development L.L.C. | Berlin J.A.,Janssen Research and Development L.L.C. | Gao C.Y.,Quantitative Solutions Inc. | Wiegand F.,Janssen Global Services L.L.C. | Wada D.R.,Quantitative Solutions Inc.
Pain Medicine | Year: 2012

Objective. To compare placebo responses in neuropathic pain syndromes. Design. Systematic literature review and meta-analysis. Setting and Patients. Randomized placebo-controlled trials assessing pain intensity or pain relief in any neuropathic pain syndrome published since 1995 with ≥5days follow-up. Interventions. Placebo response. Outcome Measures. Pain intensity and responder rates (proportion reporting ≥50% pain relief). Meta-regression models were built. Results. Ninety-four studies (N=5,317) were included in the pain intensity analysis; 47 studies (N=3,087) were included in the responder analysis. After controlling for potential confounders (e.g., subject characteristics, study design characteristics), the placebo response was found to be large and varied with the pain syndrome. Compared with diabetic neuropathic/polyneuropathic pain (DPN), the placebo response for a decline in pain intensity and responder rate was smaller in trials that assessed central pain and postherpetic neuralgia (PHN) and larger in trials that assessed HIV pain. The model-predicted mean decrease (95% confidence interval [CI]) from baseline in pain intensity (0-10 scale) was as follows: DPN, 1.45 (1.35 to 1.55); PHN, 1.16 (1.03 to 1.29); central pain, 0.44 (-0.41 to 1.30); HIV pain, 1.82 (1.51 to 2.12). The predicted responder rates (95% CI) were as follows: DPN, 20% (14.6 to 25.8); PHN, 11.5% (8.4 to 14.5); central pain, 7.2% (2.1 to 12.3); HIV pain, 42.8% (34.9 to 50.7). The type of treatment in the active arm also influenced the placebo response. Conclusions. Placebo response is influenced by the pain syndrome evaluated. These differences should be considered when evaluating novel compounds for the treatment of neuropathic pain conditions. Wiley Periodicals, Inc..

Rosenstock J.,Dallas Diabetes and Endocrine Center at Medical City | Aggarwal N.,Aggarwal and Associates Ltd. | Polidori D.,Janssen Global Services LLC | Zhao Y.,Janssen Global Services LLC | And 4 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS - This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed. RESULTS - Canagliflozin was associated with significant reductions in A1C from baseline (7.6-8.0%) to week 12: -0.79, -0.76, -0.70, -0.92, and -0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus -0.22% for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to -27 mg/dL, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low. CONCLUSIONS - Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females. © 2012 by the American Diabetes Association.

Willis M.,Swedish Institute for Health Economics | Asseburg C.,ESiOR Oy | He J.,Janssen Global Services LLC
Journal of Medical Economics | Year: 2013

Objective: This study constructed the Economic and Health Outcomes Model for type 2 diabetes mellitus (ECHO-T2DM), a long-term stochastic microsimulation model, to predict the costs and health outcomes in patients with T2DM. Naturally, the usefulness of the model depends upon its predictive accuracy. The objective of this work is to present results of a formal validation exercise of ECHO-T2DM. Methods: The validity of ECHO-T2DM was assessed using criteria recommended by the International Society for Pharmacoeconomics and Outcomes Research/Society for Medical Decision Making (ISPOR/SMDM). Specifically, the results of a number of clinical trials were predicted and compared with observed study end-points using a scatterplot and regression approach. An F-test of the best-fitting regression was added to assess whether it differs statistically from the identity (45°) line defining perfect predictions. In addition to testing the full model using all of the validation study data, tests were also performed of microvascular, macrovascular, and survival outcomes separately. The validation tests were also performed separately by type of data (used vs not used to construct the model, economic simulations, and treatment effects). Results: The intercept and slope coefficients of the best-fitting regression line between the predicted outcomes and corresponding trial end-points in the main analysis were -0.0011 and 1.067, respectively, and the R2 was 0.95. A formal F-test of no difference between the fitted line and the identity line could not be rejected (p=0.16). The high R2 confirms that the data points are closely (and linearly) associated with the fitted regression line. Additional analyses identified that disagreement was highest for macrovascular end-points, for which the intercept and slope coefficients were 0.0095 and 1.225, respectively. The R2 was 0.95 and the estimated intercept and slope coefficients were 0.017 and 1.048, respectively, for mortality, and the F-test was narrowly rejected (p=0.04). The sub-set of microvascular end-points showed some tendency to over-predict (the slope coefficient was 1.095), although concordance between predictions and observed values could not be rejected (p=0.16). Limitations: Important study limitations include: (1) data availability limited one to tests based on end-of-study outcomes rather than time-varying outcomes during the studies analyzed; (2) complex inclusion and exclusion criteria in two studies were difficult to replicate; (3) some of the studies were older and reflect outdated treatment patterns; and (4) the authors were unable to identify published data on resource use and costs of T2DM suitable for testing the validity of the economic calculations. Conclusions: Using conventional methods, ECHO-T2DM simulated the treatment, progression, and patient outcomes observed in important clinical trials with an accuracy consistent with other well-accepted models. Macrovascular outcomes were over-predicted, which is common in health-economic models of diabetes (and may be related to a general over-prediction of event rates in the United Kingdom Prospective Diabetes Study [UKPDS] Outcomes Model). Work is underway in ECHO-T2DM to incorporate new risk equations to improve model prediction. © 2013 All rights reserved: reproduction in whole or part not permitted.

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