Evaluation of the Patient Acceptable Symptom State in a pooled analysis of two multicentre, randomised, double-blind, placebo-controlled studies evaluating lumiracoxib and celecoxib in patients with osteoarthritis

Patient Acceptable Symptom State (PASS) is an absolute threshold proposed for symptomatic variables in osteoarthritis (OA) to determine the point beyond which patients consider themselves well and, as such, are satisfied with treatment. Two large previously reported studies of knee OA have shown that both lumiracoxib and celecoxib were superior to placebo in terms of conventional outcome measures. To assess the clinical relevance of these results from the patient's perspective, the same data pooled from these two studies were analysed with respect to the PASS. In total, 3,235 patients were included in two multicentre, randomised, double-blind studies of identical design. Patients were randomly assigned to receive lumiracoxib 100 mg once daily (n = 811), lumiracoxib 100 mg once daily with an initial dose of lumiracoxib 200 mg once daily for the first 2 weeks (100 mg once daily with initial dose [n = 805]), celecoxib 200 mg once daily (n = 813), or placebo (n = 806) for 13 weeks. Treatments were compared with respect to the PASS criteria (for OA pain, patient's global assessment of disease activity, and the Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3.1 [WOMAC™ LK 3.1] Function [difficulty in performing daily activities] subscale score). At week 13, 43.3%, 45.3%, and 42.2% of patients in the lumiracoxib 100 mg once daily, lumiracoxib 100 mg once daily with initial dose, and the celecoxib 200 mg once daily groups, respectively, considered their current states as satisfactory versus 35.5% in the placebo group. Similar results were observed for patient's global assessment of disease activity and WOMAC™ LK 3.1 Function subscale score. This post hoc analysis suggests that the statistical significance of the results observed with lumiracoxib or celecoxib compared with placebo using conventional outcome variables is complemented by clinical relevance to the patient. Trial registration numbers: NCT00366938 and NCT00367315

Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study

<p>Abstract</p> <p>Background</p> <p>Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate.</p> <p>Methods</p> <p>Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks.</p> <p>Results</p> <p>Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred.</p> <p>Conclusion</p> <p>The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate.</p> <p>Trial Registration</p> <p>(ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00784628">NCT00784628</a>)</p

Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes

<p>Abstract</p> <p>Background</p> <p>Down syndrome (DS; trisomy 21) is the most common genetic cause of mental retardation in the human population and key molecular networks dysregulated in DS are still unknown. Many different experimental techniques have been applied to analyse the effects of dosage imbalance at the molecular and phenotypical level, however, currently no integrative approach exists that attempts to extract the common information.</p> <p>Results</p> <p>We have performed a statistical meta-analysis from 45 heterogeneous publicly available DS data sets in order to identify consistent dosage effects from these studies. We identified 324 genes with significant genome-wide dosage effects, including well investigated genes like <it>SOD1</it>, <it>APP</it>, <it>RUNX1 </it>and <it>DYRK1A </it>as well as a large proportion of novel genes (N = 62). Furthermore, we characterized these genes using gene ontology, molecular interactions and promoter sequence analysis. In order to judge relevance of the 324 genes for more general cerebral pathologies we used independent publicly available microarry data from brain studies not related with DS and identified a subset of 79 genes with potential impact for neurocognitive processes. All results have been made available through a web server under <url>http://ds-geneminer.molgen.mpg.de/</url>.</p> <p>Conclusions</p> <p>Our study represents a comprehensive integrative analysis of heterogeneous data including genome-wide transcript levels in the domain of trisomy 21. The detected dosage effects build a resource for further studies of DS pathology and the development of new therapies.</p

The FunGenES Database: A Genomics Resource for Mouse Embryonic Stem Cell Differentiation

Embryonic stem (ES) cells have high self-renewal capacity and the potential to differentiate into a large variety of cell types. To investigate gene networks operating in pluripotent ES cells and their derivatives, the “Functional Genomics in Embryonic Stem Cells” consortium (FunGenES) has analyzed the transcriptome of mouse ES cells in eleven diverse settings representing sixty-seven experimental conditions. To better illustrate gene expression profiles in mouse ES cells, we have organized the results in an interactive database with a number of features and tools. Specifically, we have generated clusters of transcripts that behave the same way under the entire spectrum of the sixty-seven experimental conditions; we have assembled genes in groups according to their time of expression during successive days of ES cell differentiation; we have included expression profiles of specific gene classes such as transcription regulatory factors and Expressed Sequence Tags; transcripts have been arranged in “Expression Waves” and juxtaposed to genes with opposite or complementary expression patterns; we have designed search engines to display the expression profile of any transcript during ES cell differentiation; gene expression data have been organized in animated graphs of KEGG signaling and metabolic pathways; and finally, we have incorporated advanced functional annotations for individual genes or gene clusters of interest and links to microarray and genomic resources. The FunGenES database provides a comprehensive resource for studies into the biology of ES cells

Response to treatment according to criteria of Outcome Measures in Clinical Trials-Osteoarthritis Research Society International

<p><b>Copyright information:</b></p><p>Taken from "Evaluation of the Patient Acceptable Symptom State in a pooled analysis of two multicentre, randomised, double-blind, placebo-controlled studies evaluating lumiracoxib and celecoxib in patients with osteoarthritis"</p><p>http://arthritis-research.com/content/9/1/R11</p><p>Arthritis Research & Therapy 2007;9(1):R11-R11.</p><p>Published online 31 Jan 2007</p><p>PMCID:PMC1860070.</p><p></p> ***< 0.001 versus placebo logistic regression model unadjusted for multiple comparisons

Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3

<p><b>Copyright information:</b></p><p>Taken from "Evaluation of the Patient Acceptable Symptom State in a pooled analysis of two multicentre, randomised, double-blind, placebo-controlled studies evaluating lumiracoxib and celecoxib in patients with osteoarthritis"</p><p>http://arthritis-research.com/content/9/1/R11</p><p>Arthritis Research & Therapy 2007;9(1):R11-R11.</p><p>Published online 31 Jan 2007</p><p>PMCID:PMC1860070.</p><p></p>1. Function subscale score. Percentage of patients considering their state as satisfactory according to Patient Acceptable Symptom State (PASS) at weeks 2, 8, and 13. ***< 0.001 versus placebo logistic regression model unadjusted for multiple comparisons.Kaplan-Meier estimate of the probability of first sustained satisfaction with treatment maintained until week 13 according to PASS. < 0.001 versus placebo for all active treatments using both log-rank and Wilcoxon tests

Effect of risk factors on complicated and uncomplicated ulcers in the TARGET lumiracoxib outcomes study

BACKGROUND ; AIMS: Selective cyclooxygenase-2 inhibitors were developed to reduce the gastrointestinal risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs). The Therapeutic Arthritis Research and Gastrointestinal Event Trial was the largest study to evaluate primarily the gastrointestinal safety outcomes of selective cyclooxygenase-2 inhibitors. Data from the Therapeutic Arthritis Research and Gastrointestinal Event Trial were used to identify risk factors and investigate the safety of lumiracoxib in subgroups. METHODS: Patients with osteoarthritis (age, >or=50 y) were randomized to receive lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or ibuprofen 800 mg 3 times daily for 12 months. Events were categorized by a blinded adjudication committee. The primary end point was all definite or probable ulcer complications. RESULTS: For patients taking NSAIDs, factors associated with an increased risk of ulcer complications were age 65 years or older (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.48-3.59), previous history of gastrointestinal bleed or ulcer (HR, 3.61; 95% CI, 1.86-7.00), non-Caucasian racial origin (HR, 2.10; 95% CI, 1.35-3.27), and male sex (HR, 1.70; 95% CI, 1.08-2.68). With lumiracoxib, significant risk factors were age 65 years or older (HR, 3.18; 95% CI, 1.40-7.20), male sex (HR, 2.60; 95% CI, 1.25-5.40), non-Caucasian racial origin (HR, 2.16; 95% CI, 1.02-4.59), and concomitant aspirin use (HR, 2.89; 95% CI, 1.40-5.97). Increased risks in patients age 65 years and older were increased further if other risk factors were present. Lumiracoxib maintained an advantage over NSAIDs across all subgroups except aspirin use. CONCLUSIONS: Lumiracoxib was associated with a reduced risk of ulcer complications compared with NSAIDs in all significant subgroups except aspirin users

Two prospective, multicenter studies for the identification of biomarker signatures for early detection of pulmonary hypertension (PH): The CIPHER and CIPHER‐MRI studies

Publication status: PublishedFunder: Actelion Pharmaceuticals Ltd, a Johnson & Johnson CompanyAbstractA blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA‐based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER‐MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta‐analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC‐confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80–0.89] for microRNA‐alone and 0.90 [0.86–0.93] for microRNA+NT‐proBNP, and the corresponding specificities were 0.33 [0.24–0.44] and 0.28 [0.20–0.39]. Of 80 CIPHER‐MRI participants with evaluable data, 7 were considered PH‐positive by cMRI whereas 52 were considered PH‐positive by the microRNA signature. Due to low specificity, the CIPHER miRNA‐based signature for PH (either with or without NT‐proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis.</jats:p