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Evaluation of two doses of etoricoxib, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), in the treatment of Rheumatoid Arthritis in a double-blind, randomized controlled trial.

ABSTRACT: Treatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease.This was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required to have a diagnosis of RA (according to ARA 1987 revised classification criteria) and were to demonstrate symptom flare upon discontinuation of previous NSAID treatment prior to randomization. Part I was a 6-week, placebo-controlled period to assess the efficacy of etoricoxib 90 mg and etoricoxib 60 mg, each compared to placebo, as well as to each other. Part II was a 6-week period to evaluate the potential benefit of dose escalation from etoricoxib 60 mg to etoricoxib 90 mg after 6 weeks exposure to etoricoxib 60 mg in Part I compared to maintaining a steady dose of etoricoxib 60 mg throughout Parts I and II. Primary endpoints were Disease Activity Score evaluating 28 joints and C reactive protein level (DAS28-CRP) index and Patient Global Assessment of Pain (Pain) score (0-100 mm VAS) after 6 weeks of treatment in Part I. Adverse events were monitored throughout the study.In total, 1404 patients were randomized in a 2:7:7:8 ratio; 1228 patients completed Part I and 713 patients continued to Part II. Both etoricoxib doses were superior to placebo on both primary efficacy endpoints (p?=?0.004 for 60 mg and p?=?0.034 for 90 mg for DAS28-CRP; p?

SUBMITTER: Bickham K

PROVIDER: S-EPMC4977639 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Evaluation of two doses of etoricoxib, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), in the treatment of Rheumatoid Arthritis in a double-blind, randomized controlled trial.

Bickham Kara K Kivitz Alan J AJ Mehta Anish A Frontera Nancy N Shah Sandhya S Stryszak Paul P Popmihajlov Zoran Z Peloso Paul M PM

BMC musculoskeletal disorders 20160808

<h4>Background</h4>Treatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease.<h4>Methods</h4>This was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required t ...[more]

PMID: 27502582

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Project description:Human periodontal ligament (hPDL) fibroblasts play a major role during periodontitis and orthodontic tooth movement, mediating periodontal inflammation, osteoclastogenesis, and collagen synthesis. The highly COX-2-selective NSAID etoricoxib has a favorable systemic side effect profile and high analgesic efficacy, particularly for orthodontic pain. In this in vitro study, we investigated possible side effects of two clinically relevant etoricoxib concentrations on the expression pattern of mechanically strained hPDL fibroblasts and associated osteoclastogenesis in a model of simulated orthodontic compressive strain occurring during orthodontic tooth movement. hPDL fibroblasts were incubated for 72?h under physiological conditions with etoricoxib at 0??M, 3.29??M, and 5.49??M, corresponding to clinically normal and subtoxic dosages, with and without mechanical strain by compression (2?g/cm2) for the final 48?h, simulating conditions during orthodontic tooth movement in compressive areas of the periodontal ligament. We then determined gene and/or protein expression of COX-2, IL-6, PG-E2, RANK-L, OPG, ALPL, VEGF-A, P4HA1, COL1A2, and FN1 via RT-qPCR, ELISA, and Western blot analyses as well as apoptosis, necrosis, cell viability, and cytotoxicity via FACS, MTT, and LDH assays. In addition, hPDL fibroblast-mediated osteoclastogenesis was assessed by TRAP staining in coculture with RAW267.4 cells for another 72?h. Gene and protein expression of all evaluated factors was significantly induced by the mechanical compressive strain applied. Etoricoxib at 3.29??M and 5.49??M significantly inhibited PG-E2 synthesis, but not COX-2 and IL-6 gene expression nor RANK-L-/OPG-mediated osteoclastogenesis or angiogenesis (VEGF-A). Extracellular matrix remodeling (COL1A2, FN1) and bone anabolism (ALPL), by contrast, were significantly stimulated particularly at 5.49??M. In general, no adverse etoricoxib effects on hPDL fibroblasts regarding apoptosis, necrosis, cell viability, or cytotoxicity were detected. Clinically dosed etoricoxib, that is, a highly selective COX-2 inhibition, did not have substantial effects on hPDL fibroblast-mediated periodontal inflammation, extracellular matrix remodeling, RANK-L/OPG expression, and osteoclastogenesis during simulated orthodontic compressive strain.

Project description:OBJECTIVE:To assess the safety and efficacy of etoricoxib, a selective cyclo-oxygenase-2 inhibitor, in comparison with indometacin in the treatment of acute gouty arthritis. DESIGN:Randomised, double blind, active comparator controlled trial. SETTING:43 outpatient study centres in 11 countries. PARTICIPANTS:142 men and eight women (75 patients per treatment group) aged 18 years or over presenting with clinically diagnosed acute gout within 48 hours of onset. INTERVENTIONS:Etoricoxib 120 mg administered orally once daily versus indometacin 50 mg administered orally three times daily, both for 8 days. MAIN OUTCOME MEASURES:Patients' assessment of pain in the study joint over days 2 to 5 (primary end point); investigators' and patients' global assessments of response to treatment and tenderness of the study joint (key secondary end points). RESULTS:Etoricoxib showed efficacy comparable to indometacin. Patients' assessment of pain in the study joint (0-4 point Likert scale, "no pain" to "extreme pain") over days 2 to 5 showed a least squares mean change from baseline of -1.72 (95% confidence interval -1.90 to -1.55) for etoricoxib and -1.83 (-2.01 to -1.65) for indometacin. The difference between treatment groups met prespecified comparability criteria. All other efficacy end points, including those reflecting reduction in inflammation and analgesia, provided corroborative evidence of comparable efficacy. Significant pain relief was evident at the first measurement, 4 hours after the first dose of treatment. Prespecified safety analyses revealed that drug related adverse experiences occurred significantly less frequently with etoricoxib (22.7%) than with indometacin (46.7%) (P=0.003), although overall adverse experience rates were similar between the two treatment groups. CONCLUSION:Etoricoxib 120 mg once daily provides rapid and effective treatment for acute gouty arthritis comparable to indometacin 50 mg three times daily. Etoricoxib was generally safe and well tolerated in this study.

Project description:ObjectivePatients with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and are also commonly prescribed non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs). New in vitro evidence suggests that this increased CV risk may be mediated through aldosterone glucuronidation inhibition (AGI), which differs between NSAIDs (diclofenac>naproxen>indomethacin>ibuprofen). Our aim was to explore the association between ns-NSAID-related AGI and arterial dysfunction.MethodsThe extent (augmentation index, AIX%) and timing (reflected wave transit time, RWT, ms) of aortic wave reflection (measured using radial applanation pulse wave analysis, PWA, SphygmoCor device) were assessed on a single occasion in 114 consecutive RA patients without overt CV disease aged 40-65 years. A higher AIX% and lower RWT indicate arterial dysfunction. Assessment included a fasting blood sample, patient questionnaire and medical record review. Multivariate analysis was used to adjust for age, sex, mean blood pressure, smoking, cumulative erythrocyte sedimentation rate (ESR-years) and Stanford disability score.ResultsWe identified 60 patients taking ns-NSAIDs and 25 non-users. Using a ns-NSAID with the highest AGI was associated with a higher AIX% (and lower RWT) versus treatment with a ns-NSAID with the lowest AGI (diclofenac AIX% 32.3, RWT 132.7 ms vs ibuprofen AIX% 23.8, RWT 150.9 ms): adjusted mean differences AIX% 6.5 (95% CI 1.0 to 11.9; p=0.02); RWT -14.2 ms (95% CI -22.2 to -6.3; p=0.001). Indomethacin demonstrated an intermediate level of arterial dysfunction. In relation to arterial dysfunction, both indomethacin and naproxen were more similar to diclofenac than to ibuprofen.Conclusionsns-NSAID-related AGI is associated with arterial dysfunction in patients with RA. These findings provide a potentially novel insight into the CV toxicity of commonly used ns-NSAIDs. However, the findings are limited by the small number of patients involved and require further replication in a much larger study.

Project description:The aim of this study was to evaluate differences in T helper cell sub-types and osteoclast (OCs) precursors in peripheral blood between patients affected by early rheumatoid arthritis (eRA) and healthy controls. The effect of administration of cholecalcipherol on clinical and laboratory parameters was subsequently evaluated, by a parallel, randomized double blind, placebo controlled trial. Thirty nine eRA patients and 31 age-matched controls were enrolled and compared for levels of 25OH vitamin D, T helper cell sub-types, OCs precursors including both classical and non-classical and pro-inflammatory cytokines at baseline. Eligible patients were female ?18 years of age with a diagnosis of RA, as defined by the American College of Rheumatology 2010 criteria for <6 months prior to inclusion in the study. Patients with auto-immune or inflammatory diseases other than RA were excluded. Patients treated with glucocorticoids (GCs), disease modifying activity drugs and biologic agents within the past 6 months were also excluded. In the second phase of the study, eRA patients were randomly assigned to standard treatment with methotrexate (MTX) and GCs with (21) or without (18) cholecalcipherol (300,000 IU) and followed for 3 months; the randomization was done by computer generated tables to allocate treatments. Three patients didn't come back to the follow up visit for personal reasons. None of the patients experienced adverse events. The main outcome measures were T cells phenotypes, OCs precursors and inflammatory cytokines. Secondary outcome measure were clinical parameters. In eRA, 25OH vitamin D levels were significantly lower. CD4+/IFN?+,CD4+/IL4+, CD4+/IL17A+ and CD4+IL17A+IFN?+, cells were increased in eRA as well as non-classical OCs precursors, whereas T regulatory cells were not altered. TNF?, TGF?1, RANKL, IL-23 and IL-6 were increased in eRA. Non-classical OCs, IL-23 and IL-6 correlated with disease severity and activity. Standard treatment with MTX and GC ameliorated clinical symptoms and reduced IL-23, whereas it did not affect CD4+ cells sub-sets nor OCs precursors. After 3 months, the combined use of cholecalcipherol significantly ameliorated the effect of treatment on global health. In eRA, a significant imbalance in T CD4+ sub-types accompanied by increased levels of non-classical OCs precursors and pro-inflammatory cytokines was observed. A single dose of cholecalcipherol (300,000 IU) combined with standard treatment significantly ameliorates patients general health.

Project description:Optimal postoperative pain management is important to ensure patient comfort and early mobilization.In this double-blind, placebo- and active-controlled, randomized clinical trial, we evaluated postoperative pain following knee replacement in patients receiving placebo, etoricoxib (90 or 120 mg), or ibuprofen 1800 mg daily for 7 days. Patients ?18 years of age who had pain at rest ?5 (0-10 Numerical Rating Scale [NRS]) after unilateral total knee replacement were randomly assigned to placebo (N = 98), etoricoxib 90 mg (N = 224), etoricoxib 120 mg (N = 230), or ibuprofen 1800 mg (N = 224) postoperatively. Co-primary endpoints included Average Pain Intensity Difference at Rest over Days 1-3 (0- to 10-point NRS) and Average Total Daily Dose of Morphine over Days 1-3. Pain upon movement was evaluated using Average Pain Intensity Difference upon Knee Flexion (0- to 10-point NRS). The primary objective was to demonstrate analgesic superiority for the etoricoxib doses vs. placebo; the secondary objective was to demonstrate that the analgesic effect of the etoricoxib doses was non-inferior to ibuprofen. Adverse experiences (AEs) including opioid-related AEs were evaluated.The least squares (LS) mean (95% CI) differences from placebo for Pain Intensity Difference at Rest over Days 1-3 were -0.54 (-0.95, -0.14); -0.49 (-0.89, -0.08); and -0.45 (-0.85, -0.04) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.05 for etoricoxib vs. placebo). Differences in LS Geometric Mean Ratio morphine use over Days 1-3 from placebo were 0.66 (0.54, 0.82); 0.69 (0.56, 0.85); and 0.66 (0.53, 0.81) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.001 for etoricoxib vs. placebo). Differences in LS Mean Pain Intensity upon Knee Flexion were -0.37 (-0.85, 0.11); -0.46 (-0.94, 0.01); and -0.42 (-0.90, 0.06) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. Opioid-related AEs occurred in 41.8%, 34.7%, 36.5%, and 36.3% of patients on placebo, etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively.Postoperative use of etoricoxib 90 and 120 mg in patients undergoing total knee replacement is both superior to placebo and non-inferior to ibuprofen in reducing pain at rest and also reduces opioid (morphine) consumption.NCT00820027.

Dataset Information

Evaluation of two doses of etoricoxib, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), in the treatment of Rheumatoid Arthritis in a double-blind, randomized controlled trial.

Publications

Evaluation of two doses of etoricoxib, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), in the treatment of Rheumatoid Arthritis in a double-blind, randomized controlled trial.

Similar Datasets

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