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Numbers-needed-to-treat (NNT) are useful for presenting treatment response, conveying the clinical relevance of results. NNTs are typically calculated at a landmark endpoint (end of trial), but often using the last observation carried forward (LOCF), which ignores patient discontinuations. We compared NNTs in chronic low back pain (CLBP) using three separate imputation methods, using data from two identical 12-week trials comparing etoricoxib 60 mg (N=210), 90 mg (N=212), and placebo (N=217). We calculated the number of patients with improvements in pain intensity from baseline of ≥15%, ≥30%, ≥50%, and ≥70% at 2, 4, 8, and 12 weeks of treatment. For longitudinal response over time, patient discontinuations were assigned a 0% improvement from dropout forward. Landmark response at week 12 was assessed using LOCF and completer approaches, using only observed (non-missing) data. The longitudinal approach was most conservative; after 12 weeks 65% of patients taking etoricoxib had ≥15% improvement, 60% had ≥30% improvement, 45% had ≥50%, improvement, and 30% had ≥70% improvement, with placebo rates approximately 55%, 45%, 30%, and 15%, respectively. Response rates were higher with landmark analyses. Landmark NNTs at week 12 were generally similar or slightly lower (better) than those from a longitudinal approach, but results were inconsistent. Landmark analyses provide no information on response variability, as is obtained with longitudinal analysis. Outcome, imputation method, and reporting method are intimately connected and need to be considered alongside trial quality and validity to make sensible comparisons between treatments. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the 24-hour efficacy and tolerability of 2% dorzolamide/0.5% timolol fixed combination (DTFC) solution in open-angle glaucoma and ocular hypertension. RESEARCH DESIGN AND METHODS: Randomized, parallel, double-masked, multicenter study. Patients with insufficiently controlled intraocular pressure (IOP > or = 22 mmHg) were randomized to DTFC (N = 117) or timolol (N = 115). IOP was measured at baseline, 6 weeks, and 8 weeks, with measurements taken at 6 p.m., 8 p.m., 10 p.m., 2 a.m., 6 a.m., 8 a.m., 10 a.m., and 2 p.m. ClinicalTrials. gov identifier: NCT00108017 Main outcome measures: Statistically significant change in IOP from untreated baseline for DTFC at all hours at week 8. Secondary outcome measures included: IOP-lowering at week 6 at all individual time points, change from baseline to 8 weeks in mean daytime IOP (average of 8 a.m., 10 a.m., 2 p.m., 6 p.m., and 8 p.m. IOPs) and night-time IOP (10 p.m., 2 a.m., 6 a.m.), and comparison of DTFC with timolol after 8 weeks. RESULTS: Patients receiving DTFC had a statistically significant and clinically relevant reduction in IOP at week 8 compared with baseline at all eight time points (p < 0.001). Significant IOP reductions were also seen at all time points at week 6 (p < 0.001). DTFC significantly lowered mean daytime IOP and night-time IOP ( p < 0.001 for both). Timolol alone also significantly reduced IOP from baseline at 8 weeks for all diurnal time points, and mean daytime and night-time IOP ( p < 0.001 for all). Compared with timolol alone, there were significantly greater reductions with DTFC at 10 a. m. (p = 0.003) and 2 p. m. (p = 0.016), and for mean daytime IOP (p = 0.025) at 8 weeks. Significant between-treatment differences were not observed at other time points. Both treatments were well-tolerated, with no differences observed in the safety profiles between the treatment groups. CONCLUSIONS: Both DTFC and timolol provided significant IOP reduction over the entire 24-hour measurement period. Although this study was not designed or powered to compare DTFC and timolol, DTFC exhibited greater IOP-lowering than timolol during the daytime, but not at night. [ABSTRACT FROM AUTHOR]

Background and Objective: Disease history and clinical features can influence treatment response in patients with acute gout. The purpose of this pooled subgroup analysis was to assess the association of baseline disease and patient characteristics with response to treatment in acute gout using data from two identical studies.Methods: Patients > or = 18 years of age with onset of acute gout within 48 h associated with moderate, severe, or extreme pain involving less than four joints were eligible for inclusion in the primary studies, and were randomized to etoricoxib 120 mg once daily (N = 178) or indomethacin 50 mg three times daily (N = 161). The primary and secondary efficacy endpoints were analyzed using an analysis of covariance model to detect potential differential treatment responses across several subgroups: joint involvement (mono-articular vs. oligo-articular), baseline pain severity (moderate vs. severe), concomitant allopurinol and/or colchicine use (users vs. nonusers), age (< 45, 45-55, and > 55 years), gender, and race (white or other).Results: Overall, etoricoxib and indomethacin demonstrated comparable efficacy across all subgroups. Compared with patients with oligo-articular disease, those with mono-articular disease had significantly greater improvements in patient assessment of pain, patient global assessment of response to therapy (PGART), investigator global assessment of response to therapy (IGART), and study joint tenderness (p < 0.001 for all). Greater improvements were seen in patient assessment of pain (p < 0.001) and study joint tenderness (p < 0.05) for severe/extreme baseline pain compared with moderate baseline pain. Concomitant use of colchicine and/or allopurinol was associated with significantly worse IGART (p < 0.05).Conclusions: This pooled subgroup analysis demonstrated significantly greater response of acute gout to either etoricoxib or indomethacin among those with monoarticular disease, severe/extreme baseline pain, and non-use of colchicine and/or allopurinol. These results should be interpreted in the context of a pooled subgroup analysis with a limited sample size, and with the understanding that associations identified in such analyses do not define causation. Despite limitations, the results provide insights into the types of patients more likely to respond better to anti-inflammatory medication, and reiterate the importance of earlier effective control of the disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare the efficacy and tolerability of rofecoxib, hydrocodone/acetaminophen 7.5 mg/750 mg (H/A) and placebo in treating pain after arthroscopy of the knee. METHODS: A randomized, double-blind, placebo-controlled, single dose study enrolling patients experiencing moderate or severe pain after knee arthroscopy. Patients with moderate-to-severe postoperative pain received either rofecoxib 50 mg (n = 151), H/A (n = 145), or placebo (n = 147). Pain was measured over 24 h. The primary endpoint was total pain relief at 6 h for rofecoxib 50 mg compared with placebo. RESULTS: H/A (p = 0.003), but not rofecoxib (p = 0.256) was significantly more effective than placebo for total pain relief at 6 h (TOPAR6). Although analgesic onset and peak were significantly better for H/A than for both rofecoxib (p < 0.01, p < 0.05, respectively) and placebo (p < 0.05, p < 0.001, respectively), rofecoxib patients used significantly less rescue analgesia (p < 0.001) over 24 h. Rofecoxib also provided better Brief Pain Inventory Severity (p = 0.008) and Interference Domain (p = 0.045) scores at 24 h compared to placebo and had lower 24-h Pain Severity scores than H/A (p < 0.05). Treatments were generally well tolerated, with no significant difference in the frequency of patient-reported adverse events between groups. CONCLUSIONS: Rofecoxib 50 mg did not provide significantly different pain relief than placebo at 6 h, and the primary endpoint TOPAR was not attained, although it did show several efficacy benefits at 24 h, including a significant opioid-sparing effect. All treatments were well tolerated, with no significant differences observed. The limited efficacy of rofecoxib in this study contrasts to the results of previous surgical studies evaluating rofecoxib, and may be partially explained by the postoperative dosing in this arthroscopic surgical model. [ABSTRACT FROM AUTHOR]

Introduction Recent publications have described drug reaction with eosinophilia and systemic symptoms (DRESS) with topiramate. Topiramate has been associated with other severe cutaneous adverse reactions, including Stevens-Johnson syndrome, but a relationship to DRESS has not been established. To determine if there is a causal association between topiramate and DRESS, we conducted a comprehensive review of the data in the Janssen Research & Development Global Safety Database (GSD), signaling databases, and the literature. Methods The primary data were post-marketing reports of DRESS in the Janssen topiramate GSD (cumulative through 1 July 2022), representing >14,000,000 patient-years (PY) exposure. Cases were reviewed, assigned a Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) score, and assessed for overall contribution of topiramate to DRESS based on temporality, concomitant medications, dechallenge/rechallenge, and baseline patient factors. Statistical disproportionality was evaluated in European Medicines Agency's EudraVigilance (EV) safety database and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). For EV, the overall disproportionality threshold was the lower limit of the 95% confidence interval (CI) for the reporting odds ratio (ROR025) >1 and N ≥5. The overall threshold for FAERS was the Empirical Bayesian Geometric Mean (EBGM) ≥2, lower bound of the 90% CI (EB05) of >1, and N ≥3. To account for the role of concomitant drugs, Empirical Bayes regression-adjusted arithmetic mean (ERAM) scores were calculated, with a threshold ≥2, a lower bound of the 90% CI (ER05) of >1, and N ≥3. An integrated search of major biomedical literature was performed for reports of topiramate and DRESS. Results There were 17 reports of DRESS in the GSD (reporting rate 0.12/100,000 PY). RegiSCAR scores ranged from -3 to 7 (average -0.4). No cases met full diagnostic criteria and were highly confounded by the presence of other suspect drugs. Disproportionality scores exceeded thresholds for statistical significance in FAERS (N=72, EBGM=2.06, EB05=1.69), but not in EV (N=33, ROR025=0.79). When accounting for co-administered drugs, ERAM was statistically significant for carbamazepine (4.53), lamotrigine (ERAM=6.54), phenytoin (ERAM=2.91), and zonisamide (ERAM=2.25) exceeding disproportionality thresholds, but the score of topiramate was no longer significant (0.25). Conclusion A comprehensive review of all available evidence does not support a causal association between topiramate and DRESS., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Thoms et al.)

Cladribine is a purine analog used in first-line treatment of hairy cell leukemia and in relapsed/refractory chronic lymphocytic anemia. Although cladribine is typically associated with mild, self-limited skin reactions, there is increasing evidence that cladribine may increase the risk of severe cutaneous adverse reactions (SCAR) when combined with drugs classically associated with SCAR (e.g. allopurinol) beyond what would be expected for either drug alone, possibly due to cladribine-induced lymphopenia. We analyzed all SCAR cases reported for cladribine in Janssen's Global Safety Database and found that 26/35 (74.3%) reported concomitant drugs known to be associated with SCAR, most commonly sulfamethoxazole/trimethoprim (SMX/TMP) and allopurinol. In addition, a review of the WHO VigiBase showed that several drugs, including penicillins, SMX/TMP, and allopurinol had a statistically significant contribution to cladribine-associated SCAR. These results lend further support that cladribine may increase the propensity of these drugs to cause SCARs.

Introduction: The objective of this study was to describe the treatment patterns among patients with newly diagnosed multiple myeloma (MM) who had not received autologous stem cell transplantation (ASCT). It further compares the safety and clinical outcomes across different frontline regimens as well as explores whether treatment duration predicts outcomes., Methods: Patients with MM (> 45 years) who had not received ASCT were retrospectively identified from the US SEER-Medicare (Jan 2007-Dec 2016) and Optum (Jan 2007-Sep 2018) databases. Cox proportional hazard models were used to compare overall survival (OS) among bortezomib + lenalidomide + dexamethasone regimen (VRd), lenalidomide + dexamethasone regimen (Rd), cyclophosphamide + bortezomib + dexamethasone regimen (CyBorD), bortezomib + dexamethasone regimen (Vd), and other bortezomib-containing therapies based on propensity score matching. To address immortal time bias, time-fixed and time-dependent Cox models were employed to estimate the association of longer frontline treatment exposure with outcomes., Results: Mean (standard deviation; SD) age was 71 (9.8) years; and 49.51% were women. Bortezomib and lenalidomide-based combinations were the most common treatment modalities. After matching, the HR (95% CI) of OS by frontline therapies comparing VRd with Vd was 0.76 (0.66, 0.86), CyBorD was 0.87 (0.75, 1.05), for other bortezomib-based therapies was 0.56 (0.49, 0.64), Rd was 0.83 (0.73, 0.95), and for other therapies was 0.70 (0.61, 0.80). Longer frontline treatment duration was associated with better OS for overall frontline [HR (95% CI) 0.86 (0.82, 0.90)]; Vd [0.81 (0.74, 0.89)]; CyBorD [0.79 (0.64, 0.98)] and Rd [0.86 (0.78, 0.95)]., Conclusion: Results demonstrated that the frontline therapies prescribed to most patients who did not receive ASCT for MM in the United States were consistent with the NCCN guideline recommendations. Longer frontline treatment duration was associated with improved OS.

Background: Staphylococcus aureus is the most common and most important pathogen following knee and hip arthroplasty procedures. Understanding the epidemiology of invasive S. aureus infections is important to quantify this serious complication., Methods: This nested retrospective cohort analysis included adult patients who had undergone insertion of knee or hip prostheses with clean or clean-contaminated wound class at 11 hospitals between 2003-2006. Invasive S. aureus infections, non-superficial incisional surgical site infections (SSIs) and blood stream infections (BSIs), were prospectively identified following each procedure. Prevalence rates, per 100 procedures, were estimated., Results: 13,719 prosthetic knee (62%) and hip (38%) insertion procedures were performed. Of 92 invasive S. aureus infections identified, SSIs were more common (80%) than SSI and BSI (10%) or BSI alone (10%). The rate of invasive S. aureus infection/100 procedures was 0.57 [95% CI: 0.43-0.73] for knee insertion and 0.83 [95% CI: 0.61-1.08] for hip insertion. More than half (53%) were methicillin-resistant. Median time-to-onset of infection was 34 and 26 days for knee and hip insertion, respectively. Infection was associated with higher National Healthcare Safety Network risk index (p ≤ 0.0001)., Conclusions: Post-operative invasive S. aureus infections were rare, but difficult-to-treat methicillin-resistant infections were relatively common. Optimizing preventative efforts may greatly reduce the healthcare burden associated with S. aureus infections.

Staphylococcus aureus is a well-recognized, clinically important cause of nosocomial infections, and as such, a vaccine to prevent S. aureus infections would be an important achievement. A Phase IIB/III study of V710, a vaccine containing iron-regulated surface determinant B (IsdB), demonstrated significant sero-conversion rates in cardiovascular surgery patients following a single pre-surgery immunization. However, the vaccine was not efficacious in preventing bacteremia or deep sternal wound infection post-surgery, thus raising the possibility that IsdB might not be available for immune recognition during infection. The purpose of the work described herein was to evaluate and quantify the naturally occurring anti-IsdB levels at baseline and over time during infection, to understand whether IsdB is expressed during a S. aureus infection in hospitalized non-vaccinated patients. We evaluated baseline and follow-up titers in 3 populations: (1) healthy subjects, (2) hospitalized patients with non-S. aureus infections, and (3) hospitalized patients with S. aureus infections. Baseline anti-IsdB levels generally overlapped between the 3 groups, but were highly variable within each group. In healthy subjects, baseline and follow-up levels were highly correlated (Spearman's rho = 0.93), and the geometric mean fold-rise (GMFR) in anti-IsdB levels between study entry and last value was 0.9-fold (95% confidence interval (CI): 0.8 to 1.0 ; p = 0.09), showing no trend over time. The convalescent GMFR in anti-IsdB levels from baseline was 1.7-fold (95% CI: 1.3 to 2.2, p = 0.0008) during S. aureus infection, significantly different from the 1.0-fold GMFR (95% CI: 0.9-1.2, p = 0.60) in non-S. aureus infection, p = 0.005. Additionally, S. aureus isolates (51) obtained from the hospitalized patient group expressed the IsdB protein in vitro. Collectively, these data suggest that IsdB expression levels rise substantially following infection with S. aureus, but not with other pathogens, and IsdB is likely well-conserved across S. aureus strains.

Importance: Infections due to Staphylococcus aureus are serious complications of cardiothoracic surgery. A novel vaccine candidate (V710) containing the highly conserved S. aureus iron surface determinant B is immunogenic and generally well tolerated in volunteers., Objective: To evaluate the efficacy and safety of preoperative vaccination in preventing serious postoperative S. aureus infection in patients undergoing cardiothoracic surgery., Design, Setting, and Participants: Double-blind, randomized, event-driven trial conducted between December 2007 and August 2011 among 8031 patients aged 18 years or older who were scheduled for full median sternotomy within 14 to 60 days of vaccination at 165 sites in 26 countries., Intervention: Participants were randomly assigned to receive a single 0.5-mL intramuscular injection of either V710 vaccine, 60 μg (n = 4015), or placebo (n = 4016)., Main Outcome Measures: The primary efficacy end point was prevention of S. aureus bacteremia and/or deep sternal wound infection (including mediastinitis) through postoperative day 90. Secondary end points included all S. aureus surgical site and invasive infections through postoperative day 90. Three interim analyses with futility assessments were planned., Results: The independent data monitoring committee recommended termination of the study after the second interim analysis because of safety concerns and low efficacy. At the end of the study, the V710 vaccine was not significantly more efficacious than placebo in preventing either the primary end points (22/3528 V710 vaccine recipients [2.6 per 100 person-years] vs 27/3517 placebo recipients [3.2 per 100 person-years]; relative risk, 0.81; 95% CI, 0.44-1.48; P = .58) or secondary end points despite eliciting robust antibody responses. Compared with placebo, the V710 vaccine was associated with more adverse experiences during the first 14 days after vaccination (1219/3958 vaccine recipients [30.8%; 95% CI, 29.4%-32.3%] and 866/3967 placebo recipients [21.8%; 95% CI, 20.6%-23.1%], including 797 [20.1%; 95% CI, 18.9%-21.4%] and 378 [9.5%; 95% CI, 8.6%-10.5%] with injection site reactions and 66 [1.7%; 95% CI, 1.3%-2.1%] and 51 [1.3%; 95% CI, 1.0%-1.7%] with serious adverse events, respectively) and a significantly higher rate of multiorgan failure during the entire study (31 vs 17 events; 0.9 [95% CI, 0.6-1.2] vs 0.5 [95% CI, 0.3-0.8] events per 100 person-years; P = .04). Although the overall incidence of vaccine-related serious adverse events (1 in each group) and the all-cause mortality rate (201/3958 vs 177/3967; 5.7 [95% CI, 4.9-6.5] vs 5.0 [95% CI, 4.3-5.7] deaths per 100 person-years; P = .20) were not statistically different between groups, the mortality rate in patients with staphylococcal infections was significantly higher among V710 vaccine than placebo recipients (15/73 vs 4/96; 23.0 [95% CI, 12.9-37.9] vs 4.2 [95% CI, 1.2-10.8] per 100 person-years; difference, 18.8 [95% CI, 8.0-34.1] per 100 person-years)., Conclusions and Relevance: Among patients undergoing cardiothoracic surgery with median sternotomy, the use of a vaccine against S. aureus compared with placebo did not reduce the rate of serious postoperative S. aureus infections and was associated with increased mortality among patients who developed S. aureus infections. These findings do not support the use of the V710 vaccine for patients undergoing surgical interventions., Trial Registration: clinicaltrials.gov Identifier: NCT00518687.

Objective: The aim of this study is to assess the Pain Quality Assessment Scale (PQAS) in predicting pregabalin in peripheral neuropathic pain (NP)., Study Design: Post hoc analysis of a double-blind, placebo-controlled, enriched enrollment, randomized withdrawal trial evaluating pregabalin in 99 patients with NP who completed the PQAS, which comprises 20 questions regarding individual pain domains and qualities that are scored into three scales: paroxysmal, deep, and surface., Methods: Patients rated the average pain intensity and pain quality using the PQAS at baseline; average pain intensity was assessed again after 40 days of treatment with pregabalin. Associations between pretreatment PQAS scores and treatment response were estimated using Pearson's r. Logistic regression was used to identify pretitration PQAS scores contributing unique variance to predicting treatment response., Results: Fifty participants provided baseline PQAS scores and received pregabalin for the entire length of the study. Nine of 23 PQAS baseline scales and items were significantly associated with treatment response to pregabalin: the paroxysmal and deep scales, and the items assessing the following pain domains and qualities: intensity, electric, tingling, cramping, radiating, throbbing, and deep (P values range, 0.002-0.045; rs range, 0.28-0.43). The PQAS items assessing sharp, hot, and unpleasant pain items demonstrated nonsignificant trends (P < 0.10) to be associated with treatment response. In the logistic regression analysis, pretitration PQAS scores had 77% sensitivity and 83% specificity to correctly identify pregabalin responders. Significantly correlated PQAS items had a sensitivity of 85% and specificity of 76%., Conclusion: Pretitration PQAS scores reliably predicted pregabalin responders in patients with NP., (Wiley Periodicals, Inc.)

Introduction: The increased thrombotic cardiovascular (CV) risk in trials of cyclo-oxygenase-2 (COX-2) inhibitors versus placebo, and the apparent similar risk with nonsteroidal antiinflammatory drugs (NSAIDs), may be related to their potential to elevate blood pressure (BP)., Aims: We evaluated the relationship between baseline BP and change in BP on CV events (CVEs) in patients receiving NSAIDs or COX-2 inhibitors in the prospective randomized, double-blind, Multinational Etoricoxib and Diclofenac Arthritis Long-term Program (N = 34,701) comparing etoricoxib 60 or 90 mg or diclofenac 150 mg daily for a mean duration of 18 months. The main outcome measure was confirmed thrombotic CVEs. The Antiplatelet Trialists' Collaboration endpoint, all-cause mortality, CV/congestive heart failure (CHF) mortality, and CHF incidence were similarly evaluated., Results: We found that baseline systolic BP (SBP) was associated with significantly higher risk of all events (P < 0.001). Baseline diastolic BP (DBP) was inversely and significantly associated with risk of all events (P < 0.001 to P = 0.016) except CV/CHF mortality (P = 0.054). There was no significant differential effect between etoricoxib and diclofenac in relation to CVEs, except for confirmed CHF, for which the risk was significantly higher with etoricoxib (P = 0.019). Only CHF risk (P = 0.020 for both SBP and DBP change), but not thrombotic endpoints, was significantly associated with change in BP from months 0 to 4. These findings were not meaningfully altered after covariate adjustment for baseline CV risk., Conclusions: Baseline BP, but not change in BP, was significantly associated with risk of thrombotic CVEs through 18 months. The CV risk of COX-2s and NSAIDs did not appear to be related to the BP-elevating effects of these agents, although such analyses, i.e., from randomized controlled trials, are unable to definitively exclude such a relationship., (© 2011 Blackwell Publishing Ltd.)

Background: Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used., Objectives: We sought to develop a weighted and responsive measure of asthma disease activity., Methods: Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6)., Results: The ADAS-6 demonstrated content validity because its components assess different manifestations of asthma: FEV(1) (percent predicted), Asthma Quality of Life Questionnaire-Symptom domain, rescue β-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue β-agonist use diurnal variability. The ADAS-6 demonstrated cross-sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P < .0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties., Conclusions: The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Introduction: We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA)., Methods: A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15 mg or 7.5 mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP)., Results: All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures., Conclusions: Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy., Trial Registration: Clinicaltrials.gov identifier: NCT00746512.

Bacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses against Staphylococcus aureus in patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conserved S. aureus surface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 μg V710 (with or without adjuvant), 90 μg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a ≥2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a ≥2.5 GMFR in anti-IsdB antibodies compared to the baseline (P values of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis.

Objectives: In Japan, the Asthma Prevention and Management Guidelines recommend nebulized β-agonists, IV (intravenous) drip corticosteroids, as well as IV drip aminophylline for acute asthma treatment. However, current treatment for acute asthma provides inadequate benefit for some patients. We evaluated the efficacy and safety of IV montelukast added to standard therapy in Japanese patients with acute asthma exacerbations., Methods: This multicenter, randomized, double-blind, parallel-group study compared IV montelukast 7 mg, 14 mg, and placebo in Japanese patients with acute asthma exacerbations (N = 242). Fifteen- to sixty-five-year-old patients with acute asthma were treated with standard care during a screening period that lasted ≤60 minutes. Patients with FEV(1) (forced expiratory volume in 1 second) ≤70 predicted were randomly allocated to one of three treatment groups. The primary end point was the time-weighted average change in FEV(1) from baseline over 60 minutes [ΔFEV(1) (0-60 minutes)] after study drug administration. Secondary end points included the time-weighted average change in FEV(1) over 20, 40, and 120 minutes [ΔFEV(1) (0-T min)]., Results: IV montelukast 7 mg was significantly more effective than placebo for the time-weighted average ΔFEV(1) (0-60 minutes) [least squares (LS) mean 0.09 L vs. 0.01 L; p < .05]. IV montelukast 14 mg was also more effective than placebo (LS mean 0.17 L; p < .001). Similar improvements in time-weighted average [ΔFEV(1) (0-T min)] were seen at all time points (all p < .05). Both doses of IV montelukast demonstrated a significant increase in average ΔFEV(1) compared with placebo within 10 minutes of administration (p < .001 to p < .01). The tolerability of IV montelukast was similar to that of placebo., Conclusion: IV montelukast was significantly more effective than placebo in the improvement of ΔFEV(1) in Japanese patients, suggesting its role as an adjunctive therapy to existing guideline recommendations.

Classifying disease activity in asthma relies on clinical and physiological variables, but these variables do not capture all aspects of asthma that distinguish levels of disease activity. We used data from two pivotal trials of montelukast in asthma to classify disease activity as "high" or "low". We performed a principal component analysis (PCA) of disease activity using 21 efficacy outcome variables, including several novel derived outcome variables reflecting clinical and airway obstruction lability. Then we performed discriminant analysis (DA) based on disease activity classification. PCA revealed 6 factors (daytime asthma control, nighttime-predominant asthma control, airway obstruction, exacerbations, clinical lability, airway obstruction lability) that explained 76% of the variance between outcome variables. Although airway obstruction lability (comprising both diurnal variability in peak expiratory flow and diurnal variability in β-agonist use) accounted for only 6% of the explained variance in PCA, in DA it was more accurate (canonical coefficient 0.75) than traditional measures of asthma severity such as obstruction (-0.54) and daytime control (-0.56) in distinguishing between high and low disease activity. We conclude that airway obstruction lability, a parameter not typically captured in clinical trials, may contribute to more complete assessment of asthma disease activity and may define an emerging clinical target of future therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Merck V710 is a novel vaccine that contains the highly conserved Staphylococcus aureus iron surface determinant B (IsdB) protein. V710 has induced positive immune responses in healthy subjects. The purpose of the two studies described herein was to evaluate the immunogenicity and safety of two different formulations of V710. Both studies were randomized, controlled, double-blind, parallel-group trials. Study 1 compared liquid, aluminum-adjuvanted V710 (30 μg) with liquid, non-adjuvanted V710 (30 μg) in a 1:1 ratio in 64 healthy adults (18-70 years). Study 2 compared non-adjuvanted lyophilized V710 (60 μg) with saline placebo in a 4:1 ratio in 51 healthy adults (18-80 years). Blood was collected at screening and up to Day 360 postvaccination in Study 1, and at screening and up to Day 84 postvaccination in Study 2. Sera were analyzed for IsdB-specific antibodies using a total IgG assay. The primary endpoints in Study 1 were the proportion of patients with a positive immune response (≥2-fold rise in IsdB-specific IgG antibody level) the geometric mean concentration (GMC), and the geometric mean-fold rise (GMFR), all from baseline at Day 14. The primary endpoint in Study 2 was the GMFR in IsdB-specific IgG antibody concentration from baseline at Day 14. In Study 1, 84.4% responded in the adjuvanted V710 group, and 71.9% in the non-adjuvanted V710 group. The GMC was 115.4 μg/mL in the adjuvanted group and 99.1 μg/mL in the nonadjuvanted group. The GMFR in antibody concentration in the group receiving aluminum-adjuvanted V710 was 4.5 and the GMFR in the group receiving non-adjuvanted V710 was 4.0. In Study 2, the GMFR in antibody concentration in the V710 group was 5.3, and 80.5% had a positive immune response. None responded in the placebo group. Positive immune response was seen in the active treatment groups over the full duration of each study. There were no serious adverse experiences (AE) in either study, and no patients discontinued due to an AE. There were no clinically meaningful differences in AEs between groups in either study. In conclusion, V710, both with and without aluminum adjuvant, and in both liquid and lyophilized formulations, was immunogenic within 14 days of vaccination. All treatments showed similar safety profiles., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Leukotriene B4 (LTB(4)) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB(4), in addition to cysteinyl leukotrienes, could be beneficial in asthma. This was a randomized, double-blind trial of once-daily MK-0633, a potent 5-lypoxygenase inhibitor, 10 mg, 50 mg, and 100 mg, and placebo in patients 18-70 years with a history of chronic asthma, and FEV(1) ≥45 and ≤85% predicted. There was a 6-week main period and optional 18-week and 34-week periods (52 weeks total), the latter two comparing only MK-0633 100 mg and placebo. The primary endpoint was the change from baseline in FEV(1) over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, β-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-β-agonist FEV(1), and blood eosinophils. MK-0633 100 mg was significantly more effective than placebo for the change from baseline in FEV(1) (0.20 L vs. 0.13 L; p = 0.004). The other MK-0633 doses were not significantly more effective than placebo. MK-0633 (at various doses) was also more effective than placebo for β-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-β-agonist FEV(1) (p < 0.05 for all). MK-0633 was associated with a dose-dependent increase in elevated aspartate aminotransferase and alanine aminotransferase. Because of the relative benefit-risk ratio, the optional study periods were terminated after unblinding for the main study period. Overall, the benefit-risk ratio did not support the clinical utility of MK-0633 in asthma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Single-dose montelukast attenuates exercise-induced bronchoconstriction (EIB) in adults within 2 hours postdose and lasting through 24 hours. This study evaluated the onset and duration of EIB attenuation in children after a single dose of montelukast. A randomized, double-blind, placebo-controlled, two-period crossover study was performed. Patients (n = 66) aged 4-14 years, with preexercise forced expiratory volume in 1 second of (FEV(1)) ≥70% predicted and maximum percentage fall in FEV(1) of ≥20% at two screening exercise challenges were eligible. Patients were to receive single-dose montelukast (4 or 5 mg) or placebo before performing standardized exercise challenges at 2 and 24 hours postdose. A 3- to-7-day washout separated the two crossover periods. The primary end point was maximum percentage fall in FEV(1) after exercise challenge 2 hours postdose. Secondary end points included maximum percentage fall in FEV(1) after the 24-hour postdose challenge; each of the following at 2 and 24 hours postdose-maximum percentage fall in FEV(1) categorized as <10%, 10-20%, or >20%; area under the curve (AUC) during 60 minutes postchallenge; time to recovery of FEV(1) to within 5% of preexercise baseline; and need for rescue medication. The mean maximum percentage fall in FEV(1) after the 2-hour postdose exercise challenge was significantly attenuated after single-dose montelukast compared with placebo (15.35% versus 20.00%; p = 0.020). Montelukast was also significantly more effective than placebo for maximum percentage fall after the 24-hour challenge (12.92% versus 17.25%; p = 0.005), the categorized maximum percent fall in FEV(1) at 2 hours (p = 0.034), and AUC at 2 hours (p = 0.022) and 24 hours (p = 0.013). Single-dose montelukast provided rapid and sustained EIB attenuation in children. Clinicaltrials.gov identifier: NCT00534976.

Background: Clinical analgesic trials typically report response as group mean results. However, research has shown that few patients are average and most have responses at the extremes. Moreover, group mean results do not convey response levels and thus have limited value in representing the benefit-risk at an individual level. Responder analyses and numbers-needed-to-treat (NNT) are considered more relevant for evaluating treatment response. We evaluated levels of analgesic response and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score improvement and the associated NNTs., Methods: This was a post-hoc analysis of a 6-week, randomized, double-blind study (N = 387) comparing etoricoxib 90 mg, etoricoxib 120 mg, naproxen 1000 mg, and placebo in AS. Spine pain and BASDAI were measured on a 100-mm visual analog scale. The number and percentage of patients achieving ≥30% and ≥50% improvement in both BASDAI and spine pain were calculated and used to determine the corresponding NNTs. Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days of the time of discontinuation., Results: For etoricoxib 90 mg, etoricoxib 120 mg and naproxen 1000 mg, the NNTs at 6 weeks compared with placebo were 2.0, 2.0, and 2.7 respectively for BASDAI ≥30% improvement, and 3.2, 2.8, and 4.1 for ≥50% improvement. For spine pain, the NNTs were 1.9, 2.0, and 3.2, respectively, for ≥30% improvement, and 2.7, 2.5, and 3.7 for ≥50% improvement. The differences between etoricoxib and naproxen exceeded the limit of ±0.5 units described as a clinically meaningful difference for pain. Response rates and NNTs were generally similar and stable over 2, 4, and 6 weeks., Conclusions: For every 2 patients treated with etoricoxib, 1 achieved a clinically meaningful (≥30%) improvement in spine pain and BASDAI beyond that expected from placebo, whereas the corresponding values were approximately 1 in every 3 patients treated with naproxen. Use of NNTs and responder analyses provide additional, complementary information beyond population mean responses when assessing efficacy compared to placebo and amongst active therapies.

Background: The efficacy of oral montelukast in chronic asthma is well established. Montelukast is also an effective adjunctive therapy to inhaled corticosteroids (ICS) in asthma uncontrolled on ICS alone. Inhaled montelukast was recently shown to provide significant bronchodilation compared with placebo in patients with chronic asthma. The purpose of this study was to evaluate the efficacy of inhaled montelukast added to inhaled mometasone., Methods: This was an 8-week, multicenter, randomized, double-blind, placebo-controlled study comparing once-daily inhaled montelukast 1 mg plus inhaled mometasone 220 μg (delivered by separate dry powder inhalers) with placebo plus inhaled mometasone 220 μg. Men and women aged 15-85 years with chronic asthma, forced expiratory volume in 1 second (FEV(1)) 50-80% of the predicted value, and β-agonist reversibility ≥12% were eligible. Patients were required to meet a minimum symptom threshold while receiving open-label inhaled mometasone during a 3-week prestudy/run-in period. Patients received blinded (montelukast vs. placebo) treatment for 2 weeks, entered a 1-week washout period, then crossed over to the other treatment for 2 weeks. The primary endpoint was the average change from baseline in FEV(1) over the 2-week treatment period. Secondary endpoints included daytime and nighttime symptom scores. Other endpoints included short-acting β-agonist (SABA) use, asthma exacerbations, asthma control, peak expiratory flow (PEF), and blood eosinophil count., Results: A total of 134 patients were randomized. For the primary endpoint, change from baseline in FEV(1), inhaled montelukast plus inhaled mometasone was significantly more effective than placebo plus inhaled mometasone (least squares mean 0.22 L vs. 0.17 L; p = .033 [two-sided at α = 0.05]). Inhaled montelukast plus inhaled mometasone was also significantly more effective than placebo plus inhaled mometasone in improving daytime asthma symptom scores (p = .005) and nighttime asthma symptom scores (p = .015), increasing the percentage of days with asthma control (p = .004), decreasing the percentage of days with asthma exacerbations (p ≤ .001), and decreasing the blood eosinophil count (p = .013). Differences were not significant on AM or PM PEF or SABA use, although the latter approached significance (p = .073). Both treatments were well tolerated., Conclusion: Inhaled montelukast plus inhaled mometasone was significantly more effective than placebo plus inhaled mometasone in improving FEV(1), symptoms, asthma control, and blood eosinophil count.

Objective: Nonsteroidal anti-inflammatory drug (NSAID) responses in osteoarthritis (OA) are highly variable, often requiring multiple medication changes. We sought to determine pre-randomization predictors of response to NSAIDs in OA., Methods: Data were pooled from two identical 26-week double-blind, randomized flare design trials comparing etoricoxib 30 mg/day (N=475), celecoxib 200 mg/day (N=488), and placebo (N=244) in patients with OA of the hip or knee. This analysis was limited to the 12-week placebo-controlled period. Response at Week 12 was defined using Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Factors were analyzed using logistic regression and included age, race, gender, body mass index, index joint, screening (pre-washout) and baseline (post-washout) Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain, physical function, and stiffness, and patient global assessment of disease status, prior NSAID/coxib or acetaminophen use, American Rheumatology Association functional class, and disease duration., Results: We found that screening WOMAC physical function was the only factor that predicted response in all treatment groups; worse function was associated with lower odds of achieving an OMERACT-OARSI response at 12 weeks (odds ratio 0.84 placebo; 0.87 etoricoxib; 0.89 celecoxib; P<0.05 for all). However, the differences in WOMAC physical function between responders and nonresponders were small (∼5 mm on a 100-mm scale). No factor discriminated between the ability to predict placebo response from active treatment response., Conclusions: Lower levels of physical function decreased the odds of a response to NSAID treatment in OA, although the clinical significance is unknown given the small differences between responders and nonresponders. No other measured baseline variables consistently predicted response in these studies, which may reflect the known individual variability in NSAID response., (Wiley Periodicals, Inc.)

Chronic obstructive pulmonary disease (COPD) is associated with neutrophil-mediated inflammation, a potential target for treatment in COPD. We evaluated MK-0633, a 5-lipoxygenase inhibitor in patients with COPD. This was a 12 week, randomized, double-blind, multicenter study comparing MK-0633 100 mg and placebo in patients 40-75 years of age (N = 266) with COPD, post-β-agonist forced expiratory volume in 1 s (FEV(1)) 25%-75% predicted, and an FEV(1)/forced vital capacity ratio (FVC) ≤ 70%. Long-acting inhaled bronchodilators were permitted for approximately 50% of patients. The primary efficacy endpoint was the change from baseline in pre-dose (trough) FEV(1) measured over the last 2 weeks of the 12 week treatment period. The change in FEV(1) over the last 2 weeks of the 12 weeks treatment period compared to baseline was 0.015 L for MK-0633 and 0.0002 for placebo (p = 0.556). For COPD Global Evaluation, 75.4% of patients receiving MK-0633 reported feeling better vs. 59.8% of patients receiving placebo (p = 0.032). There were no other significant differences between treatments. MK-0633 was well-tolerated and comparable to placebo. The 5-LO inhibitor MK-0633 was not significantly more effective than placebo in improving FEV(1) from baseline in patients with COPD, although more patients reported feeling improved with MK-0633. Clinicaltrials.gov identifier: NCT00418613., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: The efficacy of oral montelukast has been well established in asthma and allergic rhinitis in adults and children. The purpose of this study was to evaluate dose-related bronchodilation and tolerability of inhaled montelukast., Methods: Randomized, double-blind, crossover, adaptive-design study comparing single-dose administration of inhaled montelukast versus placebo in patients age 15-65 years with chronic asthma (n = 68). Montelukast was delivered as a witnessed dose through dry powder inhaler at doses of 25, 250, or 1000 μg, and doses of 50, 100, and 500 μg could be used if needed based on a prespecified dose-response algorithm. Each administration was followed by a 4- to 7-day washout period before crossing over to the next treatment. The primary endpoint was the change from baseline in a forced expiratory volume in 1 second (FEV₁) over the first 4 hours after administration, calculated as a time-weighted average (ΔFEV₁ [0-4 hours]). Other endpoints included the onset and duration of bronchodilation and the effect of albuterol when added to inhaled montelukast., Results: Over 4 hours postdose, and compared with placebo (least-squares [LS] mean 0.03 L), inhaled montelukast 100 μg (0.13 L; p ≤ .001), 250 μg (0.10 L; p < .01), and 1000 μg (0.12 L; p ≤ .001) had significantly greater ΔFEV₁ (0-4 hours). At 24 hours postdose, inhaled montelukast 100 μg (0.10 L) and 1000 μg (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p < .05 vs. montelukast). Montelukast 1000 μg provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. -0.05 L), whereas montelukast 100 μg provided significant bronchodilation relative to placebo within 2 hours of dosing (0.09 L vs. 0.01 L). Montelukast (pooled doses) plus albuterol was significantly more effective than montelukast plus placebo for ΔFEV₁ (0-90 minutes) (0.34 L vs. 0.15 L; p = .015). The tolerability of inhaled montelukast was similar to that of placebo. No serious adverse experiences were reported., Conclusions: Inhaled montelukast provided significant bronchodilation compared with placebo as early as 20 minutes after the administration that persisted for 24 hours and provided additive bronchodilation to albuterol.

Background: Exercise-induced bronchoconstriction (EIB) can be variable in its presentation and severity. Evaluating patterns of placebo response and patient-related factors driving placebo response could facilitate more efficient clinical trials for EIB., Methods: Data were pooled from three randomized, double-blind, crossover trials evaluating single-dose montelukast 10 mg or placebo in patients (N = 160) 15-45 years of age with EIB, defined as maximum % fall in forced expiratory volume in one second (FEV₁) ≥20% after two screening exercise challenges. Serial exercise challenges were performed at 2, 8.5-12, and 24 h postdose. The authors evaluated the distribution and variability of placebo response. They also evaluated possible drivers of response, analyzing all baseline patient demographic and prerandomization screening visit pulmonary function data as single covariates in a simple univariate regression model for maximum % fall in FEV₁ while on placebo at 2 h postdose. All covariates with p values <.1 were entered into both stepwise forward and backward regression procedures to select the "best" model., Results: Placebo response was variable, and showed a significant non-normal distribution (p < .001). Significant predictors of a greater response to placebo included: higher screening FEV₁ % predicted (p <.001), smaller maximum % fall in FEV₁ in screening (p < .001), shorter time to recovery in screening (p = .007), more asthma-related health care visits in the previous year (p = .004), older age (p = .001), less frequent asthma awakenings in the previous month (p = .003), and less frequent asthma symptoms in the past year (p = .011)., Conclusion: Predictors of a larger placebo response were generally markers of less severe asthma and/or EIB. This may be related to EIB variability, spontaneous improvement, or the extent of placebo response relative to the outcomes in less severe patients.

Background: Pediatric asthma hospitalizations peak in early autumn., Objective: To determine the effectiveness of montelukast therapy in reducing the asthma burden in children when initiated prophylactically on school return., Methods: This was a randomized, multicenter, double-blind, placebo-controlled study of children with asthma aged 6 to 14 years. No minimum asthma symptoms were required, and patients could continue inhaled corticosteroid (ICS) use. Montelukast, 5 mg, chewable tablet (n = 580) or matching placebo (n = 582) was taken the night before the first day of school and nightly thereafter for 8 weeks. The primary end point was the percentage of days with worsening asthma, defined by one of the following: (1) increased beta-agonist use, (2) increased daytime symptoms, (3) awake "all night," (4) oral corticosteroid rescue or increased ICS use for worsening asthma, or (5) unanticipated health care utilization., Results: The reduction in the percentage of days with worsening asthma with montelukast use versus placebo use was not significant (24.3% vs 27.2%, P = .07). Prespecified subgroup analyses demonstrated nonsignificant trends favoring montelukast therapy in boys and older children but no effect by baseline ICS use or history of cold symptoms. Post hoc analysis showed a nonsignificant trend favoring montelukast therapy in reducing worsening asthma days for children commencing school after August 15 compared with earlier commencement., Conclusions: Montelukast use was not significantly more effective than was placebo use in reducing the percentage of days with worsening asthma when initiated at the start of the school year. The effect of montelukast treatment on the fall peak in asthma burden may depend on sex, age, and the date of school return., (Copyright 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the effect of montelukast, 5 mg, or inhaled salmeterol, 50 microg, added to inhaled fluticasone in reducing the maximum percentage decrease in forced expiratory volume in 1 second (FEV1) after a standardized exercise challenge and response to rescue bronchodilation with albuterol in children aged 6 to 14 years with persistent asthma and exercise-induced bronchoconstriction (EIB)., Methods: Randomized, double-blind, double-dummy, multicenter, 2-period, 4-week, crossover study conducted between December 22, 2005 and November 14, 2008 at 30 centers in Europe, Asia, Mexico, and South America. Patients with asthma receiving inhaled corticosteroids demonstrated an FEV1 of 70% or higher of the predicted value and EIB (defined as a decrease in FEV1 > or = 15% compared with preexercise baseline FEV1 on 2 occasions before randomization). Standardized exercise challenges were performed at baseline (prerandomization) and at the end of each active treatment period., Results: Of 154 patients randomized, 145 completed the study. Montelukast, compared with salmeterol, significantly reduced the mean maximum percentage decrease in FEV1 (10.6% vs 13.8%; P = .009), mean area under the curve for the first 20 minutes after exercise (116.0% x min vs 168.8% x min; P = .006), and median time to recovery (6.0 vs 11.1 minutes; P = .04). Response to albuterol rescue after exercise challenge was significantly greater (P < .001) with montelukast. Montelukast and salmeterol were generally well tolerated., Conclusions: Attenuation and response of EIB to albuterol rescue after exercise challenge were significantly better with montelukast than with salmeterol after 4 weeks of treatment.

Objective: To assess a walking model utilizing a set of standardized treadmill walks to measure acute analgesic response in osteoarthritis (OA) of the knee., Design: Randomized, double-blind, placebo-controlled, multiple dose, three-period crossover study. Patients > or =45 years of age (N=22) with symptomatic knee OA were randomized to naproxen 500 mg bid, tramadol/acetaminophen 37.5 mg/325 mg in forced titration, or placebo in each of three periods. Patients performed multiple 20-minute treadmill walks on Day 1 and Day 3 at a consistent self-selected pace predetermined at screening. Pain intensity (PI) during the walks was assessed on an 11-point numerical rating scale at 0, 3, 6, 9, 12, 15, 18, and 20 min. The primary endpoint was the time-weighted average (TWA) change from baseline PI on Day 3 for the two self-paced walks for the active treatments vs placebo. Time to moderate pain (TTMP) was a key secondary endpoint., Results: Compared with placebo, the TWA change from baseline PI on Day 3 was significantly better with tramadol/acetaminophen (P=0.043) but not with naproxen (P=0.089). TWA change from baseline on Day 1 was also significantly better with both tramadol/acetaminophen (P=0.001) and naproxen (P=0.048) compared with placebo. TTMP was significantly better for tramadol/acetaminophen and naproxen than placebo (P<0.001 to P=0.015) for walks on Day 1 after a single dose and on Day 3., Conclusions: This novel OA pain model was able to discriminate both tramadol/acetaminophen and naproxen from placebo after single and multiple doses. ClinicalTrials.gov identifier: NCT00772967., (Copyright 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effectiveness and tolerability of etoricoxib in patients with osteoarthritis (OA) with suboptimal response to existing pain regimens., Methods: A multicenter, prospective, open-label, single-arm study. OA patients (n = 500) taking nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics who had inadequate response as determined by their physicians (>or= 40 mm on a 0-100 mm pain scale) were switched directly to etoricoxib 60 mg once daily for 4 weeks without prior medication washout. The primary endpoint was the percentage of patients with >or= 30% improvement in Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) pain walking on a flat surface after 4 weeks of treatment. Other endpoints included WOMAC Pain, Stiffness, and Physical Function subscales, Brief Pain Inventory (BPI), investigator's global assessment of response to therapy (IGART), the Treatment Satisfaction Questionnaire for Medication (TSQM) and Short Form 36 (SF36). Safety and tolerability were assessed by collecting adverse events., Results: After switching to etoricoxib, 52% (95% confidence interval: 47%, 57%) of patients reported a clinically meaningful reduction (>or= 30%) for WOMAC pain walking on a flat surface. Disability in daily activities and pain interference were significantly improved (P < 0.0001). IGART scores improved after the switch to etoricoxib (P < 0.05). Results from TSQM demonstrated that patient perceptions of effectiveness, convenience and overall satisfaction increased. Etoricoxib was generally well tolerated in most patients. The most commonly reported adverse event was edema (4.2%)., Conclusions: In OA patients experiencing inadequate relief from a wide variety of analgesics, pain, function, quality of life, and treatment satisfaction significantly improved when switched to etoricoxib.

Background: Up to 30% of patients require hospitalization for acute asthma despite standard therapy in the emergency department. In adults, intravenous montelukast added to standard therapy significantly improved forced expiratory volume in 1 second (FEV1) and reduced hospital admissions compared with standard therapy alone., Objective: To evaluate the efficacy of intravenous montelukast added to standard therapy in children with acute asthma., Methods: This was a randomized, double-blind, placebo-controlled, multicenter study of children aged 6 to 14 years conducted from August 25, 2005 to March 17, 2008. Patients with an FEV1 of 75% or less of the predicted value after up to 120 minutes of standard therapy (e.g., oxygen, albuterol, inhaled anticholinergics, and systemic oral corticosteroids) were randomized to intravenous montelukast, 5.25 mg (n=145), or placebo (n=131) added to standard therapy. The primary end point was the time-weighted average change in FEV1 during 60 minutes (deltaFEV1[0-60 min]). Secondary end points included the percentage of patients in whom treatment failed (patients who required hospitalization or for whom a decision to discharge was not reached within 2 hours after drug administration) and the change from baseline in modified pulmonary index score after 60 minutes of treatment., Results: Montelukast was not significantly more effective than placebo for deltaFEV1[0-60 min] when added to standard therapy (0.08 vs. 0.07 L; least squares mean, 0.01; 95% confidence interval, -0.06 to 0.08; P = .78). No significant differences were found in the percentages of patients in whom treatment failed or the modified pulmonary index score after 60 minutes. Both treatments were well tolerated., Conclusions: In this study of children with acute asthma, intravenous montelukast was not significantly better than placebo in improving FEV1, symptoms, or overall hospital course.

Background: Patients with diabetes mellitus (DM) and metabolic syndrome are at increased risk of coronary heart disease (CHD). Studies have shown differential statin efficacy on low-density lipid cholesterol (LDL-C) by CHD risk strata., Objective: The aim of this study was to evaluate the consistency of effect with ezetimibe/simvastatin (E/S) combination therapy, atorvastatin, or rosuvastatin in patients with DM, metabolic syndrome, or neither condition (No DM/metabolic syndrome), stratified by the National Cholesterol Education Panel Adult Treatment Panel III (NCEP ATP III) CHD risk group., Methods: Post hoc analyses of 2 multicenter, double-blind, randomized, 6-week studies comparing E/S 10/10, 10/20, 10/40, or 10/80 mg with either atorvastatin 10, 20, 40, or 80 mg, or rosuvastatin 10, 20, or 40 mg. Treatments were compared by pooling across all doses for LDL-C reduction and NCEP LDL-C goal attainment in patients with DM, metabolic syndrome without DM, or No DM/metabolic syndrome across NCEP CHD risk strata., Results: NCEP LDL-C goal attainment was lowest in the high-risk group with atherosclerotic vascular disease (12-64%) and greatest in the moderate and low-risk groups (84-100%). In contrast, LDL-C reduction was generally similar irrespective of disease or risk subgroup. All treatments were generally well tolerated, with overall similar safety regardless of disease and risk level., Conclusions: In these studies, CHD risk strata were inversely related to the likelihood of attaining NCEP LDL-C goals, but did not appear to affect the percentage LDL-C change from baseline. This demonstrates the need for especially aggressive cholesterol lowering necessary to reach the lower LDL-C goal for high-risk patients.

Objective: We evaluated whether early response to NSAIDs predicted later response, and when this was established., Methods: We evaluated pooled data from two identical 26-week, double-blind, randomized trials comparing once-daily etoricoxib 30 mg (n = 475), celecoxib 200 mg (n = 488) and placebo (n = 244) in patients with knee or hip OA. The present analysis was limited to the 12-week placebo-controlled period. Patient-level OMERACT-OARSI response was determined at 2, 4, 8 and 12 weeks. The proportion of patients who maintained response status between these times was determined from binomial distribution using the exact method., Results: After 12 weeks of treatment, there were significantly more responders in the etoricoxib (59.8%) and celecoxib (57%) groups compared with placebo (34%; P < 0.001 for etoricoxib or celecoxib vs placebo). About 77.2% of the patients receiving etoricoxib, 75.4% celecoxib and 58% placebo (P = 0.001 vs etoricoxib; P = 0.003 vs celecoxib) who were responders at 2 weeks were also responders at 12 weeks. When comparing response agreement (responder or non-responder) at 2 weeks and 12 weeks, 74.3% of the patients receiving etoricoxib, 73.2% celecoxib and 71.3% placebo had the same response status (kappa-coefficient 0.459, 0.449 and 0.357, respectively). There were small incremental increases in agreement between Weeks 4 and 8 and 12 weeks. Logistic regression showed that agreement was not affected by index joint (P = 0.965)., Conclusions: The overwhelming majority of the patients who responded to treatment by 2 weeks remained responders at 12 weeks, with response status largely established within 2 weeks of treatment initiation. Early identification of NSAID response or non-response may allow clinicians to better and more rapidly adjust symptomatic OA management.

Purpose: To examine the response to intraocular pressure (IOP)-lowering medications as a function of glaucoma severity represented by visual field defects., Methods: Post hoc analysis of a multicenter, double-masked, parallel study comparing the 24-h efficacy of the dorzolamide/timolol fixed combination (N = 117) versus timolol alone (N = 115) in patients with open-angle glaucoma or ocular hypertension. Visual field scoring was performed independently by three glaucoma specialists. Two scoring systems were used: the Advanced Glaucoma Intervention Study (AGIS) scoring system and a classical visual field scoring system. Patients were divided into three groups based on their visual field scores. The changes from baseline daytime and nighttime mean IOP, and 24-h IOP fluctuation after 8 weeks of treatment by baseline glaucoma severity, were compared across treatments using a simple linear regression analysis., Results: Most (approximately 73%) patients had no visual field damage at baseline. With either dorzolamide/timolol or timolol alone, there was no significant difference in IOP response from baseline over 24 h based on the level of visual field damage, as measured by either the AGIS or the classic visual field scoring systems. The Pearson's rho correlations between the baseline AGIS score and the change in daytime IOP, nighttime IOP, and 24-h IOP range were 0.0024 (P = 0.97), -0.086 (P = 0.21), and 0.076 (P = 0.26), respectively. Correlations by classic score were 0.024 (P = 0.72), -0.074 (P = 0.28), and 0.061 (P = 0.37), respectively., Conclusions: This analysis showed no significant relation between the severity of baseline visual field defects and the ocular hypotensive efficacy of the dorzolamide/timolol fixed combination and timolol alone.

Aims: Non-steroidal anti-inflammatory drugs have been associated with increased risk of congestive heart failure (CHF). We aimed to assess the impact of treatment with etoricoxib or diclofenac on risk of CHF relative to baseline risk factors., Methods and Results: We performed a multivariate analysis of 34 701 patients with arthritis receiving etoricoxib 60 or 90 mg, or diclofenac 150 mg, daily for a mean of 18 months, to assess the incidence of confirmed, adjudicated CHF events resulting in emergency room visit or hospitalization. Analyses were performed using a Cox proportional hazard model to evaluate the hazard ratio (HR) between the levels of each risk marker for the incidence of CHF. Significant risk markers included history of CHF (HR: 6.69, 95% CI 3.59-12.47; P <0.0001), age > or = 65 years (2.56, 1.65-3.98; P <0.0001), and history of hypertension (1.83, 1.16-2.89; P = 0.0094) or diabetes (1.83, 1.15-2.94; P = 0.0116). Etoricoxib vs. diclofenac was a significant risk factor only when pooling the etoricoxib 90 mg cohorts (1.88; 1.13-3.10; P = 0.0143). Etoricoxib 60 mg did not significantly increase risk vs. diclofenac., Conclusion: History of CHF was highly associated with risk for CHF hospitalization. Hypertension, diabetes, and older age also increased risk modestly. There appeared to be a dose-related increase in CHF with etoricoxib compared with diclofenac, which reached statistical significance when the etoricoxib 90 mg groups (osteoarthritis and rheumatoid arthritis) were pooled.

Objective: To determine the effect of montelukast on asthma during the allergy season in children with persistent asthma and seasonal aeroallergen sensitivity., Design: This 3-week double-blind, placebo-controlled, parallel-group multicenter study compared daily montelukast 5 mg chewable tablets and placebo in patients 6-14 years of age with forced expiratory volume in 1 second (FEV(1)) > or = 60 and < or = 85% predicted, persistent asthma that is also active during allergy season, and documented sensitivity to seasonal allergens. Concomitant inhaled corticosteroid use was permitted in up to 40% of enrolled patients. The primary endpoint was the percentage change from baseline in FEV(1) over 3 weeks of treatment. Additional endpoints included the percentage change from baseline in beta-agonist use, average changes in daytime and nighttime symptom score, AM and PM peak expiratory flow rate (PEFR), investigator's global asthma evaluation, and parent/guardian global asthma evaluation at the end of the treatment period. Adverse experiences (AEs) were collected to assess safety and tolerability., Results: A total of 421 patients were randomized to montelukast (N = 203) or placebo (N = 218). For the primary endpoint, the percentage change from baseline FEV(1), montelukast was not significantly different from placebo (least squares mean 9.53% vs. 9.15%, respectively; p = 0.810). Compared with placebo, montelukast was associated with significantly lower (better) investigator's global asthma evaluation (LS mean 2.71 vs. 2.98; p < 0.05) and parent/guardian global asthma evaluation (LS mean: 2.63 vs. 2.90; p < 0.05) scores. There were no significant differences between treatment groups for the other efficacy evaluations. Both treatments were well tolerated, with no significant differences observed in AE rates., Conclusion: Montelukast did not significantly improve FEV(1) compared with placebo over three weeks of treatment during the allergy season in pediatric patients with seasonal allergen sensitivity. (ClinicalTrials.gov identifier: NCT00289874).

Objectives: To determine the proportion of responders in two identical osteoarthritis (OA) trials using Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria and to assess the comparability and correlation of individual component measurements., Methods: Data were pooled from two identical 26-week, double-blind, randomized, parallel, multicenter trials comparing once daily etoricoxib 30 mg (N=475), celecoxib 200 mg (N=488), and placebo (N=244) in patients with OA of the knee or hip. OMERACT-OARSI criteria were (1) improvement in pain or physical function > or =50% and an absolute change > or =20 mm on a 100-mm visual analog scale (VAS); or (2) improvement of > or =20% and with an absolute change > or =10 mm in at least two of the following three categories: pain, physical function, and patient's global assessment. Correlations were assessed between endpoints measured as time-weighted average change from baseline over 12 weeks using Pearson's correlation coefficient (r)., Results: There were significantly greater proportions of responders in the etoricoxib (66.2%) and celecoxib (63.5%) groups compared with the placebo group (43.0%; P<0.001). There was no difference between the two active treatment groups. There was high correlation between pain and physical function (r=0.903), pain and global assessment (r=0.778), and physical function and global assessment (r=0.820). There was high sensitivity (75-87%) and specificity (80-96%) for changes in individual component measurements to predict OMERACT-OARSI responders., Conclusions: Significantly more patients receiving etoricoxib or celecoxib than placebo were OMERACT-OARSI responders. The high correlation between individual scales composing this composite response measurement suggests some redundancies between individual components, particularly between pain and physical function.

Background: Patients with diabetes mellitus (DM) and metabolic syndrome (MS) are at increased risk of developing coronary heart disease., Objective: To compare the effects of ezetimibe/simvastatin (E/S) combination therapy, atorvastatin, and rosuvastatin in patients with DM, MS without DM, or neither disease., Methods: Subgroup analysis of data from two 6-week, randomized, double-blind trials comparing E/S 10/10, 10/20, 10/40, or 10/80 mg with either atorvastatin 10, 20, 40, or 80 mg (Study 1), or rosuvastatin 10, 20, or 40 mg (Study 2). Treatments were compared by pooling across all doses for effects on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), non-HDL-C, apolipoprotein B (ApoB), LDL-C:HDL-C, TC:HDL-C, and LDL-C goal attainment., Results: E/S provided greater improvements than atorvastatin or rosuvastatin in LDL-C, TC, HDL-C (vs atorvastatin only), non-HDL-C, LDL-C:HDL-C, TC:HDL-C, and ApoB in all disease subgroups. There were no interactions of treatment by disease subgroup for these parameters, indicating a consistent treatment difference favoring E/S effect across the disease subgroups. A greater percentage of patients receiving E/S than atorvastatin or rosuvastatin attained their individual National Cholesterol Education Program Adult Treatment Panel III LDL-C goals, LDL-C <100 mg/dL, LDL-C <70 mg/dL, and non-HDL-C goals regardless of subgroup. All treatments were well-tolerated, with generally similar adverse experience rates., Conclusions: Overall, E/S generally provided greater efficacy than either atorvastatin or rosuvastatin that was consistent across the subgroups of patients with DM, MS, or neither, in agreement with the results from the full study cohorts.

Study Design: Assessment of correlation of measures of low back pain (LBP) using data pooled from 2 identical studies., Objective: To assess the relative responsiveness of and correlation between various measures of LBP, including the Roland-Morris Disability Questionnaire (RMDQ), the LBP intensity (LBPI) visual analog scale (VAS), and patient's global assessment of response to therapy (PGART)., Summary of Background Data: Several tools are available to measure pain, functional limitation, and response to therapy for LBP. Studies have shown varying degrees of responsiveness and correlation., Methods: This was a pooled subgroup analysis of patients with chronic LBP from 2 identical studies comparing etoricoxib 60 mg, 90 mg, and placebo. LBP was assessed by the time-weighted average change from baseline over 12 weeks as measured by RMDQ, LBPI VAS, and PGART. Correlation was calculated using Pearson's correlation coefficient., Results: The correlation (r) between LBPI and RMDQ changes ranged from 0.657 and 0.703; correlations between LBPI and PGART changes ranged from 0.677 and 0.738. Cutpoints separating responders from nonresponders for all 3 measures fell near the 66.7th percentile of response and were consistent with minimal clinically significant changes identified in the literature., Conclusion: In this study, the RMDQ, LBPI VAS, and PGART showed a high degree of correlation in measuring response to therapy in LBP, suggesting clinicians may be able to simplify assessments.

Objective: To compare the efficacy of etoricoxib 30 mg with the generally maximum recommended dose of celecoxib, 200 mg, in the treatment of osteoarthritis (OA) in two identically designed studies., Methods: Two multi-centre, 26-week, double-blind, placebo-controlled, non-inferiority studies were conducted, enrolling patients who were prior non-steroidal anti-inflammatory drug (NSAID) or acetaminophen users. There were 599 patients in study 1 and 608 patients in study 2 randomized 4:4:1:1 to etoricoxib 30 mg qd, celecoxib 200 mg qd or one of two placebo groups for 12 weeks. After 12 weeks, placebo patients were evenly distributed to etoricoxib or celecoxib based on their initial enrollment randomization schedule. The primary hypothesis was that etoricoxib 30 mg would be at least as effective as celecoxib 200 mg for the time-weighted average change from baseline over 12 weeks for Western Ontario and McMaster (WOMAC) Pain Subscale, WOMAC Physical Function Subscale and Patient Global Assessment of Disease Status. Active treatments were also assessed over the full 26 weeks. Adverse experiences were collected for safety assessment., Results: In both studies, etoricoxib was non-inferior to celecoxib for all three efficacy outcomes over 12 and 26 weeks; both were superior to placebo (P < 0.001) for all three outcomes in each study over 12 weeks. The safety and tolerability of etoricoxib 30 mg qd and celecoxib 200 mg qd were similar over 12 and 26 weeks., Conclusions: Etoricoxib 30 mg qd was at least as effective as celecoxib 200 mg qd and had similar safety in the treatment of knee and hip OA; both were superior to placebo. ClinicalTrials.gov Identifiers: NCT00092768; NCT00092791.

Objective: These studies assessed the comparative efficacy of rofecoxib and valdecoxib in the treatment of acute postoperative dental pain., Methods: Two randomized, double-blind, placebo-controlled, single-dose studies were conducted in patients undergoing extraction of > or =2 third molars, with > or =1 mandibular impaction, who experienced moderate or severe pain after extraction. In study 1, patients were randomized in a 4:4:1 ratio to receive rofecoxib 50 mg, valdecoxib 20 mg, or placebo. In study 2, which was an exploratory study, patients were randomized in a 2:2:1 ratio to receive reofecoxib 50 mg, valdecoxib 40 mg, or palcebo. The primary efficacy end point was total pain relief at 12 hours (TOPAR12) for rofecoxib compared with valdecoxib 20 mg (study 1) or valdecoxib 40 mg (study 2). Tolerability was assessed based on clinical adverse experiences (AEs) and vital signs. These studies were performed before both agents were withdrawn from the market., Results: In study 1, 200 patients were randomized to receive rofecoxib 50 mg, 201 to valdecoxib 20 mg, and 49 to placebo. In study 2, 51 patients were randomized to receive rofecoxib 50 mg, 50 to valdecoxib 40 mg, and 24 to placebo. The majority of patients in both studies were female (approximately 54%) and white ( approximately 66%), with a mean age of approximately 22 years and a mean weight of approximately 75 kg. Most (approximately 58%) patients reported experiencing moderate postoperative pain. In study 1, mean TOPAR12 scores were 30.7 for rofecoxib 50 mg, 28.9 for valdecoxib 20 mg, and 5.5 for placebo; in study 2, TOPAR12 scores were 27.0 for rofecoxib 50 mg, 28.6 for valdecoxib 40 mg, and 6.9 for placebo. In both studies, the active treatments were comparable in terms of the primary end point and were statistically superior to placebo (P<0.001). In study 1, rofecoxib was associated with a longer median time to use of rescue medication compared with valdecoxib 20 mg (>24 hours vs 23 hours 58 minutes; P=0.010) and a significantly smaller proportion of patients using rescue medication over 24 hours (35.0% vs 50.2%; P<0.001). In study 2, there were no significant differences in the median time to use of rescue medication or the proportion of patients using rescue medication between active treatments. There were no significant differences in total pain relief at 4 or 8 hours, patients' global assessment, onset of analgesia, or AEs between active treatments in either study. The incidence of clinical AEs in study 1 was similar for rofecoxib 50 mg, valdecoxib 20 mg, and placebo (39.5%, 36.8%, and 49.0%, respectively). In study 2, AEs occurred significantly less frequently with rofecoxib 50 mg compared with placebo (35.3% vs 70.8%, respectively; P<0.01); there was no significant difference between the rate of AEs with valdecoxib 40 mg (50.0%) and placebo., Conclusions: Rofecoxib 50 mg had comparable analgesic efficacy to valdecoxib 20 and 40 mg in these patients with pain after dental surgery. All active treatments were well tolerated.

Objective: To compare the efficacy of rofecoxib and celecoxib for the treatment of knee or hip OA over 6 weeks., Methods: Two similarly designed, multicenter, randomized, double-blind, placebo-controlled studies. Patients were randomly assigned 3:3:3:1 in Study 1 to once daily (QD) rofecoxib 12.5 mg (N = 456), rofecoxib 25 mg (N = 459), celecoxib 200 mg (N = 456), or placebo (N = 150) and 3:3:1 in Study 2 to QD rofecoxib 25 mg (N = 471), celecoxib 200 mg (N = 460), or placebo (N = 151). There was no rofecoxib 12.5 mg arm in Study 2. The primary outcome measure of both studies was pain at night over 6 weeks for rofecoxib 25 mg vs. celecoxib 200 mg. Efficacy comparisons with rofecoxib 12.5 mg in Study 1 were included as pre-specified study objectives but not as pre-specified study hypotheses. Secondary endpoints included Patient Global Assessment of Response to Therapy (PGART) over 6 weeks and over 1 week. Safety was evaluated through the assessment of spontaneously reported adverse experiences (AEs), evaluation of vital signs, and laboratory data reported by investigators and patients., Results: For the primary endpoint, reduction in pain at night over 6 weeks in Study 1 was not significantly different between active treatments; in Study 2 rofecoxib 25 mg significantly (p = 0.023) reduced pain at night compared with celecoxib 200 mg over 6 weeks. For the secondary endpoints, in both studies, significantly (p < 0.05) more patients treated with rofecoxib 25 mg than celecoxib 200 mg had a good or excellent PGART over 6 weeks, and over the first week (p < 0.01). In both studies, there were no significant differences between active medications in the incidence of reported overall, serious, or drug-related AEs. The reported AE rates with the active treatments were generally similar to those with placebo in the two studies., Conclusions: Rofecoxib 25 mg was significantly better than celecoxib 200 mg in relieving night pain at 6 weeks in one study; this was not confirmed in the accompanying study.