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PURPOSE Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus–positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1–positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION Here, we present the longest observation to date of patients with aMCC receiving first-line anti–programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.

5570 Background: In Study 309/KEYNOTE-775, lenvatinib + pembrolizumab (L+P) demonstrated significant and clinically meaningful improvement in OS, PFS, and ORR compared with TPC in aEC pts following prior platinum-based systemic therapy. Given the medical complexity/age of EC pts, QoL analyses are critical, but often under-reported. We present results of pt-reported HRQoL for Study 309/KEYNOTE-775. Methods: Pts were randomized 1:1 to receive lenvatinib 20 mg QD PO + pembrolizumab 200 mg IV Q3W (n=411) or TPC (n=416; doxorubicin 60 mg/m2 IV Q3W or paclitaxel 80 mg/m2 IV QW, 3 wks on/1 wk off). Pt-reported HRQoL was assessed at cycle 1 day 1, day 1 of each subsequent cycle and at time of discontinuation using EORTC QLQ-C30, its EC module QLQ-EN24, and EQ-5D-5L in treated pts who had ≥1 HRQoL assessment available. Higher scores indicate better functioning/QoL (EORTC QLQ-C30, EQ-5D-5L) or worse symptom severity (QLQ-EN24). Changes in EORTC QLQ-C30 global health status (GHS)/QoL was a secondary endpoint. This was analyzed from baseline to the latest timepoint at which overall completion was ≥60% and overall compliance was ≥80%, using constrained longitudinal data analysis; other HRQoL analyses were exploratory. Results: Completion and compliance rates of EORTC QLQ-C30 were >95% in both groups at baseline. Primary analysis was conducted at wk 12 as completion rate was 80% for L+P and 62% for TPC; compliance rate was 93% for L+P and 87% for TPC. Baseline GHS/QoL scores were similar between the L+P group and TPC group: mean (SD) of 65.74 (21.87) vs 65.69 (22.71), respectively. Over 12 wks of follow-up, pts in both groups had slight decreases in GHS/QoL. Similar decreases were observed for pts receiving L+P vs TPC: -5.97 (95% CI: -8.36, -3.58) vs -6.98 (95% CI: -9.63, -4.33). The between-group difference in least-squares (LS) mean score change from baseline to wk 12 for L+P vs TPC was 1.01 points (95% CI: -2.28, 4.31). Over time, QoL scores were generally similar across treatments. Results were similar for other HRQoL endpoints (Table). Conclusions: No significant differences were observed in HRQoL scores between treatment groups. With no standard treatment approach following failure of platinum-based therapy, these data along with previously reported efficacy and safety findings from Study 309/KEYNOTE-775 further support that L+P has an overall favorable benefit/risk profile compared to chemotherapy. Clinical trial information: NCT03517449. [Table: see text]

Background Worsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A 1 antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A 1 antagonist (A 1 RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF. Methods and Results Seventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine ≥0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60. Conclusions The Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A 1 RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A 1 antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy.

Aim: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are both associated with increased risk for atherosclerotic coronary heart disease (CHD). Thus, it is useful to know the relative efficacy of lipid-altering drugs in these patient populations. Methods: A double-blind, parallel group trial of adult patients with hypercholesterolaemia at high-CHD risk receiving atorvastatin 40 mg/day compared atorvastatin 40 mg plus ezetimibe 10 mg (ezetimibe) vs. doubling atorvastatin to 80 mg. This post hoc analysis reports lipid efficacy results in patients grouped by diagnosis of T2DM, MetS without T2DM or neither. Per cent change from baseline at week 6 was assessed for LDL-C, total cholesterol, HDL-C , non-HDL-C , Apo A-I, Apo B and triglycerides. Safety was monitored through clinical and laboratory adverse events (AEs). Results: Compared with doubling atorvastatin, atorvastatin plus ezetimibe resulted in greater reductions in LDL-C, triglycerides, Apo B, non-HDL-C, total cholesterol and lipid ratios in the T2DM, MetS and neither groups. Treatment effects were of similar magnitude across patient groups with both treatments, except triglycerides, which were slightly greater in the T2DM and MetS groups vs. neither group. Changes in HDL-C , Apo A-I and high sensitivity C-reactive protein (hs-CRP) were comparable for both treatments in all three groups. Safety and tolerability profiles were generally similar between treatments and across patient groups, as were the incidence of liver and muscle AEs. Conclusions: Compared with doubling atorvastatin to 80 mg, addition of ezetimibe to atorvastatin 40 mg produced greater improvements in multiple lipid parameters in high-CHD risk patients with T2DM, MetS or neither, consistent with the significantly greater changes observed in the full study cohort (clinical trial # NCT00276484).

The percentage of change from baseline in low-density lipoprotein (LDL) cholesterol after the addition of ezetimibe 10 mg to atorvastatin 40 mg was compared with uptitration to atorvastatin 80 mg. In this multicenter, double-blind, parallel-group study, adult hypercholesterolemic patients using atorvastatin 40 mg/day were randomly assigned to atorvastatin 40 mg plus ezetimibe 10 mg or uptitration to atorvastatin 80 mg. After 6 weeks of treatment, compared with atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe significantly reduced the primary end point of LDL cholesterol by -27% versus atorvastatin 80 mg by -11% (p

The aim of this study was to evaluate the efficacy and safety of ezetimibe 10 mg added to atorvastatin 20 mg compared with doubling atorvastatin to 40 mg in patients with hypercholesterolemia at moderately high risk for coronary heart disease who did not reach low-density lipoprotein (LDL) cholesterol levels

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.

Background Montelukast has proven efficacy in the treatment of chronic asthma and seasonal allergic rhinitis, but it has not been evaluated in the subpopulation of asthmatic patients with seasonal asthma symptoms. Objective To determine the effectiveness of montelukast treatment in improving the control of asthma symptoms during the allergy season in patients with active asthma and seasonal aeroallergen sensitivity. Methods Adults with a history of chronic asthma who are also symptomatic during the allergy season and with skin test sensitivity to seasonal aeroallergens were enrolled in a randomized, parallel-group, multicenter study with a 1-week, single-blind, placebo run-in period followed by 3 weeks of doubleblind treatment during the spring of 2004. After the run-in period, eligible patients were randomly assigned to receive either oral montelukast (10 mg) or placebo. Daytime and nighttime asthma symptom scores, β-agonist use, and morning and evening peak expiratory flow rates were recorded daily using an electronic diary. The primary end point was mean change from baseline to week 3 in the daytime asthma symptom score. Results Of 455 randomized patients, 433 completed the study. Compared with placebo, treatment with montelukast resulted in a significant improvement from baseline in the daytime asthma symptom score (−0.54 vs −0.34; P = .002) and in β-agonist use, nighttime symptoms, and peak expiratory flow rates. Few patients in the montelukast and placebo groups discontinued study participation because of asthma (1.3% and 3.0%, respectively). Conclusion In patients with chronic asthma and seasonal aeroallergen sensitivity, montelukast treatment provided significant asthma control during the allergy season compared with placebo.

To determine analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with acetaminophen/codeine 600/60 mg, we conducted a double-blind, randomized, placebo- and active-comparator-controlled, parallel-group study.Patients (N = 390) experiencing moderate or severe pain postextraction of 2 or more third molars, with at least 1 mandibular impaction, were randomized to placebo (n = 30), rofecoxib (n = 180), or codeine/acetaminophen 60/600 mg (n = 180). Time to confirmed perceptible pain relief, and patient evaluations of pain intensity, pain relief, and global assessments were recorded.For total pain relief over 6 hours (primary end point), rofecoxib was superior to codeine/acetaminophen (15.5 vs 10.7; P.001). Rofecoxib was statistically significantly superior to codeine/acetaminophen with respect to TOPAR4, patient global assessment, peak pain relief, and duration of analgesic effect. Median onset of analgesia was similar for both drugs. The codeine/acetaminophen group had more patients with 1 or more adverse events.Rofecoxib provided superior analgesic efficacy compared with codeine/acetaminophen with fewer gastrointestinal and nervous system adverse events.

The relative efficacy of rofecoxib, diclofenac sodium, and placebo were compared in the treatment of acute pain after bunionectomy surgery.This was a double-blind, randomized, two-part study of 252 patients with moderate-to-severe pain the day after first metatarsal bunionectomy. Patients were treated with a single dose of rofecoxib 50 mg (N = 85), enteric-coated diclofenac sodium 100 mg (N = 85), or placebo (N = 82) on study Day 1 (Part I), and subsequently with daily rofecoxib 50 mg or placebo (diclofenac patients switched to placebo) over study Days 2-5 (Part II). Patients rated their pain at 16 time points over the first 24 h. Primary endpoint was total pain relief over 8 h (TOPAR8). Pre-specified secondary endpoints on Day 1 included onset of analgesia, peak pain relief, and duration of response. For Part II, supplemental analgesia use with rofecoxib compared to placebo was pre-specified for analysis over Days 2-5, with the focus on Days 2-3. Adverse experiences were recorded over Days 1-5.For TOPAR8 scores, rofecoxib 50 mg was significantly more effective than placebo (9.5 vs. 3.7, p0.001) and diclofenac (9.5 vs. 5.0, p0.001). Onset of analgesia was more rapid with rofecoxib than placebo (p = 0.003) and diclofenac (p = 0.019); proportion of patients achieving onset within 4 h with rofecoxib, diclofenac, and placebo was 46%, 27%, and 23%, respectively. Peak pain relief was greater with rofecoxib (1.8) than diclofenac (1.2, p = 0.004) and placebo (1.0, p0.001). Diclofenac and placebo patients required supplemental analgesia sooner than rofecoxib patients (2:03 h vs. 4:02 h, p0.001 and 1:41 h vs. 4:02 h, p0.001). Rofecoxib patients used significantly less (p0.001) supplemental analgesia than placebo patients over Days 2-3 (1.1 tablets/day vs. 2.1 tablets/day) and Days 2-5 (0.9 tablets/day vs. 1.8 tablets/day). No significant differences in adverse experiences between treatments were seen.Rofecoxib 50 mg was significantly more effective than placebo on all measures of treatment of post-bunionectomy pain. Rofecoxib 50 mg was significantly more effective than diclofenac sodium 100 mg based on Day 1 endpoints of total pain relief, onset time, and duration of response. All study medications were generally well tolerated.

Objective : To describe the variability of the asthma phenotype in patients with mild persistent asthma enrolled in the Mild Asthma Montelukast versus Inhaled Corticosteroid (MIAMI) study. Methods : The variability of asthma rescue-free days, asthma symptoms, albuterol use, medical resource use, and exercise limitations among patients with documented mild persistent asthma was compared between the month before study enrollment and the last 2 weeks of the run-in period. Results : Patients eligible for randomization ( n =400), aged 15–85 years, exhibited symptoms (mean±sd) 3.6±1.3days/week, β -agonist use 3.5±1.3 days/week, and normal FEV 1 (94.0±9.9% predicted) during the last 2 weeks of the run-in period. In the year before enrollment, medical intervention for asthma flares was common: 38.5% made office visits, 15.8% had oral corticosteroids, and 8.3% required emergency room or hospitalized care. In the month before enrollment, 11.8% experienced daily symptoms, and 28.3% had limitations of normal activity. Patients with daily symptoms in the month before study enrollment, compared with those having less-than-daily symptoms, experienced fewer rescue-free days ( P =0.024) and had more days per week with symptoms ( P =0.008) and requiring albuterol ( P =0.048) during the run-in; FEV 1 was similar for both groups (93.1% vs. 94.2% predicted, respectively). Conclusion : Patients with mild persistent asthma reported a substantial disease burden in the year before enrollment. The asthma burden experienced by these patients both before and during the run-in period was of sufficient severity to support the recommendation that mild persistent asthma should be managed with daily controller therapy.

To compare the efficacy of a single dose of rofecoxib 50 mg with a single dose of oxycodone/acetaminophen 10/650 mg over 6 h as well as with a multidose regimen of oxycodone/acetaminophen 10/650 mg followed by oxycodone/acetaminophen 5/325 mg over 24 h.In this double-blind, randomized, two-phase study, patients with moderate to severe pain after surgical extraction ofor= 2 third molars, including one mandibular impaction, were treated with rofecoxib 50 mg, oxycodone/acetaminophen 10/650 mg (singledose phase) followed by 5/325 mg every 6h as needed (multidose phase), or placebo. Patients rated their pain relief and intensity at 18 time points over 24 h. Efficacy was measured over 6 and 24 h by total pain relief (TOPAR), sum of pain intensity difference (SPID), and patient global assessment of response to therapy (PGART). Primary endpoint for the single dose comparison was TOPAR over 6 h; SPID was the key 24-h endpoint. Onset of analgesic effect, peak analgesic single dose of oxycodone/acetaminophen. effect, and duration of analgesic effect were also evaluated. Adverse experiences were recorded.271 patients were randomized to treatment with rofecoxib (n = 121), oxycodone/acetaminophen (n = 120), or placebo (n = 30). For the single dose comparison, rofecoxib-treated patients achieved pain relief at least as effective as oxycodone/acetaminophentreated patients as assessed by TOPAR6 (12.9 vs 11.3, 95% CI on difference = [-0.1, 3.2], p = 0.059). Patients also rated a single dose of rofecoxib as at least as effective as multidose oxycodone/acetaminophen over 24 h on SPID24 (21.9 vs 18.1, 95% CI on difference = [-1.0, 8.8], p = 0.122). Patients treated with oxycodone/ acetaminophen had a shorter time to onset of analgesia than patients treated with rofecoxib (24 vs 35 min, p0.05). Patients in the active treatment groups achieved similar peak effects during the single-dose phase. Individuals treated with rofecoxib demonstrated a longer duration of analgesic effect than those treated with a Patients on active treatment demonstrated better efficacy than patients on placebo on these prespecified endpoints (p0.001 for both comparisons). Fewer rofecoxib than oxycodone/acetaminophen patients experienced adverse events (47.9 vs 75.8%, p0.001), including nausea (19.0 vs 42.5%, p0.001), vomiting (9.9 vs 24.2%, p0.01), and dizziness (7.4 vs 31.7%, p0.001).Patients treated with a single dose of rofecoxib 50 mg achieved an overall analgesic effect at least as effective as patients treated with a single-dose of oxycodone/acetaminophen 10/650 mg over 6 h and multidose oxycodone/acetaminophen over 24 h, with fewer adverse experiences of nausea (p0.001), vomiting (p0.01), and dizziness (p0.001).

We conducted a multicenter, single-blind, randomized comparison of the immunogenicity and safety of three manufacturing-scale lots of 7.5 μg liquid Haemophilus influenzae type b polysaccharide- Neisseria meningitidis conjugate vaccine (PRP-OMPC) and a single lot of 15.0 μg lyophilized PRP-OMPC. A total of 908 infants were entered into the study. Each infant received two primary injections intramuscularly 2 months apart beginning at age 2–6 months and a booster injection at 12–15 months. Blood samples for serology were obtained before each injection and 1 month after the second and the booster dose. Immune responses were measured by radioimmunoassay. Approximately 80% of the infants achieved a titer >1.0 μg ml −1 after the second primary dose of all four lots tested; the geometric mean titer (GMT) was ca 3 μg ml −1 for each vaccine group. After the booster dose, more than 90% of infants from each vaccine group had a titer >1.0 μg ml −1 ; GMTs ranged from 8 to 10 μg ml −1 . No serious vaccine-associated adverse reactions were reported. Thus the 7.5 μg liquid PRP-OMPC vaccine was at least as immunogenic and well tolerated as the 15.0 μg lyophilized vaccine.

Age, gender, and race are factors that influence atherosclerotic coronary heart disease (CHD) risk and may conceivably affect the efficacy of lipid-altering drugs.Post hoc analysis of two multicenter, 6-week, double-blind, randomized, parallel-group trials assessed age (65 and ≥ 65 years), gender, and race (white, black, and other) effects on atorvastatin plus ezetimibe versus up-titration of atorvastatin in hypercholesterolemic patients with CHD risk. High CHD risk subjects with low-density lipoprotein (LDL) cholesterol levels ≥ 70 mg/dL (~1.81 mmol/L) during stable atorvastatin 40 mg therapy were randomized to atorvastatin 40 mg plus ezetimibe 10mg, or up-titrated to atorvastatin 80 mg. Moderately high CHD risk subjects with LDL cholesterol levels ≥ 100 mg/dL (~2.59 mmol/L) with atorvastatin 20mg were randomized to atorvastatin 20mg plus ezetimibe 10mg, or atorvastatin 40 mg.Although some variability existed, age, gender, and race subgroups did not substantially differ from the entire patient population with regard to lipid-altering findings. Ezetimibe plus atorvastatin produced greater percent reductions in LDL cholesterol, total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B than up-titration of atorvastatin for all subgroups. HDL cholesterol and apolipoprotein AI changes were small and variable.Treatment efficacy in age, gender, and race subgroups did not substantially differ from the entire study population. Ezetimibe combined with atorvastatin generally produced greater incremental reductions in LDL cholesterol and several other key lipid parameters compared with doubling the atorvastatin dose in hypercholesterolemic patients with high or moderately high CHD risk. These results suggest that co-administration of ezetimibe with statins is a useful therapeutic option for treatment of dyslipidemia in differing patient populations.

Background Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels Results Both treatments significantly reduced LDL-C (and the cholesterol content of most LDL subfractions [LDL1-4]) apolipoprotein B, non-HDL-C levels, but did not reduce the proportion of smaller, more dense LDL particles; in fact, the proportion of Pattern B was numerically increased. Results were generally similar in patients with triglyceride levels Conclusions When assessing the effects of escalating cholesterol-lowering therapy, effects upon Pattern B alone to assess coronary heart disease risk may be misleading when interpreted without considerations of other lipid effects, such as reductions in LDL-C, atherogenic lipoprotein particle concentration, and non-HDL-C levels. Trial Registration (Registered at clinicaltrials.gov: Clinical trial # NCT00276484)

Few clinical studies have focused on the efficacy of lipid-lowering therapies in patientsor = 65 years of age. The percentage of change from baseline in low-density lipoprotein (LDL) cholesterol and the percentage of patients achieving prespecified LDL cholesterol levels after 12 weeks of ezetimibe 10 mg plus atorvastatin versus up titration of atorvastatin were assessed in subjectsor = 65 years old with hyperlipidemia and at high risk of coronary heart disease. After stabilization of atorvastatin 10-mg therapy, 1,053 patients,or = 65 years old, at high risk of coronary heart disease, with and without atherosclerotic vascular disease and a LDL cholesterol level that was not70 or100 mg/dl, respectively, were randomized to receive ezetimibe added to atorvastatin 10 mg for 12 weeks versus up titration to atorvastatin 20 mg for 6 weeks followed by up titration to atorvastatin 40 mg for an additional 6 weeks. Ezetimibe added to atorvastatin 10 mg resulted in significantly greater changes at week 6 in LDL cholesterol (p0.001), significantly more patients with atherosclerotic vascular disease achieving a LDL cholesterol level of70 mg/dl (p0.001), and significantly more patients without atherosclerotic vascular disease achieving a LDL cholesterol level of100 mg/dl (p0.001) at weeks 6 and 12 compared to atorvastatin 20 mg or atorvastatin 40 mg. In addition, ezetimibe plus atorvastatin 10 mg resulted in significantly greater changes at week 6 in total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B (all p0.001), and HDL cholesterol (p = 0.021) compared with atorvastatin 20 mg and significantly greater changes at week 12 in LDL cholesterol, non-HDL cholesterol, apolipoprotein A-I (p = 0.001), total cholesterol, apolipoprotein B (p0.030), and HDL cholesterol (p0.001) compared with atorvastatin 40 mg. Both treatments were generally well tolerated, with comparable safety profiles. In conclusion, adding ezetimibe to atorvastatin 10 mg produced significantly greater favorable changes in most lipids at 6 and 12 weeks and significantly greater attainment of prespecified LDL cholesterol levels than doubling or quadrupling the atorvastatin dose in patientsor =65 years old at high risk for coronary heart disease.

The aim of this study was to evaluate the efficacy and safety of ezetimibe 10 mg added to atorvastatin 20 mg compared with doubling atorvastatin to 40 mg in patients with hypercholesterolemia at moderately high risk for coronary heart disease who did not reach low-density lipoprotein (LDL) cholesterol levels100 mg/dl with atorvastatin 20 mg. In this 6-week, multicenter, double-blind, randomized, parallel-group study, 196 patients treated with atorvastatin 20 mg received atorvastatin 20 mg plus ezetimibe 10 mg or atorvastatin 40 mg for 6 weeks. Adding ezetimibe 10 mg to atorvastatin 20 mg produced significantly greater reductions in LDL cholesterol than increasing atorvastatin to 40 mg (-31% vs -11%, p0.001). Significantly greater reductions were also seen in non-high-density lipoprotein cholesterol, total cholesterol, and apolipoprotein B (p0.001). Significantly more patients reached LDL cholesterol levels100 mg/dl with atorvastatin 20 mg plus ezetimibe compared with atorvastatin 40 mg (84% vs 49%, p0.001). The 2 treatment groups had comparable results for high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, and high-sensitivity C-reactive protein. The incidences of clinical and laboratory adverse experiences were generally similar between groups. In conclusion, the addition of ezetimibe 10 mg to atorvastatin 20 mg was generally well tolerated and resulted in significantly greater lipid-lowering efficacy compared with doubling atorvastatin to 40 mg in patients with hypercholesterolemia at moderately high risk for coronary heart disease.

These studies assessed the comparative efficacy of rofecoxib and valdecoxib in the treatment of acute postoperative dental pain.Two randomized, double-blind, placebo-controlled, single-dose studies were conducted in patients undergoing extraction ofor =2 third molars, withor =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.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 (P0.001). 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%; P0.001). 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; P0.01); there was no significant difference between the rate of AEs with valdecoxib 40 mg (50.0%) and placebo.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.

Purpose To determine whether montelukast is as effective as fluticasone in controlling mild persistent asthma as determined by rescue-free days. Subjects and methods Participants aged 15 to 85 years with mild persistent asthma (n = 400) were randomized to oral montelukast (10 mg once nightly) or inhaled fluticasone (88 μg twice daily) in a year-long, parallel-group, multicenter study with a 12-week, double-blind period, followed by a 36-week, open-label period. Results The mean percentage of rescue-free days was similar between treatments after 12 weeks (fluticasone: 74.9%, montelukast: 73.1%; difference=1.8%, 95% confidence interval [CI]: −3.2% to 6.8%) but not during the open-label period (fluticasone: 77.3%, montelukast: 71.1%; difference=6.2%, 95% CI: 0.8% to 11.7%). Although both fluticasone and montelukast significantly improved symptoms, quality of life, and symptom-free days during both treatment periods, greater improvements occurred with fluticasone in lung function during both periods and in asthma control during open-label treatment. Post hoc analyses revealed a difference in rescue-free days favoring fluticasone in participants in the quartiles for lowest lung function and greatest albuterol use at baseline. Conclusion In patients with mild persistent asthma, rescue-free days and most asthma control measures improved similarly with fluticasone or montelukast over the short term, but with prolonged open-label treatment, asthma control improved more with fluticasone. Improved asthma control with fluticasone appeared to occur in those with decreased lung function and greater albuterol use at baseline. In the remaining patients, the two treatments appeared to be comparable. These results suggest that classification criteria for mild persistent asthma may need to be re-evaluated.

Background For patients whose asthma is uncontrolled with low-dose inhaled corticosteroids, addition of alternative therapy instead of increasing the steroid dose is recommended by current treatment guidelines. Objective To compare montelukast, a oncedaily leukotriene receptor antagonist, and salmeterol, a twice-daily, long-acting β-agonist, concomitantly administered with inhaled fluticasone, according to the percentage of patients without an asthma attack for 1 year. Methods A randomized, doubleblind, double-dummy, multicenter study was conducted. Adult patients with moderate-to-severe persistent asthma (ages 14-73 years) receiving inhaled fluticasone (220 μg/d) who remained symptomatic during a 4-week run-in period were randomized to the addition of salmeterol (84 μg/d) or montelukast (10 mg/d) for 48 weeks. Results Of the 1,473 randomized patients, 743 were randomized to montelukast and 730 to salmeterol; 1,059 patients completed the study. Eighty percent of patients in the montelukast group and 83.3% of patients in the salmeterol group remained attack free during the 48 weeks of treatment (relative risk, 1.20; 95% confidence interval, 0.96-1.49). Montelukast significantly reduced blood eosinophil counts compared with salmeterol, whereas salmeterol significantly increased prealbuterol forced expiratory volume in 1 second, asthma-specific quality of life, morning peak expiratory flow rate, and decreased nocturnal awakenings compared with montelukast. Differences between treatments were small, and both treatments were generally well tolerated. Conclusions Addition of montelukast or salmeterol to an inhaled corticosteroid similarly protected most patients from experiencing an asthma attack during a 1-year period, but, based on noninferiority limits, the study was inconclusive with regard to a difference between treatment groups.

The objective of this study was to evaluate parental preference for the treatment of asthmatic children with oral montelukast sodium or inhaled cromolyn sodium. Additionally, we wanted to compare the two drugs in terms of patient preference for treatment, patient and parent satisfaction with treatment, frequency of inhaled albuterol use, adherence to treatment, and safety. This was a 12-week randomized, open-label, crossover study conducted in 42 primary care and asthma/allergy specialty centers in the United States. Three hundred thirty-three asthmatic patients, ages 6 to 11 years, who had a forced expiratory volume in 1 second (FEV1) of 60%-85% (inclusive) of predicted value withor = 12% reversibility after administration of an inhaled beta-agonist and who used albuterol on at least 7 of the last 14 days of the run-in period. After a 2- to 3-week run-in period, patients were randomized either to 4 weeks of montelukast (5-mg chewable tablet once daily) followed by a 2-week washout period, then 4 weeks of cromolyn (two puffs 4 times daily from a metered-dose inhaler) or to the reverse sequence. More parents preferred montelukast (87%) than cromolyn (12%; p0.001). More patients preferred montelukast (82%) than cromolyn (17%; p0.001). Daily albuterol use (puffs/day) was reduced by 38% during montelukast therapy vs. 23% during cromolyn therapy. Seventy-eight percent of patients reported being highly adherent to montelukast therapy compared with 42% to cromolyn therapy (p0.001). Fewer patients receiving montelukast discontinued because of asthma exacerbation (1.0% vs. 5.0%, respectively), and fewer patients reported worsening asthma while receiving montelukast (3.5% vs. 7.5%, p = 0.036). Parents' and patients' preference, parents' and patients' satisfaction, and patients' adherence to therapy were all significantly better with oral montelukast compared with inhaled cromolyn. Beta-agonist use was decreased when taking montelukast, which was safe and well-tolerated.

In recent studies of acute pain and primary dysmenorrhea, rofecoxib, a nonsteroidal anti-inflammatory drug that selectively targets the cyclooxygenase-2 enzyme, was found to be similar in efficacy to ibuprofen and naproxen sodium.The purpose of this study was to determine the analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with the combination of codeine 60 mg/acetaminophen 600 mg in a model of postsurgical dental pain.In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate or severe pain after the surgical extraction ofor = 2 third molars, at least 1 of which was a mandibular impaction, were randomized to receive placebo, rofecoxib 50 mg, or codeine 60 mg/acetaminophen 600 mg. Patient evaluations of pain intensity, pain relief, and global assessments were recorded throughout the 24-hour period after dosing. The 2-stopwatch method was used to determine time to confirmed perceptible pain relief. The primary end point assessing overall analgesic effect was total pain relief over 6 hours (TOPAR6). Secondary end points were patient global assessment of response to therapy (PGART) at 6 hours, onset of analgesia, peak analgesic effect, and duration of analgesia.A total of 393 patients were enrolled; 182 received rofecoxib, 180 received codeine/acetaminophen, and 31 received placebo. The overall analgesic effect of rofecoxib 50 mg was greater than that of codeine 60 mg/acetaminophen 600 mg for TOPAR6 (12.4 vs 7.0; P0.001) and PGART at 6 hours (P0.001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen. Peak analgesic effect as measured by peak pain relief scores during the first 6 hours was significantly greater in the rofecoxib group compared with the codeine/acetaminophen group (P0.001), as was the duration of analgesic effect measured by the time to rescue analgesia (9.6 hours vs 2.3 hours, P0.001). Adverse events were reported in 33.0%, 46.1%, and 32.3% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively. The most common adverse events were nausea (6.0%, 25.0%, and 9.7%, respectively) and vomiting (3.8%, 18.3%, and 6.5%, respectively). Significantly more patients in the codeine/acetaminophen group than in the rofecoxib group experienced adverse events overall (P0.050) and nausea in particular (P0.001).In this study of moderate to severe postoperative dental pain, the analgesic efficacy of rofecoxib 50 mg was greater than that of codeine/acetaminophen, with a lower incidence of adverse events and nausea.

Rofecoxib (VIOXX®) is a selective inhibitor of cyclo-oxygenase-2 and is indicated for the treatment of acute pain. Prior acute pain studies showed similar analgesic efficacy of rofecoxib 50 mg compared with analgesics doses of non-selective NSAIDs. We performed a randomized, double-blind trial to evaluate the efficacy and safety of rofecoxib, a standard fixed formulation of codeine with acetaminophen, and placebo in the treatment of acute pain. Three-hundred ninety-three patients with moderate or severe pain after surgical extraction of at least two 3rd molars were randomized to receive a single dose of rofecoxib 50 mg (n = 182), codeine 60 mg with acetaminophen 600 mg (n = 180), or placebo (n = 31). Efficacy was assessed at 11 pre-specified time points after dosing by pain relief and pain intensity scores. Patient global assessment of study medication was also performed. Baseline characteristics were similar among the groups. The mean age was 21 years; 69.0% were female; and 78.6% had a pain intensity score of “moderate.” For the primary endpoint, total pain relief over 6 hours, rofecoxib was more effective than codeine/acetaminophen (p codeine/acetaminophen; p < 0.001). The time to rescue medication was longer for rofecoxib compared to codeine/acetaminophen (p < 0.001). More patients on codeine/acetaminophen experienced clinical adverse events than rofecoxib (p < 0.05). Patients receiving codeine/acetaminophen versus rofecoxib had higher incidences of nausea (25.0% vs 6.0%; p < 0.001) and vomiting (18.3% vs 3.8%; p < 0.001). In this study, rofecoxib had superior efficacy and gastrointestinal safety compared to codeine/acetaminophen, which provides support for the use of rofecoxib as an alternative option to opioid analgesics in the treatment of acute post-surgical pain.

Rationale To compare the bronchodilator response to albuterol after a standard exercise challenge in patients receiving montelukast (M) or salmeterol (S) added to low-dose fluticasone (F). Methods Randomized, double-blind multicenter study. Patients with asthma (N=91, ages 15–60) receiving F (110 μg twice daily) who remained symptomatic and had a history of exercise-induced bronchoconstriction (EIB) were randomized to addition of M (10 mg) or S (42 μg BID) for 4 weeks. At weeks 1 and 4, patients exercised on a treadmill for 6 minutes at near-maximum heart rate; at 15 and 45 minutes after exercise, patients received 180 μg albuterol by inhalation. Serial spirometry was performed both before and after albuterol administration. FEV1 was expressed as the percent change from pre-exercise baseline. Results Baseline pre-exercise FEV1 percent predicted was 81.3 ± 1.5% in the M+F group and 78.9 ± 1.7% in the S+F group. Before treatment, patients in both groups had a significant increase in FEV1 in response to post-exercise albuterol (M+F: 11.9 ± 1.2%; S+F: 14.5 ± 1.6%). After 4 weeks, only S+F perceptibly improved pre-exercise FEV1 (7.5 ± 1.1% versus 2.1 ± 1.1%, p Conclusions The rescue response to albuterol after EIB in patients taking fluticasone is preserved with addition of montelukast but is significantly diminished with addition of salmeterol.

Objectives: To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids (ICS) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction.Methods: A double-blind, placebo-controlled study was performed at 16 centers in the United States. Patients with asthma (n=122, ages 15–58) whose symptoms were uncontrolled on low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were randomized to receive either montelukast (10mg once daily), salmeterol (50μg twice daily), or placebo for 4 weeks. Standardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline, week 1 and 4.Results: Maximum achievable forced expiratory volume in 1s (FEV1) percent predicted after rescue beta2-agonist improved in the montelukast (+1.5%) and placebo (+1.2%) groups at 4 weeks, but diminished in the salmeterol (−3.9%) group (P