A Comprehensive Analysis of Topiramate and Drug Reaction With Eosinophilia and Systemic Symptoms.

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.

Increased risk of severe cutaneous adverse reactions when cladribine is used together with other medications with a propensity for skin reactions.

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.

Treatment Pattern and Outcomes in Newly Diagnosed Multiple Myeloma Patients Who Did Not Receive Autologous Stem Cell Transplantation: A Real-World Observational Study : Treatment pattern and outcomes in patients with multiple myeloma.

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.

Staphylococcus aureus infections following knee and hip prosthesis insertion procedures.

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.

Naturally occurring IgG antibody levels to the Staphylococcus aureus protein IsdB in humans.

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.

Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial.

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.

Predicting response to pregabalin from pretreatment pain quality: clinical applications of the pain quality assessment scale.

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.

The asthma disease activity score: a discriminating, responsive measure predicts future asthma attacks.

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 ß-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue ß-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.

Ultrasound of metacarpophalangeal joints is a sensitive and reliable endpoint for drug therapies in rheumatoid arthritis: results of a randomized, two-center placebo-controlled study.

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.

Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis.

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.

The efficacy and tolerability of intravenous montelukast in acute asthma exacerbations in Japanese patients.

OBJECTIVES: In Japan, the Asthma Prevention and Management Guidelines recommend nebulized ß-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.

Airway obstruction lability helps distinguish levels of disease activity in asthma.

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 ß-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.

Blood pressure and cardiovascular outcomes in patients taking nonsteroidal antiinflammatory drugs.

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.

The pain quality response profile of pregabalin in the treatment of neuropathic pain.

OBJECTIVE: To identify and describe the response profile of pregabalin on the qualities of pain associated with peripheral neuropathy. METHODS: A post hoc analysis to examine the effects of pregabalin on pain quality in patients with moderate-to-severe peripheral neuropathic pain was performed using data from an enriched enrollment randomized withdrawal proof-of-concept study. Patients rated the quality of their pain experience using the Pain Quality Assessment Scale (PQAS) at baseline, after a 12-day titration period, after a 9-day maintenance period, and after a 19-day randomized withdrawal period. Pretitration to posttitration and prewithdrawal to postwithdrawal changes in PQAS paroxysmal, surface, and deep pain scale scores were examined. RESULTS: PQAS data were available for 99 of the 104 participants who entered all phases of the study. There were significant (P<0.006, Bonferroni adjusted for multiple tests) improvements pretitration to posttitration in all 3 PQAS subscales, with a greater effect on paroxysmal and deep pain than on surface pain. During the withdrawal phase, pregabalin was significantly (P<0.006) more effective than placebo for improvements in paroxysmal and surface pain only, although the pregabalin group continued to show numerical improvement in deep pain relative to placebo. DISCUSSION: Pregabalin had a greater effect on PQAS-assessed paroxysmal pain than on surface or deep pain in patients with peripheral neuropathy. The findings corroborate previous research demonstrating differential effects of analgesic drugs across pain qualities, further emphasizing the need to assess individual pain qualities in addition to overall pain intensity.

The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic asthma.

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, ß-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-ß-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 ß-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-ß-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.

The immunogenicity and safety of different formulations of a novel Staphylococcus aureus vaccine (V710): results of two Phase I studies.

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.

Sensitivity of single-domain versus multiple-domain outcome measures to identify responders in chronic low-back pain: pooled analysis of 2 placebo-controlled trials of etoricoxib.

OBJECTIVES: A composite responder index for chronic low-back pain (CLBP) has recently been proposed to evaluate the efficacy of CLBP treatments in clinical trials. We compared the responsiveness of this composite measure with a number of single-item responder definitions. METHODS: We pooled data from 2 placebo-controlled studies of etoricoxib in CLBP to evaluate 5 response criteria: 30% pain intensity (PI) reduction; 50% PI reduction; 20 mm absolute reduction (100 mm PI visual analog scale); patient global assessment of response to therapy (PGART); and the composite criteria of 30% reduction in PI+30% improvement in PGART of disease status+no worsening in function. We used bootstrap analysis and logistic regression to assess the ability to differentiate etoricoxib and placebo, and the κ coefficient to assess agreement among the responder criteria. RESULTS: The criterion of a 20 mm improvement in PI resulted in the greatest proportion (71.5%) of patients being classified as responders and all criteria separated etoricoxib from placebo (P≤0.0001). PGART had the highest discriminant ability (odds ratio 5.90), and was significantly (P<0.05) more discriminant than the 20 mm and ≥30% improvements and the composite criteria. After adjusting for all other measures, only PGART continued to show a significant treatment effect for etoricoxib versus placebo (P=0.0003). Kappa values contrasting the composite criteria and the single-item measures ranged from 0.59 to 0.85. DISCUSSION: These findings do not support the superiority of a composite index over single-item ratings of PI and PGART ratings, but do suggest that PGART ratings may be more responsive to treatment, perhaps because they measure something in addition to change in PI.

Longitudinal numbers-needed-to-treat (NNT) for achieving various levels of analgesic response and improvement with etoricoxib, naproxen, and placebo in ankylosing spondylitis.

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.

Intermittent or daily montelukast versus placebo for episodic asthma in children.

BACKGROUND: No standard, optimal treatment exists for severe intermittent (ie, episodic) asthma in children. However, evidence suggests that both daily and episode-driven montelukast are effective for this phenotype. OBJECTIVE: To assess the regimen-related efficacy of montelukast in treating pediatric episodic asthma. METHODS: A multicenter, randomized, double-blind, double-dummy, parallel-group, 52-week study was performed in children 6 months to 5 years of age comparing placebo with two regimens of montelukast 4 mg: (1) daily; or (2) episode-driven for 12 days beginning with signs/symptoms consistent with imminent cold or breathing problem. The main outcome measure was the number of asthma episodes (symptoms requiring treatment) culminating in an asthma attack (symptoms requiring physician visit, emergency room visit, corticosteroids, or hospitalization). RESULTS: Five hundred eighty-nine patients were randomized to daily montelukast, 591 to intermittent montelukast, and 591 to placebo. Compared with placebo, no significant difference was seen between daily montelukast (P = .510) or intermittent montelukast (P = .884) in the number of asthma episodes culminating in an asthma attack over 1 year. Daily montelukast reduced symptoms over the 12-day treatment period of asthma episodes compared with placebo (P = .045). Beta-agonist use was reduced with both daily (P = .048) and intermittent montelukast (P = .028) compared with placebo. However, because of prespecified rules for multiplicity adjustments (requiring a positive primary endpoint), statistical significance for secondary endpoints cannot be concluded. All treatments were well tolerated. CONCLUSIONS: Montelukast did not reduce the number of asthma episodes culminating in an asthma attack over 1 year in children 6 months to 5 years of age, although numerical improvements occurred in some endpoints.