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.

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.

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.

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.

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.

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.

The efficacy and tolerability of inhaled montelukast plus inhaled mometasone compared with mometasone alone in patients with chronic asthma.

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 ß-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 ß-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.

Predictors of response to cyclo-oxygenase-2 inhibitors in osteoarthritis: pooled results from two identical trials comparing etoricoxib, celecoxib, and placebo.

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.

Onset and duration of attenuation of exercise-induced bronchoconstriction in children by single-dose of montelukast.

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.

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.

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.

Baseline predictors of placebo response in exercise-induced bronchoconstriction (EIB): pooled regression analysis >from three studies of montelukast in EIB.

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.

A phase I randomized, placebo-controlled, dose-exploration study of single-dose inhaled montelukast in patients with chronic asthma.

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.

Early response to COX-2 inhibitors as a predictor of overall response in osteoarthritis: pooled results from two identical trials comparing etoricoxib, celecoxib and placebo.

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.

Baseline factors associated with congestive heart failure in patients receiving etoricoxib or diclofenac: multivariate analysis of the MEDAL program.

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.

The efficacy of montelukast during the allergy season in pediatric patients with persistent asthma and seasonal aeroallergen sensitivity.

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).

Rofecoxib 50 mg and valdecoxib 20 or 40 mg in adults and adolescents with postoperative pain after third molar extraction: results of two randomized, double-blind, placebo-controlled, single-dose studies.

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.

Rofecoxib 12.5 mg, rofecoxib 25 mg, and celecoxib 200 mg in the treatment of symptomatic osteoarthritis: results of two similarly designed studies.

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.