Davis Gates

Efficacy and safety characteristics of mometasone furoate/formoterol fumarate fixed-dose combination in subjects with moderate to very severe COPD: findings from pooled analysis of two randomized, 52-week placebo-controlled trials

Background The clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). Methods Two 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged ≥40 years), and pooled study results are presented herein. Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension. Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV1), area under the curve from 0 to 12 hours postdose (AUC0–12 h), and morning predose/trough FEV1 from baseline to the week 13 endpoint. Key secondary efficacy variables were St George’s Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint. Results In the 26-week treatment period, significantly greater increases in FEV1 AUC0–12 h occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P ≤ 0.032). These increases were over three-fold greater with MF/F 400/10 than with MF 400. Also, significantly greater increases in morning predose/trough FEV1 occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P < 0.05). The increase was four-fold greater with MF/F 400/10 than with F 10. All active treatment groups achieved minimum clinically important differences from baseline (>4 units) in St George’s Respiratory Questionnaire scores at week 26. Symptom-free nights increased by ≥14% in the MF/F 400/10, MF 400, and F 10 groups (P ≤ 0.033 versus placebo). The incidence of exacerbations was lower in the MF/F groups (≤33.3%) than it was in the MF, formoterol, and placebo groups (≥33.8%) over the 26-week treatment period. The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment. Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups. Differences in rates of individual treatment-emergent adverse events were <3% between treatment groups. Rates of pneumonia were low (≤2%) across all treatment groups. Conclusion Patients treated with MF/F demonstrated significant improvements in lung function, health status, and exacerbation rates. Although significant improvements were seen with both doses, a trend showing a dose-response effect was observed in the lung function measurements.

Mometasone furoate improves nasal and ocular symptoms of seasonal allergic rhinitis in adolescents.

Seasonal allergic rhinitis (SAR) is common in adolescents. However, few studies have investigated the effectiveness of intranasal corticosteroids (INSs) for nasal and ocular symptoms of SAR solely in adolescents. The purpose of this study was to determine the safety and efficacy of the INS mometasone furoate nasal spray (MFNS) in adolescents; a post hoc analysis was conducted of adolescents who had participated in a study with adults. Data were analyzed retrospectively for subjects aged 12–17 years with moderate or severe SAR randomized to mometasone furoate, 200 meg once daily (n = 86), or placebo (n = 82) for 15 days in a multicenter, double-blind, placebo-controlled study. Symptom scores (0 = none to 3 = severe) were recorded in diaries twice daily. End points included changes from baseline in total nasal symptom score (TNSS), individual nasal symptom score (rhinorrhea, congestion, itching, and sneezing), and total ocular symptom score (TOSS). Over 15 days, a significantly greater decrease from baseline in mean TNSS was observed in subjects receiving mometasone furoate (–2.47; −28.8%) compared with those receiving placebo (–0.9; −9.6%; p < 0.001). Significant improvement versus placebo was seen for each full day of treatment. Mometasone furoate significantly improved individual nasal symptoms (p ≤ 0.03) and TOSS (p = 0.011) versus placebo. The incidence of adverse events was similar for both treatment groups. MFNS, 200 meg once daily, is an effective and well-tolerated treatment for symptoms of SAR in adolescents.

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 β-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue β-agonist use diurnal variability. The ADAS-6 demonstrated cross-sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P < .0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties. CONCLUSIONS The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size.

Mometasone furoate nasal spray increases the number of minimal-symptom days in patients with acute rhinosinusitis

BACKGROUND Acute rhinosinusitis (ARS) is triggered by viral or, uncommonly, bacterial infection, causing inflammatory symptoms for ≤12 weeks. OBJECTIVE To investigate effects of mometasone furoate nasal spray (MFNS) vs amoxicillin and placebo on minimal-symptom days. METHODS A double-blind, parallel-group, placebo- and active-controlled 15-day study randomly assigned patients 12 years of age or older to MFNS 200 μg twice daily, MFNS 200 μg once daily, amoxicillin 500 mg 3 times daily, or placebo. Patients had baseline rhinosinusitis major symptom score (MSS; combined rhinorrhea, postnasal drip, congestion, sinus headache, facial pain) of ≥5 and ≤12 (maximum: 15) for 7 to 28 days; scores were similar among groups. Minimal-symptom days and minimal-congestion days were defined post hoc by average am/pm MSS ≤4 and average AM/PM congestion ≤1. RESULTS MFNS twice daily (n = 234) showed more minimal-symptom days vs placebo (n = 246) (62.69% vs 50.33%; P < .0001) or amoxicillin (n = 248) (54.35%; P = .0040). The MFNS QD was associated with numerically more minimal-symptom days than amoxicillin or placebo (54.72%; P ≤ .8982). MFNS was associated with more minimal-congestion days than placebo (72.97%, 67.73%, and 56.67% for twice daily, once daily, and placebo; P < .0001, each vs placebo) and MFNS BID with more minimal-congestion days than amoxicillin (72.97% vs 64.15%; P = .0007). Median time to first minimal-symptom day sustained until study end was 8.5 days for MFNS BID vs. 11 for placebo (P = .0085). CONCLUSION MFNS 200 μg twice daily significantly increased minimal-symptom days vs amoxicillin or placebo in patients with ARS. Results of this intranasal corticosteroids (INS) therapy indicate it can improve outcomes and potentially reduce inappropriate antibiotic use.

Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol.

Study Question What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ≥ 11 mm and/or estradiol (E2) levels? Summary Answer The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles ≥ 11 mm. What Is Known Already In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1–2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol. Study Design, Size, Duration From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses. Participants/Materials, Setting, Methods The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG), and a combination of both, were determined. Main Results and the Role of Chance The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS. Limitations, Reasons for Caution This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins. Wider Implications of the Findings For patients with 19 follicles or more ≥11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy. Trial Registration ClinicalTrials.gov NCT00702845 NCT00696800 NCT00696878

Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis.

A meta-analysis was conducted of individual patient data (n = 3292) from three randomized controlled trials of corifollitropin alfa versus rFSH: Engage (150 µg corifollitropin alfa n = 756; 200 IU rFSH n = 750), Ensure (100 µg corifollitropin alfa n = 268; 150 IU rFSH n = 128), and Pursue (150 µg corifollitropin alfa n = 694; 300 IU rFSH n = 696). Women with regular menstrual cycles aged 18-36 and body weight >60 kg (Engage) or ≤60 kg (Ensure), or women aged 35-42 years and body weight ≥50 kg (Pursue), received a single injection (100 µg or 150 µg) of corifollitropin alfa (based on body weight and age) or daily rFSH. The difference (corifollitropin alfa minus rFSH) in the number of oocytes retrieved was +1.0 (95% CI: 0.5-1.5); vital pregnancy rate: -2.2% (95% CI: -5.3%-0.9%); ongoing pregnancy rate: -1.7% (95% CI: -4.7%-1.4%); and live birth rate: -2.0% (95% CI: -5.0%-1.1%). The odds ratio for overall OHSS was 1.15 (95% CI: 0.82-1.61), and for moderate-to-severe OHSS: 1.29 (95% CI: 0.81-2.05). A single dose of corifollitropin alfa for the first 7 days of ovarian stimulation is a generally well-tolerated and similarly effective treatment compared with daily rFSH.

Validation and agreement across four versions of the asthma control questionnaire in patients with persistent asthma

OBJECTIVE The objectives of this study were to: 1) examine the psychometric properties of three shortened versions of the Asthma Control Questionnaire (ACQ) and their comparative performance with the original 7-item ACQ in persistent asthma patients; and 2) explore the concordance of asthma control outcomes from the four versions of the ACQ when compared with international guidelines for asthma control. METHOD Post-hoc analyses of two large (n=737 and n=772) Phase III, randomized, double-blind, parallel-group, multi-center placebo-controlled studies of mometasone furoate/formoterol fumarate combination formulation compared with monotherapies in subjects with persistent asthma previously treated with low-dose or medium-dose inhaled glucocorticoids. This study examined the psychometric performance of the four ACQ versions and the concordance between these four versions with each other and international guidelines. RESULTS The psychometric results for all four versions of the ACQ were robust, with Cronbach alphas ≥0.82 and test-retest ICCs ≥0.75. All versions of the ACQ were strongly correlated with each other (r≥0.97), as well the overall score from the AQLQ12+ for both baseline and change scores (|r|≥0.74). When the four ACQ versions were compared to each other, both cross sectional and longitudinal change concordances were mostly substantial, but agreements were lower when compared to international guidelines classifications. CONCLUSION All ACQ versions have similar and strong psychometric properties. Classifications of change over time using the original ACQ and a six-item version without SABA use provided generally fair to moderate agreement with the international guidelines criteria for asthma control.

Relieving nasal congestion in children with seasonal and perennial allergic rhinitis: efficacy and safety studies of mometasone furoate nasal spray

BackgroundIn surveys of children with allergic rhinitis (AR), nasal congestion has been identified as the most frequently experienced and bothersome symptom. This analysis was conducted to investigate the effect of mometasone furoate nasal spray (MFNS) on congestion in children with AR.MethodsTwo multicenter, double-blind, placebo-controlled studies randomly assigned children to MFNS 100 μg or placebo, 1 spray/nostril QD for 4 weeks (Study 1: ages 6–11 years with seasonal AR [SAR] ≥1 year; Study 2: ages 3–11 years with perennial AR [PAR] ≥1 year). Least square (LS) means were obtained from an ANCOVA model with treatment and study center effects, with baseline score as a covariate. We conducted post hoc evaluation of changes from baseline in AM/PM PRIOR (average of reflective AM and PM scores) nasal congestion (0=none to 3=severe).ResultsStudy 1: MFNS (n=134) reduced congestion significantly more than placebo (n=135) on day 2 (P=.004) and on 23/29 days (P≤.037). Change from baseline was −0.53 and −0.28 for MFNS and placebo (P<.001) over days 1–15 and −0.64 and −0.38 for MFNS and placebo (P<.001) over days 1–29. Study 2: MFNS (n=185) reduced congestion significantly more than placebo (n=189) on day 3 (P=.015) and on 22/29 days (P≤.047). Change from baseline was −0.56 and −0.36 for MFNS and placebo (P<.001) over days 1–15 and −0.64 and −0.45 for MFNS and placebo (P<.001) over days 1–29. MFNS was well tolerated, with no unusual or unexpected adverse events.ConclusionMFNS effectively relieved nasal congestion and was well tolerated in children with SAR or PAR.

Effects of intranasal mometasone furoate on itchy ear and palate in patients with seasonal allergic rhinitis

BACKGROUND Intranasal steroids relieve nasal symptoms and ocular itch in allergic rhinitis. Itchy ear and palate are also common and bothersome symptoms but have received little attention in clinical trials of allergic rhinitis. OBJECTIVE To ascertain the efficacy of mometasone furoate nasal spray in alleviating itchy ear and palate in seasonal allergic rhinitis. METHODS Data were pooled from 4 randomized, double-blind, placebo-controlled trials of mometasone furoate nasal spray, 200 μg/d. Participants rated ear and palate itching from baseline through treatment day 15 as follows: 0, none; 1, mild; 2, moderate; and 3, severe. RESULTS A total of 962 study participants received mometasone furoate nasal spray or placebo. Baseline least squares mean itchy ear and palate score was 1.81 for participants receiving mometasone furoate nasal spray (n = 480) and 1.85 for participants receiving placebo (n = 482). Mometasone furoate nasal spray was associated with a greater decrease in itchy and ear palate score vs placebo during the 15-day study period (least squares mean change, -0.73 vs -0.45; P < .001). The difference reached significance on day 2 and persisted through day 15 (P ≤ .01 for each day). Results were similar in a subgroup of patients (n = 305) with moderate-to-severe symptoms at baseline. Adverse events with mometasone furoate nasal spray were similar to those observed in other studies of intranasal steroid therapy. CONCLUSION These preliminary findings suggest that mometasone furoate nasal spray effectively treats itchy ear and palate in individuals with seasonal allergic rhinitis. Itchy ear and palate is a relevant end point for future clinical trials of allergic rhinitis.

Osteoarthritis patients with pain improvement are highly likely to also have improved quality of life and functioning. A post hoc analysis of a clinical trial

Abstract Background This analysis evaluated whether osteoarthritis patients achieving the greatest pain control and lowest pain states also have the greatest improvement in functioning and quality of life. Methods Patients (n = 419) who failed prior therapies and who were switched to etoricoxib 60 mg were categorized as pain responders or non-responders at 4 weeks based on responder definitions established by the Initiative on Methods, Measurement, and Pain (IMMPACT) criteria, including changes from baseline of ≥15%, ≥30%, ≥50%, ≥70% and a final pain status of ≤3/10 (no worse than mild pain). Pain was assessed at baseline and 4 weeks using 4 questions from the Brief Pain Inventory (BPI) (worst pain, least pain, average pain, and pain right now), and also using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. We examined the relationship between pain responses with changes from baseline in two functional measures (the BPI Pain Interference questions and the WOMAC Function Subscale) as well as changes from baseline in quality of life (assessed on the SF-36 Physical and Mental Component Summaries). We also sought to understand whether these relationships were influenced by the choice of the pain instrument used to assess response. We contrast the mean difference in improvements in the functional and quality of life instruments based on pain responder status (responder versus non-responder) and the associated 95% confidence limits around this difference. Results Patients with better pain responses were much more likely to have improved functional responses and improved quality of life, with higher mean changes in these outcomes versus pain nonresponders, regardless of the choice of IMMPACT pain response definition (e.g., using any of 15%, 30%, 50%, 70% change from baseline) or the final pain state of ≤3/10. There was an evident gradient, where higher levels of pain response were associated with greater mean improvements in function and quality of life. The finding that greater pain responses led to greater functional improvements and quality of life gains was not dependent on the manner in which pain was evaluated. Five different pain instruments (e.g., the 4 questions on pain from the BPI pain questionnaire and the WOMAC pain subscale) consistently demonstrated that pain responders had statistically significantly greater improvements in function and quality of life compared to pain non-responders. This suggests these results are likely to be generalizable to any validated pain measure for osteoarthritis. Conclusions Pain is an efficient outcome measure for predicting broader patient response in osteoarthritis. Patients who do not achieve timely, acceptable pain states over 4 weeks were less likely to experience functional or quality of life improvements. Implications Good pain improvements in osteoarthritis with a valid pain instrument are a proxy for good improvements in both function and quality of life. Therefore proper osteoarthritis pain assessment can lead to efficient evaluations in the clinic.