Purpose:This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). Patients and Methods:The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). Results:112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). Conclusion:There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

A planned change from Bricanyl (R) (terbutaline) Turbuhaler (R) M2 to M3 device required a phannacodynamic study to evaluate therapeutic equivalence of the two devices. Because of the flat dose-response curve for this type of agent over this dose range when assessing bronchodilation, a bronchoprotection study was considered more feasible. In this double-blind, double-dummy, muldcende, single-dose, two-factor, crossover study, patients with stable mild-to-moderate asthma were randomised to 0.5 or 1.5 mg terbutaline via Turbuhaler (R) M2 or Turbuhaler (R) M3 followed by a methacholine challenge test. Primary outcome variable: concentration of methacholine causing a 20% fall in FEV1 (PC20). Pairwise contrasts were constructed with 95% CIs to determine assay sensitivity for M2 and M3 devices and therapeutic equivalence at each dose level (95% CI for M3:M2 devices within pre-specified limit [0.67-1.50]) and the relative dose-potency (RDP) between M3 and M2 determined with 90% CL Sixty patients were randomised and all completed the study. Between-device ratios of PC20 (M3:M2) were 0.92 (95% CI: 0.75-1.13) for 0.5 mg and 0.88 (95% CI 0.72-1.08) for 1.5 mg and estimated RDP was 1.20 (0.96-1.53). In conclusion, a methacholine provocation study (PC20 primary variable) is a useful alternative to the standard bronchodilation study when assessing therapeutic equivalence of a bronchodilator.

Objective: These studies evaluated the safety and efficacy of enteric-coated budesonide for the induction and maintenance of remission of mild-to-moderate Crohn's disease (CD) in children.Methods: The consecutive, multicenter, open-label, non-comparative studies enrolled patients aged 6-17 years. In the induction study, patients with active CD of the ileum and/or ascending colon received budesonide 9mg or 6mg once daily for 8 weeks; in the maintenance study, patients in remission received budesonide 6mg once daily for 12 weeks. The primary objective was assessment of safety, including glucocorticosteroid-related side effects and serum cortisol levels. Efficacy was assessed using the Pediatric Crohn's Disease Activity Index (PCDAI), and health-related quality of life (HRQoL) using the IMPACT-III questionnaire.Results: In the induction study (n=108), most adverse events were related to CD, commonly abdominal pain; possible glucocorticosteroid-related effects included acne and increased appetite but without significant weight gain. Subnormal morning cortisol levels were observed in 32 of 103 patients after 8 weeks. Budesonide reduced disease activity from baseline (meanstandard deviation, 9.1 +/- 8.5 vs. 19.1 +/- 10.1, p<.001) with 58.1% of patients reaching remission (PCDAI <10); HRQoL improved (p<.001). In the maintenance study (n=50), mean disease activity worsened (p=.047) with HRQoL unchanged (p=.33).Conclusions: Budesonide treatment was generally well tolerated, although the potential for adrenal suppression was noted. Budesonide was effective for induction of remission in children with mild-to-moderate CD but not for maintaining remission (ClinicalTrials.gov identifiers: NCT01444092, NCT01453946).

OBJECTIVE The rate of rebleeding from peptic ulcers could differ between Asian and Western populations. This study aimed to determine whether the observed twofold difference in rebleeding rates in two similarly designed clinical trials (one in Hong Kong [n = 240], the other in a predominantly Western population [n = 764, ClinicalTrials.gov identifier: NCT00251979]) can be explained by differences in baseline patient characteristics. METHODS Two‐factor and multifactor analyses (adjusted by demographics, established risk factors for peptic ulcer and peptic ulcer bleeding, and disease severity variables) were performed using pooled data from the two studies. Cox regression analysis was used to predict the rebleeding risk at 3 days. RESULTS In the two‐factor analysis (placebo vs esomeprazole/omeprazole and Western study vs Hong Kong study), data trended towards a reduced risk of rebleeding in the Western study (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.44–1.07, P = 0.094). The risk of rebleeding was similar in both studies after adjusted for multiple factors (HR 1.10, 95% CI 0.60–1.99, P = 0.767). The strongest predictor of rebleeding (apart from study drug) was a classification of American Society of Anesthesiologists (ASA) grade IV (HR 4.15, 95% CI 1.49–11.56, P = 0.006). When such patients were excluded, the difference in rebleeding rates between the studies reduced. CONCLUSION The difference in rebleeding rates between the two studies is explained by the factors in our analysis, most importantly a classification of ASA grade IV, suggesting that other differences, including ethnicity, did not influence the rebleeding rate.

OBJECTIVES: Our aims were to assess risks of early rebleeding after successful endoscopic hemostasis for Forrest oozing (FIB) peptic ulcer bleeding (PUBs) compared with other stigmata of recent hemorrhage (SRH).METHODS: These were post hoc multivariable analyses of a large, international, double-blind study (NCT00251979) of patients randomized to high-dose intravenous (IV) esomeprazole (PPI) or placebo for 72 h. Rebleeding rates of patients with PUB SRH treated with either PPI or placebo after successful endoscopic hemostasis were also compared.RESULTS: For patients treated with placebo for 72 h after successful endoscopic hemostasis, rebleed rates by SRH were spurting arterial bleeding (FIA) 22.5%, adherent clot (FIIB) 17.6%, non-bleeding visible vessel (FIIA) 11.3%, and oozing bleeding (FIB) 4.9%. Compared with FIB patients, FIA, FIIB, and FIIA had significantly greater risks of rebleeding with odds ratios (95% CI's) from 2.61 (1.05, 6.52) for FIIA to 6.66 (2.19, 20.26) for FIA. After hemostasis, PUB rebleeding rates for FIB patients at 72 h were similar with esomeprazole (5.4%) and placebo (4.9%), whereas rebleed rates for all other major SRH (FIA, FIIA, FIIB) were lower for PPI than placebo, but the treatment by SRH interaction test was not statistically significant.CONCLUSIONS: After successful endoscopic hemostasis, FIB patients had very low PUB rebleeding rates irrespective of PPI or placebo treatment. This implies that after successful endoscopic hemostasis the prognostic classification of FIB ulcers as a high-risk SRH and the recommendation to treat these with high-dose IV PPI's should be re-evaluated.

The rate of rebleeding from peptic ulcers could differ between Asian and Western populations. This study aimed to determine whether the observed twofold difference in rebleeding rates in two similarly designed clinical trials (one in Hong Kong [ n  = 240], the other in a predominantly Western population [ n  = 764, ClinicalTrials.gov identifier: NCT00251979]) can be explained by differences in baseline patient characteristics. Two-factor and multifactor analyses (adjusted by demographics, established risk factors for peptic ulcer and peptic ulcer bleeding, and disease severity variables) were performed using pooled data from the two studies. Cox regression analysis was used to predict the rebleeding risk at 3 days. In the two-factor analysis (placebo vs esomeprazole/omeprazole and Western study vs Hong Kong study), data trended towards a reduced risk of rebleeding in the Western study (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.44–1.07, P  = 0.094). The risk of rebleeding was similar in both studies after adjusted for multiple factors (HR 1.10, 95% CI 0.60–1.99, P  = 0.767). The strongest predictor of rebleeding (apart from study drug) was a classification of American Society of Anesthesiologists (ASA) grade IV (HR 4.15, 95% CI 1.49–11.56, P   =  0.006). When such patients were excluded, the difference in rebleeding rates between the studies reduced. The difference in rebleeding rates between the two studies is explained by the factors in our analysis, most importantly a classification of ASA grade IV, suggesting that other differences, including ethnicity, did not influence the rebleeding rate.

Background/Objective: To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler((R)) devices by evaluating its protective effect against methacholine-induced bronchoconstriction in stable asthma.Methods: In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable mild-to-moderate asthma (FEV1 >= 80% predicted) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler((R)) M2 or Turbuhaler((R)) M3 followed by a methacholine challenge test. The primary outcome variable was the concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had a PC20 methacholine < 8 mg/mL that was reproducible after 2 weeks, and a stable baseline FEV1 at all visits (90-110% of enrolment value).Results: 60 patients (mean age 31.1 years [range:18-64]; mean FEV1 92.1% predicted normal [78.4 -120.6%]) were randomised to treatment; all completed the study. There was a clear dose-response for both devices. The within-device ratios (1.5 mg:0.5 mg) were 1.79 and 1.87 for Turbuhaler((R)) M3 and M2, respectively (both p < 0.001). The between-device ratios (M3:M2) were 0.92 (95% CI: 0.75-1.13) for 0.5 mg and 0.88 (95% CI 0.72-1.08) for 1.5 mg. Both confidence intervals lie inside the interval 0.67-1.50, which was the pre-specified condition for equivalent effect.Conclusions: Bronchoprotection using a standardised methacholine challenge model proved to be an effective design to elucidate therapeutic equivalence between devices in patients with mild-to-moderate asthma. The findings indicate that patients may switch from one type of Turbuhaler((R)) to the other without adjustment of therapy. Moreover, they show the robustness and utility of this study design and its suitability for investigating therapeutic equivalence. (c) 2017 Elsevier Ltd. All rights reserved.

Background/objective To demonstrate therapeutic equivalence of terbutaline via two different Turbuhaler® devices by evaluating its protective effect against methacholine-induced bronchoconstriction in patients with stable asthma. Methods In this double-blind, double-dummy, multicentre, single-dose, 4-way crossover study, patients with stable, mild-to-moderate asthma (FEV1 ≥ 80% predicted normal) were randomised to 0.5 or 1.5 mg terbutaline via either Turbuhaler® M3 or M2 followed by a methacholine challenge test. Primary outcome variable: concentration of methacholine causing a 20% drop in FEV1 (PC20). Patients had to have a PC20 methacholine < 8 mg/mL, reproducible after 2 weeks, and a stable baseline FEV1 at all visits (90–110% of enrolment value). Results 60 patients were randomised to treatment and completed the study. There was a clear dose–response for both devices. The within-device ratios (1.5 mg: 0.5 mg) were 1.79 and 1.87 for Turbuhaler M3 and M2, respectively (both p < 0.001). The between-devices ratio (M3:M2) was 0.92 (95% CI: 0.75–1.13) for 0.5mg and 0.88 (95% CI 0.72–1.08) for 1.5 mg. Both CIs lie inside the interval (0.67–1.50), which was the pre-specified condition for equivalent effect. Conclusions Bronchoprotection with PC20 as the outcome measure in a standardised methacholine challenge model proved to be a useful design to show therapeutic equivalence between devices in patients with mild to moderate asthma. This model provides robust reproducible data, involves smaller patient numbers with fewer dropouts resulting in reduced costs versus a conventional efficacy study.

Most patients with gastroesophageal reflux disease experience symptomatic relapse after stopping acid-suppressive medication. The aim of this study was to compare willingness to continue treatment with esomeprazole on-demand versus continuous maintenance therapy for symptom control in patients with non-erosive reflux disease (NERD) after 6 months.

Background:AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohn's disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD. Methods:We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed. Results:In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported. Conclusions:Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.

OBJECTIVE:To assess the long-term effect on symptoms and quality of life of esomeprazole 20 mg once daily, a recommended dose for maintenance therapy of gastroesophageal reflux disease (GERD). RESEARCH DESIGN AND METHODS:This is a post hoc analysis of 5 year data from patients in the LOTUS trial (ClinicalTrials.gov identifier: NCT00251927) who were randomized to esomeprazole 20 mg once daily. All participants had chronic, symptomatic GERD responsive to treatment. Gastrointestinal symptoms were assessed by physicians and by using patient-reported outcome instruments. Investigations included gastrointestinal endoscopy (with biopsy sampling), 24 hour esophageal pH monitoring and laboratory measurements. RESULTS:In total, 157 of 256 patients randomized to esomeprazole 20 mg once daily remained on this dose until the end of follow-up or study discontinuation, whereas 99 patients had their dose increased because of inadequate symptom control (of these, 29 subsequently returned to the allocated dose). On logistic regression, a long objectively defined GERD history, smoking, female sex, absence of Helicobacter pylori infection and high supine baseline acid reflux into the esophagus were associated with an increased likelihood of requiring dose escalation to esomeprazole 40 mg daily (all p < 0.05). Symptoms were fairly stable and quality of life was normal throughout follow-up in patients remaining on esomeprazole 20 mg once daily, with no more than mild symptom severity, and mean (standard deviation) percentage time with intraesophageal pH <4 was reduced from 10.7 (10.7) pre-randomization to 6.3 (10.2) at 6 months and 4.9 (7.3) at 5 years. The number of serious adverse events was low (0.079 per patient per year). LIMITATIONS:Post hoc analysis with no control group. CONCLUSIONS:Esomeprazole at a maintenance dose of 20 mg once daily offers effective long-term treatment for chronic GERD in patients initially responsive to the medication, with durable symptom control and sustained reductions in intraesophageal acid exposure.

test, rapid urease test or serology and subjects with positive results for at least one assay were classified as H. pylori-positive.Collected data were compared between the two groups.Results: 1007 Patients with PUD were identified, 172 (male 56.4%, mean age 63.2 years) in the period 2001/2002 and 835 (male 60.1%, mean age 65.6 years) in the period 2006-2010.The rate of endoscopic PUD increased from roughly 100 to 165 per year over the study period.Overall, 48.8% of patients had gastric ulcer, 41.8% had duodenal ulcer and 9.4% of patients had peptic ulcer in both localisations, with no differences between the two study groups.Data regarding the H. pylori infection and aspirin/NSAID intake could not be retrieved in 16.1% and 2.4% of patients, respectively.Overall, the prevalence of H. pylori infection decreased significantly from 52.8% to 38.4% (p=0.004)whereas the prevalence of aspirin/NSAID intake increased significantly from 37.5% to 47% (p=0.03)among patients with PUD.In both groups roughly 15% of PUD patients had both risk factors.The proportion of idiopathic peptic ulcers was 27% and 30% in group 1 and 2, respectively.Conclusions: The rate of endoscopic PUD in our institution increased over the study period.The prevalence of major aetiological factors for PUD changed substantially with a decrease of H. pyloripositive PUD and an increase of PUD associated with aspirin/NSAID intake.

OBJECTIVES:High-quality data regarding the efficacy of acid-suppressive treatment for unexplained chest pain are lacking. The aim of this study was to evaluate the efficacy of esomeprazole in primary-care treatment of patients with unexplained chest pain stratified for frequency of reflux/regurgitation symptoms.METHODS:Patients with a ≥ 2-week history of unexplained chest pain (unrelated to gastroesophageal reflux) who had at least moderate pain on ≥ 2 of the last 7 days were stratified by heartburn/regurgitation frequency (≤ 1 day/week (stratum 1) vs. ≥ 2 days/week (stratum 2)) and randomized to 4 weeks of double-blind treatment with twice-daily esomeprazole 40 mg or placebo. Chest pain relief during the last 7 days of treatment (≤ 1 day with minimal symptoms assessed daily using a 7-point scale) was analyzed by stratum in keeping with the predetermined analysis plan.RESULTS:Overall, 599 patients (esomeprazole: 297, placebo: 302) were randomized. In stratum 1, more esomeprazole than placebo recipients achieved chest pain relief (38.7% vs. 25.5%; P=0.018); no between-treatment difference was observed in stratum 2 (27.2% vs. 24.2%; P=0.54). However, esomeprazole was superior to placebo in a post-hoc analysis of the whole study population (combined strata; 33.1% vs. 24.9%; P=0.035).CONCLUSIONS:A 4-week course of high-dose esomeprazole provided statistically significant relief of unexplained chest pain in primary-care patients who experienced infrequent or no heartburn/regurgitation, but there was no such significant reduction in patients with more frequent reflux symptoms.

Background: The aim of this study was to develop a shortened Crohn's Disease Activity Index (CDAI). Methods: A short CDAI was developed retrospectively using patient‐level data from four budesonide clinical trials to select variables from the full CDAI which best predicted health‐related quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ), using the multiple linear regression model. The validity, reliability, and responsiveness of the short CDAI compared to the original CDAI were determined using data from nine clinical trials of budesonide. Results: The variables selected for the short CDAI were abdominal pain, diarrhea frequency, and general well‐being. In all nine studies involving 1373 patients with active and inactive CD (5863 visits), the Pearson correlation coefficients between the short CDAI scores and the original CDAI scores at baseline (r = 0.899, P < 0.001), and the score differences (r = 0.963, P < 0.001) were excellent. The short CDAI accounted for 82.4% of the variance of the original CDAI. The intraclass correlation coefficient for the short CDAI was marginally better than that for the full CDAI, and both demonstrated good reliability (r = 0.600 versus r = 0.549). In patients with active CD who remitted during follow‐up, the mean short CDAI scores decreased from 247 to 97, a score difference of 150 ± 60 points (P < 0.001). In patients with stable CD who relapsed, the mean short CDAI scores increased from 109 to 244 points, a score difference of 135 ± 62 points (P < 0.001). Conclusions: The short CDAI is a valid, reliable, and responsive tool for the measurement of CD activity. (Inflamm Bowel Dis 2011;)

Methods: A short CDAI was developed retrospectively using patient-level data from four budesonide clinical trials to select variables from the full CDAI which best predicted health-related quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ), using the multiple linear regression model. The validity, reliability, and responsiveness of the short CDAI compared to the original CDAI were determined using data from nine clinical trials of budesonide.

Background: Patients with chronic obstructive pulmonary disease (COPD) often experience symptoms and problems with activities early in the morning. This is the first study to compare the effect of budesonide/formoterol and salmeterol/fluticasone on lung function, symptoms and activities early in the morning. Methods: Lung function (peak expiratory flow [PEF] and forced expiratory volume in 1 second [FEV 1 ]) and symptoms were measured at bedside and activities were measured during the morning using a six-item questionnaire concerning basic morning routines. In a randomised, double-blind, multicentre, cross-over study, 442 patients with COPD aged ≥40 years (pre-bronchodilator FEV 1 ≤50%; FEV 1 /vital capacity <70%) received budesonide/formoterol (320/9 µg, one inhalation twice daily) dry powder inhaler (DPI) or salmeterol/fluticasone (50/500 µg, one inhalation twice daily) DPI daily, for 1 week each, separated by a 1- to 2-week washout. Lung function (PEF and FEV 1 ) shortly after rising from bed in the morning, symptoms and basic morning activities were assessed by electronic diary (e-Diary) recordings. Results: Budesonide/formoterol and salmeterol/fluticasone treatment increased morning PEF 5 minutes post-dose, measured as a mean improvement from baseline over the full study period (primary endpoint; adjusted mean change: 15.1 l/min and 14.2 l/min, respectively [difference 1.0 l/min; p = 0.603]). Mean morning FEV 1 improved more following budesonide/ formoterol treatment versus salmeterol/fluticasone at 5 minutes (0.12 l versus 0.09 l; p = 0.090) and 15 minutes (0.14 l versus 0.10 l; p < 0.05) post-dose. Budesonide/formoterol demonstrated a more rapid onset of effect as reflected by increases in e-Diary-recorded PEF and FEV 1 from pre-dose to 5 and 15 minutes post-dose (all p < 0.001) and spirometry at the clinic measured after the first dose (FEV 1 p < 0.001; 5 minutes post-dose). Improvements in symptom scores within 15 minutes after drug administration were similar for both drugs, but budesonide/formoterol treatment resulted in significantly greater improvements in total morning activities score (getting washed, dried, dressed, eating breakfast and walking around the home; 0.22 versus 0.12 respectively, p < 0.05). Both treatments were well tolerated. Conclusions: Short-term treatment with budesonide/formoterol DPI or salmeterol/fluticasone DPI was effective in patients with COPD. Budesonide/formoterol had a more rapid onset of effect compared with salmeterol/fluticasone and resulted in greater improvements in ability to perform morning activities despite the lower inhaled corticosteroid dose.

Background: In a 3-year study, adult patients who recently developed asthma (symptoms for less than I year) were treated for 2 years with the inhaled corticosteroid (ICS) budesonide (early therapy) or terbutaline. During the third year of the study, terbutaline-treated patients received budesonide (delayed therapy). Differences in lung function and bronchial responsiveness to histamine were observed between the 2 groups.Objective: We compared the effects of early versus delayed budesonide therapy after a 10-year follow-up period (13 years after the study began) and current real-life data.Methods: Of the original 103 patients, 90 were re-examined 13 years after study initiation. After the third year of the study, all patients had their medications, including the dose of ICS, individually adjusted.Results: After the follow-up period, lung function was within the normal range for the entire group (all patients); bronchial responsiveness significantly improved compared with baseline data. No statistically significant differences in clinical or functional variables were found between patients given early or delayed budesonide therapy. However, the delayed therapy group had a higher neutrophil count and higher concentrations of eosinophilic cationic protein and myeloperoxidase in induced sputum. This group had also used more asthma medication and hospital days.Conclusions: Patients with relatively mild asthma who received ICS within 12 months of their first asthma symptoms or after a 2-year delay achieved equally good functional control of asthma after 10 years of individualized therapy. However, the delayed therapy group exhibited slightly less optimal disease control and more signs of airway inflammation. (J Allergy Clin Immunol 2009;124:1180-5.)

BACKGROUND & AIMS: Current guidelines recommend empirical, noninvasive approaches to manage dyspeptic patients without alarm symptoms, but concerns about missed lesions persist; the cost savings afforded by noninvasive approaches must be weighed against treatment delays. We investigated the prevalence of malignancies and other serious abnormalities in patients with dyspepsia and the cost of detecting these by endoscopy. METHODS: We studied 2741 primary-care outpatients, 18-70 years in age, who met Rome II criteria for dyspepsia. Patients with alarm features (dysphagia, bleeding, weight loss, etc) were excluded. All patients underwent endoscopy. The cost and diagnostic yield of an early endoscopy strategy in all patients were compared with those of endoscopy limited to age-defined cohorts. Costs were calculated for a low, intermediate, and high cost environment. RESULTS: Endoscopies detected abnormalities in 635 patients (23%). The most common findings were reflux esophagitis with erosions (15%), gastric ulcers (2.7%), and duodenal ulcers (2.3%). The prevalence of upper gastrointestinal malignancy was 0.22%. If all dyspeptic patients 50 years or older underwent endoscopy, 1 esophageal cancer and no gastric cancers would have been missed. If the age threshold for endoscopy were set at 50 years, at a cost of $500/endoscopy, it would cost $82,900 (95% Cl, $35,714-$250,000) to detect each case of cancer. CONCLUSIONS: Primary care dyspeptic patients without alarm symptoms rarely have serious underlying conditions at endoscopy. The costs associated with diagnosing an occult malignancy are large, but an age cut-off of SO years for early endoscopy provides the best assurance that an occult malignancy will not be missed.

OBJECTIVES:The Crohn's Disease Activity Index (CDAI) is used to judge efficacy in clinical trials. We explored the effect of CDAI response definitions for induction on study efficiency.METHODS:We analyzed primary CDAI data from induction studies in patients with mildly to moderately active Crohn's disease, not receiving concomitant aminosalicylates, corticosteroids, or immunomodulator therapy, and without fistulizing or stricturing complications. The 12 definitions of clinical response included: CDAI decrease from baseline by 50, 70, 100, or 150 points; decrease by 25% from baseline and by 70 or 100 points; CDAI <100 or 150 points; CDAI <150 points plus decrease by 70 or 100 points; CDAI <150 points at any time sustained for the duration of the trial; or decrease in the CDAI by 70 points for the last two consecutive visits. Response definitions were ranked according to ability to optimize the effect difference between treatment arms. The effect of time, baseline disease activity (CDAI 200–299 or ≥300 points), and previous surgical resections on response definitions were evaluated and ranked. Multivariate analysis on additional factors of age (<40 or ≥40 yr), gender and duration of disease (<2 or ≥2 yr) were performed to determine predictors of response when applied to these CDAI definitions.RESULTS:Treatment effect differences in placebo-controlled studies were maximized by response definitions that incorporated either a decrease CDAI ≥70 points for the last two consecutive visits or decrease in baseline CDAI ≥100 points, and remained optimal when evaluated for the composite effect of time, baseline activity, and prior resections. A decrease in baseline CDAI ≥100 points had some advantages over a decrease CDAI ≥70 points over two visits in terms of study efficiency, as it produced a lower control response rate and was not influenced by any of the baseline factors.CONCLUSION:Clinical trial efficiency for induction studies in patients with mildly to moderately active Crohn's disease can be improved by using either a decrease in CDAI by ≥70 points for the last two consecutive visits or a decrease in baseline CDAI by ≥100 points as the primary end point for the trial. These findings are valid for patients with ileocecal Crohn's disease not refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients who do not have stricturing or penetrating complications. It is unclear if these CDAI response criteria would similarly increase study efficiency in trials that recruited patients with moderately to severely active disease, patients refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients with stricturing or penetrating complications.