Misspecification of at-risk periods and distributional assumptions in estimating COPD exacerbation rates: The resultant bias in treatment effect estimation.

In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at-risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol

Blood Eosinophils: A Biomarker of Response to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease.

Rationale. Blood eosinophilia has been shown to be associated with a significant proportion of COPD exacerbations and stratifies the clinical response to systemic corticosteroids. The FORWARD study was a randomised, double-blind, parallel group trial that compared 48 weeks treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP/FF) vs. FF, in severe COPD patients with a history of exacerbations. Objectives. We hypothesised that there would be treatment differences in response to BDP/FF when stratifying by baseline blood eosinophil count in a post hoc analysis. Methods. The patients (N=1,184) were stratified into four quartile groups based on the baseline eosinophil count and analyses on exacerbation rate, change in pre dose FEV1 and St. George’s Respiratory Questionnaire [SGRQ] total score over 48 weeks were performed across these. A predictive model of future exacerbations was developed based upon baseline blood eosinophil count and other factors. Results. The adjusted treatment difference over 48 weeks between the BDP/FF and FF groups was largest within the highest baseline blood eosinophil quartile (≥279.8/µl /µl). Within this quartile a significant (i) 46% reduction in exacerbation rate, (ii) 0.102 L improvement in pre bronchodilator FEV1 and (iii) 5.9 units improvement in SGRQ total score were seen in favour of BDP/FF. Predictive modelling suggested that the risk of exacerbations was influenced by baseline blood eosinophils in patients treated with FF alone, but not in patients treated with BDP/FF. Conclusions. The presence of a significant blood eosinophilia seems to be associated with a particularly favorable response to ICS/LABA therapy in COPD patients

Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD.

Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD