Lung function and respiratory symptoms in a 1-year randomized smoking cessation trial of varenicline in COPD patients

SummaryThere are few data concerning changes in lung function and respiratory symptoms in smokers with chronic obstructive pulmonary disease (COPD) weeks to months after quitting smoking. We examined serial changes in spirometry and Clinical COPD Questionnaire (CCQ) scores (measuring respiratory symptoms and health-related quality of life) in COPD participants by smoking status during a smoking cessation trial.In this randomized, double-blind trial, smokers with mild-to-moderate COPD were treated with varenicline 1 mg b.i.d. or placebo for 12 weeks and followed to Week 52. Primary endpoints of abstinence were previously reported. Secondary endpoints were mean changes from baseline in post-bronchodilator forced expired volume in 1 s (FEV1) and CCQ scores.Change from baseline in post-bronchodilator FEV1 was significantly improved in continuous abstainers (121.8 mL) vs. continuous smokers (37.9 mL) at Week 12 (P = 0.0069), but not at Weeks 24 or 52. Mean change from baseline at Week 12 in CCQ Total Score was significantly better in continuous abstainers (−1.04) vs. continuous smokers (−0.53; P < 0.0001): this improvement was sustained at Weeks 24 and 52.In a 1-year cessation trial of smokers with COPD, continuous abstinence compared with continuous smoking significantly improved post-bronchodilator FEV1 at Week 12 (although the difference narrowed subsequently) and CCQ Total Scores at Week 12, with sustained improvement thereafter.(Trial registry: http://www.clinicaltrials.gov; trial identifier: NCT00285012

The evolutionary young miR-1290 favors mitotic exit and differentiation of human neural progenitors through altering the cell cycle proteins.

Regulation of cellular proliferation and differentiation during brain development results from processes requiring several regulatory networks to function in synchrony. MicroRNAs are part of this regulatory system. Although many microRNAs are evolutionarily conserved, recent evolution of such regulatory molecules can enable the acquisition of new means of attaining specialized functions. Here we identify and report the novel expression and functions of a human and higher primate-specific microRNA, miR-1290, in neurons. Using human fetal-derived neural progenitors, SH-SY5Y neuroblastoma cell line and H9-ESC-derived neural progenitors (H9-NPC), we found miR-1290 to be upregulated during neuronal differentiation, using microarray, northern blotting and qRT-PCR. We then conducted knockdown and overexpression experiments to look at the functional consequences of perturbed miR-1290 levels. Knockdown of miR-1290 inhibited differentiation and induced proliferation in differentiated neurons; correspondingly, miR-1290 overexpression in progenitors led to a slowing down of the cell cycle and differentiation to neuronal phenotypes. Consequently, we identified that crucial cell cycle proteins were aberrantly changed in expression level. Therefore, we conclude that miR-1290 is required for maintaining neurons in a differentiated state

Baseline Severity as Predictor of Change in St George's Respiratory Questionnaire Scores in Trials of Long-acting Bronchodilators with COPD Patients.

Background: In trials oflong-acting bronchodilators, health status is an important trial outcome, however the influence of baseline severity on response measured by St George's Respiratory Questionnaire (SGRQ) is not known. We have compared SGRQ changes between patients with chronic obstructive pulmonary disease (COPD) of mild-moderate severity or dyspnea (Global initiative for chronic Obstructive Lung disease [GOLD] grades 1 and 2; modified Medical Research Council [mMRC] grades 1 and 2) to those with severe-very severe severity or dyspnea (GOLD grades 3 and 4; mMRC grades 3 and 4). Methods: Combined individual patient data from the COPD Biomarkers Qualification Consortium database (trials of long-acting bronchodilators) were used comprising of patients from short-term (≤1-year duration; n=10802) and medium-term (2-4 years' duration; n=8963) studies. A repeated measures analysis of variance (ANOVA) was used to determine the effects of baseline severity (GOLD/mMRC) on SGRQ response to treatment. All treatment arms were combined. Results: In short-term studies, milder patients showed a greater response than those with more severe disease in terms of GOLD grade (partial Eta(2) = 0.03, p < 0.0001) and mMRC grade (partial Eta(2) = 0.05, p < 0.0001). Similar results were seen in the medium-term studies (partial Eta(2) = 0.02, p < 0.0001; mMRC: partial Eta(2) = 0.05, p < 0.0001,). Conclusions: Patients with less severe airflow limitation and less severe dyspnea showed larger improvements in SGRQ score than more severely obstructed or dyspneic patients. Although these severity influences are small (2%-5% of the variance in SGRQ score), they do suggest that pre-specified separate analyses are warranted to test for differences in response, based on baseline severity

Responder Analyses for Treatment Effects in COPD Using the St George's Respiratory Questionnaire.

Background: Patient-reported outcomes data in clinical trials are usually reported as mean values, interpreted in comparison to a minimum clinically important difference (MCID) and ignoring the possibility of a sizable proportion of patients experiencing a worthwhile benefit when the majority did not. This analysis tested the reliability of calculated responder rates (from chronic obstructive pulmonary disease [COPD] patients) with the St George's Respiratory Questionnaire (SGRQ) using a range of responder cut-points above and below the MCID (4 units). Methods: Individual patient data (i.e., data from long-acting bronchodilator [LAB] and inhaled corticosteroids [ICS]/long-acting beta2-agonist [LABA] randomized clinical studies) in the COPD Biomarker Qualification Consortium database were used: short-term (≤1-year duration; 14,814 patients,) and medium-term (2-4 years; 12,043 patients). Responder rates versus placebo across SGRQ score change thresholds ranging from -1.5 to -8.0 were tested; differences were expressed as the odds ratio (OR) of a patient exceeding the threshold versus no change or deterioration. Results: The ORs measuring benefit of active treatment were similar across thresholds in short-term studies (LAB, ORs 1.40-1.42; LABA/ICS, 1.50-1.56) and medium-term LAB studies (ORs 1.34-1.43), whereas ORs in medium-term studies with LABA/ICS intervention showed a trend for higher response rates at higher values of threshold cut-points (1.64-1.79). In short-term studies, different thresholds had little effect on the OR between active drugs versus a trend for lower ORs with lower thresholds in medium-term studies. Conclusions: The OR for a treatment effect compared with placebo appears consistent across a range of responder cut-points. In medium-term trials, the treatment difference between active drugs suggests that use of a lower threshold would not increase the odds of observing a measured treatment difference

St George's Respiratory Questionnaire Score Predicts Outcomes in Patients with COPD: Analysis of Individual Patient Data in the COPD Biomarkers Qualification Consortium Database.

Background: We aimed to estimate the usefulness of a disease specific health status measure, the St George's Respiratory Questionnaire (SGRQ), to predict outcomes in patients with chronic obstructive pulmonary disease (COPD). Methods: Individual patient-data of 12043 patients from long-term randomized clinical trials (2-4 years' duration) in the COPD Biomarkers Qualification Consortium database were analyzed. The adverse COPD outcomes were: exacerbations of COPD, hospital admissions due to exacerbation and all-cause mortality. Cox proportional hazards regression was used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for quartiles of SGRQ scores at baseline and time to first event, and time from first to second event, where appropriate. Results: The risk of adverse COPD outcomes increased with each increasing quartile of SGRQ score for all time to first event analyses. When comparing the lowest versus the highest quartile, the event risk (HRs [95% CIs]) increased by 40% for exacerbations (1.40 [1.29, 1.51]); 2-fold for hospital admissions (2.01 [1.78, 2.28]) and more than 2-fold for all-cause mortality (2.30 [1.91, 2.78]). For second event analyses in a subset of eligible patients, these trends persisted albeit with reduced risk estimates for exacerbations. Conclusions: Among patients with COPD, health status measured by a SGRQ score predicted exacerbations of COPD, hospital admissions due to exacerbations and their recurrence and death after adjustment. These data support the rationale for a health status measure use as a drug development tool and suggest that a health status measure may also have a role in risk assessment for COPD patients in routine medical care

Socioeconomic Status as a Determinant of Health Status Treatment Response in COPD Trials.

Background: Randomized controlled trials (RCTs) often recruit patients from low and high socioeconomic status (SES) countries, but little is known about the effect of SES on clinical outcomes, particularly patient-centered measures of symptomatic benefit. Methods: Combined individual chronic obstructive pulmonary disease (COPD) patient data from the placebo and long-acting bronchodilator arms of 17 RCTs (from the COPD Biomarkers Qualification Consortium database) were analyzed. Health status was measured using the St George's Respiratory Questionnaire (SGRQ) (minimum clinically important difference [MCID]: 4 units). Trials were grouped into short-term (≤12 months) and medium-term (>12 months to 48 months). A participant's country of residence was categorized into Low/Medium or High SES using World Health Organization criteria. Results: Data from 19765 individuals (6109 Low/Medium SES) were available. Patients in Low/Medium SES countries had more severe disease at baseline. Improvement in SGRQ score with placebo was ≈2 units greater in Low/Medium than in High SES countries; at its greatest, the improvement from baseline exceeded the MCID in Low/Medium countries. This difference was maintained for at least 1 year. Improvement with bronchodilator was also greater in Low/Medium versus High SES countries; overall there was no evidence that the treatment effect versus placebo was different between countries of different SES status. Conclusions: Participants in Low/Medium SES countries experienced significantly larger treatment effects, irrespective of treatment group (placebo and bronchodilator). Despite this, COPD patients in Low/Medium SES countries experienced a health status gain from long-acting bronchodilator treatment that is similar to that seen in High SES countries

The COPD Biomarkers Qualification Consortium Database: Baseline Characteristics of the St George's Respiratory Questionnaire Dataset.

The COPD Biomarkers Qualification Consortium (CBQC) is a public-private partnership formed in 2010 with a goal of qualifying biomarkers and clinical assessment tools for use in clinical or nonclinical decision-making and particularly within the regulatory context. The St George's Respiratory Questionnaire (SGRQ) is a measure of health-related quality of life widely used in clinical research. The aim of the CBQC working group on SGRQ was to construct an individual patient level database of clinical trial data that included the SGRQ, to use this to confirm the reliability and validity of the SGRQ as an outcome measure of health status, and investigate its use as a predictor of future events (exacerbations and mortality). This manuscript describes the formulation of the CBQC database and presents the baseline demographic and clinical characteristics of the integrated SGRQ database overall, and by study type (short-term [≤1 year], medium-term [2-4 years] and observational studies). Distribution of baseline SGRQ scores varied little by demographic determinants except for income region in the observational data set (low-middle income countries +10 units compared with high income, p<0.0001) and this observation held across studies. SGRQ scores increased with increasing modified Medical Research Council dyspnea scores (mean differences ranged 6.9-17.9 units) and with increasing airflow limitations (Global initiative for chronic Obstructive Lung Disease grades 1 to 4; differences ranged 4.5-16.1 units), consistent across study types. As a method of cross-sectional comparison, the SGRQ appears to be relatively free of bias from demographic factors although care should be taken when making cross sectional comparisons of scores between patients in countries at different levels of socio-economic development/

Gait deficiencies associated with peripheral artery disease are different than chronic obstructive pulmonary disease

Objective: Previous studies have indicated that patients with peripheral artery disease (PAD), display significant differences in their kinetic and kinematic gait characteristics when compared to healthy, aged-matched controls. The ability of patients with chronic obstructive pulmonary disease (COPD) to ambulate is also limited. These limitations are likely due to pathology-driven muscle morphology and physiology alterations establish in PAD and COP, respectively. Gait changes in PAD were compared to gait changes due to COPD to further understand how altered limb muscle due to disease can alter walking patterns. Both groups were independently compared to healthy controls. It was hypothesized that both patients with PAD and COPD would demonstrate similar differences in gait when compared to healthy controls. Methods: Patients with PAD (n=25), patients with COPD (n=16), and healthy older control subjects (n=25) performed five walking trials at self-selected speeds. Sagittal plane joint kinematic and kinetic group means were compared. Results: Peak values for hip flexion angle, braking impulse, and propulsive impulse were significantly reduced in patients with symptomatic PAD compared to patients with COPD. After adjusting for walking velocity, significant reductions (p Conclusions: The results of this study demonstrate that while gait patterns are impaired for patients with PAD, this is not apparent for patients with COPD (without PAD). PAD (without COPD) causes changes to the muscle function of the lower limbs that affects gait even when subjects walk from a fully rested state. Altered muscle function in patients with COPD does not have a similar effect