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Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast.

ABSTRACT: BACKGROUND:Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators, but above all, CD8+ T-lymphocytes, macrophages and neutrophils are important players in disease pathogenesis. Roflumilast, a first-in-class, potent and selective phosphodiesterase 4 (PDE4) inhibitor, reduces the rate of exacerbations in patients with a high risk of future exacerbations and has been shown to reduce inflammatory cells and mediators in induced sputum, a surrogate of airway inflammation. However, these anti-inflammatory effects are yet to be confirmed in another robust study directly assessing inflammatory markers in bronchial sub-mucosa. METHODS/DESIGN:An international, 16-week, randomized, double-blind, placebo-controlled, parallel-group study investigating the effects of roflumilast 500 ?g once-daily versus placebo on inflammatory parameters in bronchial biopsy tissue specimens, sputum and blood serum. One hundred and fifty patients with COPD and chronic bronchitis for at least 12 months will be recruited into the study and randomized in a 1:1 ratio to receive either roflumilast or placebo. The primary endpoint will be the number of CD8+ cells (cell counts per mm2) in bronchial biopsy tissue specimens (sub-mucosa) and the key secondary endpoint will be the number of CD68+ cells (cell counts per mm2), assessed by indirect immunohistochemistry. DISCUSSION:It is hypothesized that treatment with roflumilast reduces the characteristic inflammation found in the airways of patients with moderate-to-severe COPD, compared with placebo. The design of the present study has built on the work of previous bronchial biopsy studies available in the literature. It is hoped that it will reveal the cellular mechanisms underlying the anti-inflammatory effects of roflumilast and identify potentially important biomarkers and other surrogate endpoints in patients with COPD. The design and rationale for this trial are described herein.

SUBMITTER: Barnes NC

PROVIDER: S-EPMC3927659 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast.

Barnes Neil C NC Saetta Marina M Rabe Klaus F KF

BMC pulmonary medicine 20140131

<h4>Background</h4>Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators, but above all, CD8+ T-lymphocytes, macrophages and neutrophils are important players in disease pathogenesis. Roflumilast, a first-in-class, potent and selective phosphodiesterase 4 (PDE4) inhibitor, reduces the rate of exacerbations in patients with a high risk of future exacerbations and has been shown to reduce inflammatory cells and media ...[more]

PMID: 24484726

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Project description:BackgroundType 2 diabetes mellitus is preventable through lifestyle intervention. Diabetes prevention programmes (DPPs) aim to deliver prevention-based behaviour change interventions to reduce incidence. Such programmes vary from usual primary care in terms of where, how, and by whom they are delivered. Implementation is therefore likely to face new commissioning, incentive and delivery challenges. We report on the implementation of a national DPP in NHS England, and identify lessons learned in addressing the implementation challenges.MethodsIn 2017/18, we conducted 20 semi-structured telephone interviews covering 16 sampled case sites with the designated lead(s) responsible for local implementation of the programme. Interviews explored the process of implementation, including organisation of the programme, expectations and attitudes to the programme, funding, target populations and referral and clinical pathways. We drew on constant comparative methods to analyse the data and generate over-arching themes. We complemented our qualitative data with a survey focused on variation in the financial incentives used across sites to ensure usual primary care services recruited patients to new providers.ResultsWe identified five over-arching areas of learning for implementing this large-scale programme: 1) managing new providers; 2) promoting awareness of services; 3) recruiting patients; 4) incentive payments; and 5) mechanisms for sharing learning. In general, tensions appeared to be caused by a lack of clear roles/responsibilities between hierarchical actors, and lack of communication. Both local sites and the national NHS coordination team gained experience through learning by doing. Initial tensions with roles and expectations have been worked out during implementation.ConclusionsImplementing a national disease prevention programme is a major task, and one that will be increasingly faced by health systems globally as they aim to adjust to demand pressures. We provide practical learning opportunities for the wider uptake and sustainability of prevention programmes. Future implementers might wish to define clear responsibilities for each actor prior to implementation, ensure early engagement with new providers, offer mechanisms/forums for sharing learning, generate evidence and provide advice on incentive payments, and prioritise public and professional awareness of the programme.

Project description:BackgroundDrug overdose has become a leading cause of accidental death in the United States. Between 2000 and 2015, the rate of deaths from drug overdoses increased 137%, including a 200% increase in the rate of overdose deaths involving opioids (including opioid pain relievers and heroin). Unnecessary opioid prescribing is one of the factors driving this epidemic.ObjectivesThe primary objective of this paper is to share lessons learned while conducting a randomized trial to de-implement opioids for post-extraction pain management utilizing clinical decision support (CDS) with and without patient education. The lessons learned from conducting this trial in a real-world setting can be applied to future dissemination and implementation oral health research.MethodsThe sources informing lessons learned were generated from qualitative interviews conducted with 20 of the forty-nine dental providers involved in the study following the implementation phase of the trial. Ongoing policy, social and environmental factors were tracked throughout the study.ResultsDental providers in the trial identified the impact of training that involved health professionals sharing information about the personal impact of pain and opioid use. Additionally, they found utility in being presented with a dashboard detailing their prescribing patterns related to other dentists. For the 30 general dentists with access to the CDS, use of its portal varied widely, with most using it 10%-49% of the time related to extractions.ConclusionsIn the context of a downward trend in opioid prescribing and considering the influence of the COVID pandemic during the trial, dental providers indicated benefit in training about negative personal impacts of prescribing opioids, and personally relevant feedback about their prescribing patterns. Only modest use of the CDS was realized. Implementation of this trial was impacted by governmental and health system policies and the COVID pandemic, prompt the consideration of implications regarding continuing ways to limit opioid prescribing among dental providers.

Project description:Introduction: Peri-operative window trials, using molecular biomarkers as surrogate endpoints for treatment response, offer investigators a uniqueopportunity to obtain intact tumor samples at 2 different time-points and thus evaluate potential biomarkers over a short period of time. Here we report results of a pilot trial designed to determine if treatment-mediated changes in gene expression can be detected after a 10-day exposure to anastrozole in estrogen receptor (ER)-positive breast cancer compared to untreated controls. Methods: Paired tumor samples (biopsy and surgical) were obtained from 26 postmenopausal women with ER-positive breast cancer. Patients were assigned anastrozole (1mg/dy) for 10 days immediately prior to surgery (13 cases) or no treatment (13 controls). 502 cancer-related genes were examined by the DASL FFPE-based cDNA array (moderated t-test, p ≤ .005). Surrogate biomarkers reflecting changes in gene expression were examined by immunohistochemistry (IHC) (Wilcoxon rank-based test, p < .05). Results: Sufficient RNA was available from 19 paired samples (8 controls, 11 cases). There was no difference in age, tumor size, grade, or baseline biomarker expression between groups. Within each group, 18 genes, reflecting roles in proliferation, angiogenesis, and apoptosis showed differential expression over time from biopsy to surgery (p < 0.005). Dysregulation of estrogen-related genes was present only in the treated group. Comparison between groups identified 5 genes that were significantly dysregulated between controls and treated cases (BAG1/ING1/ERBB4/IFNGR1/TFDP1). Reduction in Ki-67 index was observed in 7 (54%) treated cases in 1 (7.7%) control patient. Conclusions: Short-term (10-day) exposure to anastrozole resulted in significant dysregulation of 18 out of 502 cancer-related genes, and Ki-67 was reduced in 54% of cases. However, the local effects of wound healing may represent a confounding factor in the interpretation of peri-operative window trials as exposed by the changes in gene expression and the increased Ki-67 index in the control group. Prospective, paired tumor samples (biopsy and surgical) were obtained from 26 postmenopausal women with ER-positive breast cancer. Patients were assigned anastrozole (1mg/dy) for 10 days immediately prior to surgery (13 cases) or no treatment (13 controls). 502 cancer-related genes were examined by the DASL FFPE-based cDNA array. Sufficient RNA for gene expression analysis was obtained from 19/26 (73%) FFPE paired (biopsy and surgery) samples (8 controls, 11 anastrozole-treated patients

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Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast.

Publications

Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast.

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