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Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol.

ABSTRACT: Many patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting ?2-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]). Roflumilast is approved to treat severe COPD in patients with chronic bronchitis--and a history of frequent exacerbations--as an add-on to bronchodilators.The REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment) study (identification number RO-2455-404-RD, clinicaltrials. gov identifier NCT01329029) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations.REACT is a 1-year randomized, double-blind, multicenter, phase III/IV study of roflumilast 500 ?g once daily or placebo on top of a fixed long-acting ?2-agonist/inhaled corticosteroid combination. A concomitant long-acting muscarinic antagonist will be allowed at stable doses. The primary outcome is the rate of moderate or severe COPD exacerbations. Using a Poisson regression model with a two-sided significance level of 5%, a sample size of 967 patients per treatment group is needed for 90% power. COPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year will be recruited.It is hypothesized that because roflumilast (a phosphodiesterase-4 inhibitor) has a different mode of action to bronchodilators and inhaled corticosteroids, it may provide additional benefits when added to these treatments in frequent exacerbators. REACT will be important to determine the role of roflumilast in COPD management. Here, the design and rationale for this important study is described.

SUBMITTER: Calverley PM

PROVIDER: S-EPMC3393336 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol.

Calverley Peter M A PM Martinez Fernando J FJ Fabbri Leonardo M LM Goehring Udo-Michael UM Rabe Klaus F KF

International journal of chronic obstructive pulmonary disease 20120620

<h4>Background</h4>Many patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting β2-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]). Roflumilast is approved to treat severe COPD in patients with chronic bronchitis--and a history of frequent exacerbations--as an add-on to bronchodilators.<h ...[more]

PMID: 22791991

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Project description:Differential susceptibility to recurrent infection and exacerbation in COPD is not well understood. Here we investigated the potential impact of genetic variation in Fatty Acid Binding Protein 5 (FABP5), a metabolic regulator we previously demonstrated to be downregulated in COPD and further downregulated in patients reporting one or more exacerbation. Through negative binomial analysis of the COPDGene SNP dataset, we identified 5 novel linked single nucleotide polymorphisms (SNPs) across the FABP5 locus that were significantly associated with severe exacerbations in a Non-Hispanic White cohort (rs4338057, rs12549270, rs202275, rs202277, and rs202279). We integrated multiple sources of previously published data to prioritize SNPs most likely to exert regulatory function. Ultimately, rs202275 emerged as the lead candidate due to unique alignment with the loading site of a bidirectional RNA Pol II signature of active enhancer utilization in our recently published patient-derived airway epithelial PRO-seq dataset, suggesting a critical regulatory role for the region harboring this variant. Using Micro-C genome-wide chromosome conformation capture, we found that the region harboring rs202275 makes three-dimensional physical contacts with the FABP5 transcription start site (TSS), suggesting the SNP region could regulate FABP5 transcription through a looping mechanism. To examine SNP function, we analyzed previously deposited gene-array data (GEO Accession #GSE42057) from peripheral blood mononuclear cell (PBMC) samples and found that COPD patients carrying the rs202275 risk allele (T) express significantly lower levels of FABP5 compared to non-carrier patients. Seahorse real-time mitochondrial respiration assays in freshly isolated PBMCs further revealed disrupted oxidative phosphorylation in cells from patients carrying the rs202275 risk allele. As macrophage polarization from pro-inflammatory toward pro-resolving phenotype is dependent on oxidative metabolism, the functional impact of the rs202275 risk allele and associated reduction in FABP5 transcription may contribute to increased or prolonged systemic inflammation, thereby increasing susceptibility to exacerbation in COPD.

Project description:BackgroundRoflumilast, a once-daily, selective phosphodiesterase-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. The RE(2)SPOND study is examining whether roflumilast, when added to an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) fixed-dose combination (FDC), further reduces exacerbations. The methodology is described herein.MethodsIn this Phase IV, multicenter, double-blind, placebo-controlled, parallel-group trial, participants were randomized 1:1 (stratified by long-acting muscarinic antagonist use) to receive roflumilast or placebo, plus ICS/LABA FDC, for 52 weeks. Eligible participants had severe COPD associated with chronic bronchitis, had two or more moderate-severe exacerbations within 12 months, and were receiving ICS/LABA FDC for ≥3 months. The primary efficacy measure is the rate of moderate or severe COPD exacerbations per participant per year. The secondary efficacy outcomes include mean change in prebronchodilator forced expiratory volume in 1 second (FEV1) over 52 weeks, rate of severe exacerbations, and rate of moderate, severe, or antibiotic-treated exacerbations. Additional assessments include spirometry, rescue medication use, the COPD assessment test, daily symptoms using the EXACT-Respiratory symptoms (E-RS) questionnaire, all-cause and COPD-related hospitalizations, and safety and pharmacokinetic measures.ResultsAcross 17 countries, 2,354 participants were randomized from September 2011 to October 2014. Enrollment goal was met in October 2014, and study completion occurred in June 2016.ConclusionThis study will further characterize the effects of roflumilast added to ICS/LABA on exacerbation rates, lung function, and health of severe-very severe COPD participants at risk of further exacerbations. The results will determine the clinical benefits of roflumilast combined with standard-of-care inhaled COPD treatment.

Project description:ObjectiveTo develop a practicable nomogram aimed at predicting the risk of severe exacerbations in COPD patients at three and five years.MethodsCOPD patients with prospective follow-up data were extracted from Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) obtained from National Heart, Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center. We comprehensively considered the demographic characteristics, clinical data and inflammation marker of disease severity. Cox proportional hazard regression was performed to identify the best combination of predictors on the basis of the smallest Akaike Information Criterion. A nomogram was developed and evaluated on discrimination, calibration, and clinical efficacy by the concordance index (C-index), calibration plot and decision curve analysis, respectively. Internal validation of the nomogram was assessed by the calibration plot with 1000 bootstrapped resamples.ResultsAmong 1711 COPD patients, 523 (30.6%) suffered from at least one severe exacerbation during follow-up. After stepwise regression analysis, six variables were determined including BMI, severe exacerbations in the prior year, comorbidity index, post-bronchodilator FEV1% predicted, and white blood cells. Nomogram to estimate patients' likelihood of severe exacerbations at three and five years was established. The C-index of the nomogram was 0.74 (95%CI: 0.71-0.76), outperforming ADO, BODE and DOSE risk score. Besides, the calibration plot of three and five years showed great agreement between nomogram predicted possibility and actual risk. Decision curve analysis indicated that implementation of the nomogram in clinical practice would be beneficial and better than aforementioned risk scores.ConclusionOur new nomogram was a useful tool to assess the probability of severe exacerbations at three and five years for COPD patients and could facilitate clinicians in stratifying patients and providing optimal therapies.

Dataset Information

Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol.

Publications

Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol.

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