Early Diagnostic BioMARKers in Exacerbations of COPD: the MARKED Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Respiratory symptoms: c-LRTI-VAS
研究概览
简要总结
Acute exacerbations of COPD (AECOPD) are episodes of acute worsening of respiratory symptoms that require additional therapy. Exacerbations play a pivotal role in the burden and progressive course of COPD (1). Each event contributes to a progressive decline in lung function (2), reduced health status, low physical activity level (3) and increased health care costs (4). As such, disease management is predominantly based on the prevention of these episodes (1). Yet, in the Netherlands, 30.000 people are admitted to the hospital for an AECOPD every year (5). Although most AECOPD have an infectious origin (6), the underlying mechanisms are heterogeneous and predicting their occurrence in individual patients currently remains unsuccessful (7-9). Furthermore, there is a lack of our understanding in the longitudinal alterations in microbial composition and host-microbiome interactions in the stable state, at AECOPD and during recovery in patients with COPD. This knowledge is essential to improve the early and accurate diagnosis of (the different types of) AECOPD, and for the development of novel antimicrobial and other therapeutic targets and subsequent personalized treatment. These challenges need to be addressed in order to reduce the future impact of these events, avoid unnecessary treatments of individual patients, reduce healthcare utilization and improve overall care for patients with COPD. The current 'Early diagnostic BioMARKers in Exacerbations of COPD' (MARKED) study was designed to investigate several of these gaps in the management of COPD exacerbations.
It is anticipated that complex biomarker panels, rather than a single biomarker, will be identified. Since AECOPD are heterogeneous events in terms of origin, trigger, severity, duration, need for treatment and overall clinical presentation (1, 6, 10-15), we expect to identify different biomarker panels for different subtypes of AECOPD. Furthermore, AECOPD diagnosis relies heavily on the exclusion of differential diagnoses (1), which further rules out the potential of a single predictive AECOPD biomarker.
详细描述
The MARKED study is an exploratory, prospective, single-center, longitudinal, observational study with eight weeks follow-up. The primary objective is to explore which biomarkers from a panel of frequently measured biomarkers (symptoms, vital signs, lung function parameters and spontaneous sputum, nasopharyngeal swabs, stool and blood samples) predict an exacerbation and/or respiratory infection in patients with COPD. Furthermore, secondary objectives are:
I. to investigate longitudinal alterations in microbial composition and host-microbiome interactions in the stable state, at AECOPD and during recovery.
II. to study the heterogeneity of AECOPD by comprehensive clinical, functional, microbial, proteomic, transcriptomic, genetic, metabolomic, inflammatory and biochemical characterization of these events.
III. to determine the correlation between microbial alterations in the airways/gut and inflammatory biomarkers in blood during longitudinal follow up.
IV. to longitudinally investigate biomarkers of AECOPD in clinically relevant subgroups of patients with COPD (e.g. current versus ex-smokers, high versus low blood eosinophils, frequent vs. infrequent exacerbators).
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥40 years old
- •≥10 pack years of smoking
- •primary diagnosis of COPD and post-bronchodilator ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC) of less than 0.
- •clinical indication for inpatient pulmonary rehabilitation in Ciro
- •provided written informed consent
排除标准
- •current, i.e. <12 months, (secondary) diagnosis of asthma according to the referring physician
- •unstable concurrent cardiovascular, metabolic, renal, gastro-intestinal and musculoskeletal chronic diseases, as judged by the investigator
- •chronic use of oral corticosteroids >10 mg prednisolone/day
- •initiation of maintenance therapy with macrolides <6 weeks prior to study entry
- •anemia, defined as hemoglobin level <8.1 mmol/L in men and <7.5 mmol/L in women
- •participation in a study involving investigational or marketed products concomitantly or <8 weeks prior to study entry
- •unable to read, speak or understand Dutch
结局指标
主要结局
Respiratory symptoms: c-LRTI-VAS
时间窗: 8 weeks
The COPD- Lower Respiratory Tract Infection Visual Analogue Scales (c-LRTI-VAS). The higher the score, the higher the disease burden. Scale: 0-100 mm. Assessment: daily.
Vital signs: oxygen saturation
时间窗: 8 weeks
Oxygen saturation (SpO2). Assessment: daily.
Biomarkers: spontaneous sputum
时间窗: 8 weeks
* 16S rRNA and ITS sequencing, WMTS, proteomics and metabolomics. Assessment: enrollment, thrice-weekly (M-W-F) and exacerbation. * Cell differentials and traditional bacterial culture at enrollment and exacerbation.
Vital signs: blood pressure
时间窗: 8 weeks
Systolic and diastolic blood pressure (mmHg). Assessment: daily.
Pre-bronchodilator FEV1
时间窗: 8 weeks
Absolute (L) and percentage of predicted (% pred) of the forced expiratory volume in 1 second (FEV1). Assessment: daily.
Pre-bronchodilator PEF
时间窗: 8 weeks
Absolute (L/s) and percentage of predicted (% pred) of the peak expiratory flow (PEF). Assessment: daily.
Biomarkers: stool
时间窗: 8 weeks
Whole metagenomic shotgun sequencing, and metabolomics. Assessment: enrollment, exacerbation, and outcome assessment.
Vital signs: heart rate
时间窗: 8 weeks
Heart rate (beats per minute). Assessment: daily.
Vital signs: breathing frequency
时间窗: 8 weeks
Breathing frequency (breaths per minute). Assessment: daily.
Pre-bronchodilator FVC
时间窗: 8 weeks
Absolute (L) and percentage of predicted (% pred) of the forced vital capacity (FVC). Assessment: daily.
Biomarkers: venous blood
时间窗: 8 weeks
* SNP (associated with COPD, exacerbations and microbial infections) sequencing. Assessment: enrollment. * WMTS. Assessment: enrollment, exacerbation and outcome assessment. * ELISA-based multiplex cytokine analysis, anti-bacterial titer analysis, metabolomics, proteomics and WMTS. Assessment: enrollment, thrice-weekly (M-W-F), exacerbation and outcome assessment.
Vital signs: body temperature
时间窗: 8 weeks
Body temperature (degree Celsius). Assessment: daily.
Respiratory symptoms: EXACT
时间窗: 8 weeks
The EXAcerbations of Chronic pulmonary disease Tool (EXACT). The higher the score, the higher the disease burden. Scale: total score 0-100 points. Assessment: daily.
Biomarkers: nasopharyngeal swabs
时间窗: 8 weeks
16S rRNA and ITS sequencing, and whole metatranscriptomic sequencing (WMTS). Assessment: enrollment, thrice-weekly (Monday-Wednesday-Friday) and exacerbation.
次要结局
- Post-bronchodilator PEF(8 weeks)
- Body plethysmography(8 weeks)
- Diffusing capacity(8 weeks)
- Exacerbation markers(8 weeks)
- Post-bronchodilator FVC(8 weeks)
- Post-bronchodilator FEV1(8 weeks)
- mMRC(8 weeks)
- HADS(8 weeks)
- Exercise capacity(8 weeks)
- CAT(8 weeks)
- Hematology(8 weeks)
- Arterial blood gas(8 weeks)
- Basic characteristics(8 weeks)
- Respiratory muscle strength(8 weeks)
- Muscle function(8 weeks)
- Chemistry(8 weeks)
研究者
Frits M. E. Franssen
Principal Investigator
Center of Expertise for Chronic Organ Failure