Markers of COPD Exacerbations

NCT05315674 | Unknown

• 1 other identifier: MARKED
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

COPD; COPD Exacerbation

Keywords

COPD; COPD Exacerbation; Microbiota; Biomarker

Outcome Measures

Primary Outcomes (14)

• Respiratory symptoms: EXACT

  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.

  8 weeks

• Respiratory symptoms: c-LRTI-VAS

  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.

  8 weeks

• Vital signs: blood pressure

  Systolic and diastolic blood pressure (mmHg). Assessment: daily.

  8 weeks

• Vital signs: heart rate

  Heart rate (beats per minute). Assessment: daily.

  8 weeks

• Vital signs: oxygen saturation

  Oxygen saturation (SpO2). Assessment: daily.

  8 weeks

• Vital signs: body temperature

  Body temperature (degree Celsius). Assessment: daily.

  8 weeks

• Vital signs: breathing frequency

  Breathing frequency (breaths per minute). Assessment: daily.

  8 weeks

• Pre-bronchodilator FEV1

  Absolute (L) and percentage of predicted (% pred) of the forced expiratory volume in 1 second (FEV1). Assessment: daily.

  8 weeks

• Pre-bronchodilator FVC

  Absolute (L) and percentage of predicted (% pred) of the forced vital capacity (FVC). Assessment: daily.

  8 weeks

• Pre-bronchodilator PEF

  Absolute (L/s) and percentage of predicted (% pred) of the peak expiratory flow (PEF). Assessment: daily.

  8 weeks

• Biomarkers: nasopharyngeal swabs

  16S rRNA and ITS sequencing, and whole metatranscriptomic sequencing (WMTS). Assessment: enrollment, thrice-weekly (Monday-Wednesday-Friday) and exacerbation.

  8 weeks

• Biomarkers: venous blood

  * 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.

  8 weeks

• Biomarkers: spontaneous sputum

  * 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.

  8 weeks

• Biomarkers: stool

  Whole metagenomic shotgun sequencing, and metabolomics. Assessment: enrollment, exacerbation, and outcome assessment.

  8 weeks

Secondary Outcomes (16)

• Basic characteristics

  8 weeks

• Post-bronchodilator FEV1

  8 weeks

• Post-bronchodilator FVC

  8 weeks

• Post-bronchodilator PEF

  8 weeks

• Body plethysmography

  8 weeks

Study Arms (2)

Exacerbators

Patients who experience ≥1 inpatient AECOPD

Diagnostic Test: Frequent assessment of biomarker panel

Non-exacerbators

Patients without inpatient AECOPD

Diagnostic Test: Frequent assessment of biomarker panel

Interventions

Frequent assessment of biomarker panel DIAGNOSTIC_TEST

During the eight-week inpatient follow-up period there will be daily follow-up of respiratory symptoms, vitals and spirometry, and a thrice weekly collection of spontaneous sputum, nasal swabs and venous blood. These assessments will be repeated at acute worsening of respiratory symptoms at which a stool sample will also be collected.

Exacerbators; Non-exacerbators

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with a primary diagnosis of COPD admitted for inpatient pulmonary rehabilitation at Ciro (Horn, The Netherlands).

You may qualify if:

• ≥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 0.70.
• clinical indication for inpatient pulmonary rehabilitation in Ciro
• provided written informed consent

You may not qualify if:

• 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

Sponsors & Collaborators

• Center of Expertise for Chronic Organ Failure: lead
• AstraZeneca: collaborator

Study Sites (1)

Ciro

Horn, Limburg, 6085 NM, Netherlands

RECRUITING

Related Publications (18)

• GOLD. Global strategy for the prevention, diagnosis and management of chronic obstructive pulmonary disease - 2022 report.

  BACKGROUND

• Dransfield MT, Kunisaki KM, Strand MJ, Anzueto A, Bhatt SP, Bowler RP, Criner GJ, Curtis JL, Hanania NA, Nath H, Putcha N, Roark SE, Wan ES, Washko GR, Wells JM, Wendt CH, Make BJ; COPDGene Investigators. Acute Exacerbations and Lung Function Loss in Smokers with and without Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017 Feb 1;195(3):324-330. doi: 10.1164/rccm.201605-1014OC.

  PMID: 27556408 BACKGROUND

• Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1418-22. doi: 10.1164/ajrccm.157.5.9709032.

  PMID: 9603117 BACKGROUND

• European Lung White Book: European Respiratory Society; 2003.

  BACKGROUND

• CBS Doodsoorzakenstatistiek [Available from: www.cbs.nl.

  BACKGROUND

• Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007 Sep 1;370(9589):786-96. doi: 10.1016/S0140-6736(07)61382-8.

  PMID: 17765528 BACKGROUND

• Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood Eosinophils and Exacerbations in Chronic Obstructive Pulmonary Disease. The Copenhagen General Population Study. Am J Respir Crit Care Med. 2016 May 1;193(9):965-74. doi: 10.1164/rccm.201509-1869OC.

  PMID: 26641631 BACKGROUND

• MacNee W, Donaldson K. Exacerbations of COPD: environmental mechanisms. Chest. 2000 May;117(5 Suppl 2):390S-7S. doi: 10.1378/chest.117.5_suppl_2.390s.

  PMID: 10843983 BACKGROUND

• Viniol C, Vogelmeier CF. Exacerbations of COPD. Eur Respir Rev. 2018 Mar 14;27(147):170103. doi: 10.1183/16000617.0103-2017. Print 2018 Mar 31.

  PMID: 29540496 BACKGROUND

• Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010 Sep 16;363(12):1128-38. doi: 10.1056/NEJMoa0909883.

  PMID: 20843247 BACKGROUND

• Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick M, Haldar K, Kebadze T, Duvoix A, Lindblad K, Patel H, Rugman P, Dodson P, Jenkins M, Saunders M, Newbold P, Green RH, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011 Sep 15;184(6):662-71. doi: 10.1164/rccm.201104-0597OC.

  PMID: 21680942 BACKGROUND

• Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, Fabbri LM, Johnston SL. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006 May 15;173(10):1114-21. doi: 10.1164/rccm.200506-859OC. Epub 2006 Feb 16.

  PMID: 16484677 BACKGROUND

• Wilkinson TMA, Aris E, Bourne S, Clarke SC, Peeters M, Pascal TG, Schoonbroodt S, Tuck AC, Kim V, Ostridge K, Staples KJ, Williams N, Williams A, Wootton S, Devaster JM; AERIS Study Group. A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD. Thorax. 2017 Oct;72(10):919-927. doi: 10.1136/thoraxjnl-2016-209023. Epub 2017 Apr 21.

  PMID: 28432209 BACKGROUND

• Dima E, Kyriakoudi A, Kaponi M, Vasileiadis I, Stamou P, Koutsoukou A, Koulouris NG, Rovina N. The lung microbiome dynamics between stability and exacerbation in chronic obstructive pulmonary disease (COPD): Current perspectives. Respir Med. 2019 Oct;157:1-6. doi: 10.1016/j.rmed.2019.08.012. Epub 2019 Aug 21.

  PMID: 31450162 BACKGROUND

• Bouquet J, Tabor DE, Silver JS, Nair V, Tovchigrechko A, Griffin MP, Esser MT, Sellman BR, Jin H. Microbial burden and viral exacerbations in a longitudinal multicenter COPD cohort. Respir Res. 2020 Mar 30;21(1):77. doi: 10.1186/s12931-020-01340-0.

  PMID: 32228581 BACKGROUND

• Braeken DCW, Spruit MA, Houben-Wilke S, Smid DE, Rohde GGU, Wouters EFM, Franssen FME. Impact of exacerbations on adherence and outcomes of pulmonary rehabilitation in patients with COPD. Respirology. 2017 Jul;22(5):942-949. doi: 10.1111/resp.12987. Epub 2017 Jan 31.

  PMID: 28139873 BACKGROUND

• World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4. doi: 10.1001/jama.2013.281053. No abstract available.

  PMID: 24141714 BACKGROUND

• Waeijen-Smit K, DiGiandomenico A, Bonnell J, Ostridge K, Gehrmann U, Sellman BR, Kenny T, van Kuijk S, Peerlings D, Spruit MA, Simons SO, Houben-Wilke S, Franssen FME. Early diagnostic BioMARKers in exacerbations of chronic obstructive pulmonary disease: protocol of the exploratory, prospective, longitudinal, single-centre, observational MARKED study. BMJ Open. 2023 Mar 3;13(3):e068787. doi: 10.1136/bmjopen-2022-068787.

  PMID: 36868599 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Biosamples of spontaneous sputum, the nasopharynx, venous blood and stool will be frequently collected.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Frits ME Franssen, Prof. Dr.

  Center of Expertise for Chronic Organ Failure

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kiki Waeijen-Smit, MSc

CONTACT

+31475587601; kikismit@ciro-horn.nl

Frits ME Franssen, Prof. Dr.

CONTACT

+31475587602; fritsfranssen@ciro-horn.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 8, 2022
• First Posted: April 7, 2022
• Study Start: July 25, 2022
• Primary Completion: January 1, 2025
• Study Completion: December 1, 2025
• Last Updated: September 6, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)