Drivers of Eosinophilic COPD Exacerbations

COPD Exacerbation Clinical Trial

— DICE  

Official title:

Drivers of Eosinophilic COPD Exacerbations

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04961060
• Other study ID #: NL75151.042.20
• Status: Recruiting
• Start date: July 2021
• Est. completion date: January 2025

Study information

• Verified date: July 2021
• Source: University Medical Center Groningen
• Contact: Lisa H van Smoorenburg, MSc.
• Phone: +3150 361 6102
• Email: l.h.van.smoorenburg[@]umcg.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Main objective: investigate gene expression differences in nasal epithelium and sputum between eosinophilic COPD exacerbations and other subtypes.

Description:

Main objective: investigate gene expression differences in nasal epithelium and sputum between eosinophilic COPD exacerbations and other subtypes to better understand why some patients are more at risk for eosinophilic COPD exacerbations. Secondary objectives: 1. Investigate differences in microbiome composition and immunophenotyping profiles in peripheral blood per subtype. 2. Assess for clinical differences between all COPD exacerbation subtypes. 3. Assess if and how baseline meta-transcriptomics either in nasal epithelium or sputum and blood immunophenotyping can be utilized to predict COPD exacerbation subtype. 4. Determine if the microbiome in sputum and nasal epithelial material are comparable. 5. Determine if different subtypes of COPD exacerbations respond differently to standard treatment with oral prednisolone (40 mg daily) with or without antibiotics. 6. To evaluate if metabolic responses during recovery are different in patients with increased systemic inflammation compared to patients without systemic inflammation at exacerbation

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: January 2025
• Est. primary completion date: September 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

1. COPD patient admitted to the hospital for an acute exacerbation of COPD

2. Physician diagnosed COPD according to the GOLD 2020 guidelines, including symptoms consistent with COPD, post-bronchodilator FEV1 < 80% predicted and FEV1/FVC < 70%.

3. Age > 40 years.

4. Smoker or ex-smoker, = 10 pack years of smoking.

Exclusion Criteria:

1. Current asthma, or prior physician diagnosis of asthma without a symptom- free interval of at least 10 years before the age of 40.

2. Chronic use of prednisolone.

3. Use of systemic corticosteroids =4 days prior to hospital admission.

4. Necessity (upon hospitalization) for non-invasive ventilation or ICU admission.

5. Pneumonia at presentation documented by chest roentgenography.

6. Any other clinically relevant lung disease deemed to interfere with the concept of the study design.

7. Allergy to systemic corticosteroids or to antibiotics.

8. Females of childbearing potential without an efficient contraception unless they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH >40 mIU/mL or the use

of one or more of the following acceptable methods of contraception:

1. Surgical sterilization (e.g. bilateral tubal ligation, hysterectomy).

2. Hormonal contraception (implantable, patch, oral, injectable).

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/suppository.

4. Continuous abstinence

9. Pregnancy or lactation.

10. Known immunodeficiency.

11. Life expectancy less than 60 days

Related Conditions & MeSH terms

• COPD Exacerbation
• Eosinophilia
• Pulmonary Disease, Chronic Obstructive

Locations

Country	Name	City	State
Netherlands	Univesity Medical Center Groningen	Groningen
Netherlands	University Maastricht	Maastricht	Limburg

Sponsors (3)

Lead Sponsor	Collaborator
University Medical Center Groningen	GlaxoSmithKline, Maastricht University

Country where clinical trial is conducted

Netherlands, 

References & Publications (19)

Aguirre-Gamboa R, Joosten I, Urbano PCM, van der Molen RG, van Rijssen E, van Cranenbroek B, Oosting M, Smeekens S, Jaeger M, Zorro M, Withoff S, van Herwaarden AE, Sweep FCGJ, Netea RT, Swertz MA, Franke L, Xavier RJ, Joosten LAB, Netea MG, Wijmenga C, Kumar V, Li Y, Koenen HJPM. Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits. Cell Rep. 2016 Nov 22;17(9):2474-2487. doi: 10.1016/j.celrep.2016.10.053. Epub 2016 Nov 3. — View Citation

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. — View Citation

Bi R, Liu P. Sample size calculation while controlling false discovery rate for differential expression analysis with RNA-sequencing experiments. BMC Bioinformatics. 2016 Mar 31;17:146. doi: 10.1186/s12859-016-0994-9. — View Citation

Boudewijn IM, Lan A, Faiz A, Cox CA, Brouwer S, Schokker S, Vroegop SJ, Nawijn MC, Woodruff PG, Christenson SA, Hagedoorn P, Frijlink HW, Choy DF, Brouwer U, Wisman M, Postma DS, Fingleton J, Beasley R, van den Berge M, Guryev V. Nasal gene expression changes with inhaled corticosteroid treatment in asthma. Allergy. 2020 Jan;75(1):191-194. doi: 10.1111/all.13952. Epub 2019 Jul 15. — View Citation

Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 2011 Sep 10;378(9795):1015-26. doi: 10.1016/S0140-6736(11)60988-4. Review. — View Citation

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Celli BR, Locantore N, Tal-Singer R, Riley J, Miller B, Vestbo J, Yates JC, Silverman EK, Owen CA, Divo M, Pinto-Plata V, Wouters EFM, Faner R, Agusti A; ECLIPSE Study Investigators. Emphysema and extrapulmonary tissue loss in COPD: a multi-organ loss of tissue phenotype. Eur Respir J. 2018 Feb 7;51(2). pii: 1702146. doi: 10.1183/13993003.02146-2017. Print 2018 Feb. — View Citation

Criner GJ, Celli BR, Brightling CE, Agusti A, Papi A, Singh D, Sin DD, Vogelmeier CF, Sciurba FC, Bafadhel M, Backer V, Kato M, Ramírez-Venegas A, Wei YF, Bjermer L, Shih VH, Jison M, O'Quinn S, Makulova N, Newbold P, Goldman M, Martin UJ; GALATHEA Study Investigators; TERRANOVA Study Investigators. Benralizumab for the Prevention of COPD Exacerbations. N Engl J Med. 2019 Sep 12;381(11):1023-1034. doi: 10.1056/NEJMoa1905248. Epub 2019 May 20. — View Citation

Ditz B, Christenson S, Rossen J, Brightling C, Kerstjens HAM, van den Berge M, Faiz A. Sputum microbiome profiling in COPD: beyond singular pathogen detection. Thorax. 2020 Apr;75(4):338-344. doi: 10.1136/thoraxjnl-2019-214168. Epub 2020 Jan 29. Review. — View Citation

Gao P, Gibson PG, Zhang J, He X, Hao Y, Li P, Liu H. The safety of sputum induction in adults with acute exacerbation of COPD. Clin Respir J. 2013 Jan;7(1):101-9. doi: 10.1111/j.1752-699X.2012.00291.x. Epub 2012 Apr 23. — View Citation

Imkamp K, Berg M, Vermeulen CJ, Heijink IH, Guryev V, Kerstjens HAM, Koppelman GH, van den Berge M, Faiz A. Nasal epithelium as a proxy for bronchial epithelium for smoking-induced gene expression and expression Quantitative Trait Loci. J Allergy Clin Immunol. 2018 Jul;142(1):314-317.e15. doi: 10.1016/j.jaci.2018.01.047. Epub 2018 Mar 6. — View Citation

Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009 Sep;34(3):648-54. doi: 10.1183/09031936.00102509. — View Citation

Liesker JJ, Bathoorn E, Postma DS, Vonk JM, Timens W, Kerstjens HA. Sputum inflammation predicts exacerbations after cessation of inhaled corticosteroids in COPD. Respir Med. 2011 Dec;105(12):1853-60. doi: 10.1016/j.rmed.2011.07.002. Epub 2011 Jul 29. — View Citation

Mayhew D, Devos N, Lambert C, Brown JR, Clarke SC, Kim VL, Magid-Slav M, Miller BE, Ostridge KK, Patel R, Sathe G, Simola DF, Staples KJ, Sung R, Tal-Singer R, Tuck AC, Van Horn S, Weynants V, Williams NP, Devaster JM, Wilkinson TMA; AERIS Study Group. Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations. Thorax. 2018 May;73(5):422-430. doi: 10.1136/thoraxjnl-2017-210408. Epub 2018 Jan 31. — View Citation

Narendra DK, Hanania NA. Targeting IL-5 in COPD. Int J Chron Obstruct Pulmon Dis. 2019 May 16;14:1045-1051. doi: 10.2147/COPD.S155306. eCollection 2019. Review. — View Citation

Pavord ID, Chanez P, Criner GJ, Kerstjens HAM, Korn S, Lugogo N, Martinot JB, Sagara H, Albers FC, Bradford ES, Harris SS, Mayer B, Rubin DB, Yancey SW, Sciurba FC. Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017 Oct 26;377(17):1613-1629. doi: 10.1056/NEJMoa1708208. Epub 2017 Sep 11. — View Citation

Travers J, Rothenberg ME. Eosinophils in mucosal immune responses. Mucosal Immunol. 2015 May;8(3):464-75. doi: 10.1038/mi.2015.2. Epub 2015 Mar 25. Review. — View Citation

Wang Z, Singh R, Miller BE, Tal-Singer R, Van Horn S, Tomsho L, Mackay A, Allinson JP, Webb AJ, Brookes AJ, George LM, Barker B, Kolsum U, Donnelly LE, Belchamber K, Barnes PJ, Singh D, Brightling CE, Donaldson GC, Wedzicha JA, Brown JR; COPDMAP. Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study. Thorax. 2018 Apr;73(4):331-338. doi: 10.1136/thoraxjnl-2017-210741. Epub 2017 Dec 21. — View Citation

Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010 Nov;238(1):247-62. doi: 10.1111/j.1600-065X.2010.00951.x. Review. Erratum in: Immunol Rev. 2011 Mar;240(1):317. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in gene expression profiles in sputum by RNA sequencing	Change in gene expression profiles in sputum between the four groups using RNA sequencing. The differences between the expression levels of transcripts (counts) will be analyzed.	At admission and after 6-8 weeks after discharge.
Primary	Change in gene expression profiles in nasal epithelium by using RNA sequencing	Change in gene expression profilesin nasal epithelium between the four groups using RNA sequencing. The differences between the expression levels of transcripts (counts) will be analyzed.	At admission and after 6-8 weeks after discharge.
Secondary	Microbiome composition in sputum by using RNA sequencing.	Differences in microbiome composition in sputum between the four groups by using RNA sequencing.	At admission, at day 5 of admission and 6-8 weeks after discharge.
Secondary	Phenotype blood cell population by flow cytometry.	Differences in blood cell population between the four groups as measured by flow cytometry.	At admission, at day 5 of admission and 6-8 weeks after discharge.
Secondary	Phenotypic analysis of the T cell compartment by staining of whole blood or isolated peripheral blood mononuclear cells using antibodies	Differences in the T cell compartment between the four groups by staining of whole blood or isolated peripheral blood mononuclear cells using antibodies.	At admission, at day 5 of admission and 6-8 weeks after discharge.
Secondary	Comparison of microbiome composition in sputum and nasal epithelial material by RNA sequencing.	Measure microbiome composition in sputum and nasal epithelium by RNA sequencing. Compare them by the bacterial taxa which are significantly different between groups	At admission and 6-8 weeks after discharge.
Secondary	Clinical differences between groups by the COPD Assessment Test (CAT).	Differences in number of participants per group with a high impact of COPD related symptoms as assessed by the CAT.	Every day of hospital admission.
Secondary	Clinical differences between groups by peak flow measurements.	Differences in number of participants per group with a low peak expiratory flow rate as measured by a handheld peak flow meter.	Every day of hospital admission.