Eosinopenia in Severe COPD Exacerbation

Chronic Obstructive Pulmonary Disease Clinical Trial

— A-TREC  

Official title:

Associates of, and Time to Recovery From, Eosinopenia in Severe COPD Exacerbation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06188065
• Other study ID #: SCI65
• Status: Recruiting
• Start date: January 22, 2024
• Est. completion date: July 2026

Study information

• Verified date: January 2024
• Source: Northumbria Healthcare NHS Foundation Trust
• Contact: Stephen Bourke, MBChB, PhD
• Phone: 0191 293 4351
• Email: stephen.bourke[@]nhct.nhs.uk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goals of this observational study are to identify factors independently associated with admission eosinopenia in patients with a severe exacerbation of chronic obstructive pulmonary disease (COPD) and to determine when blood eosinophil count (BEC) will recover to baseline stable state in patients who are admitted to hospital with a severe exacerbation of COPD and associated eosinopenia.

The main aims of the study are to:

1. Identify demographic, physiological and clinical factors independently associated with admission eosinopenia in patients with a severe exacerbation of COPD

2. Assess the time to recovery from eosinopenia to stable BEC following a severe exacerbation of COPD

Description:

Blood eosinophils are a type of white blood cell that play a role in the immune system including fighting infection. They have numerous roles but are primarily involved in inflammation. They are recruited from the blood into sites of inflammation.

The blood eosinophil count (BEC) can be used as a biomarker to predict whether the addition of inhaled corticosteroid (ICS) to long-acting bronchodilators (LABD) will be beneficial in reducing future COPD exacerbations. This association is based on BEC being measured when patients are clinically stable. Patients with a higher BEC are more likely to gain these benefits where as conversely, patients with a lower BEC are less likely to benefit and the risk of side effects such as pneumonia will likely outweigh any potential benefit. Current national and international COPD guidelines suggest the use of BEC as a biomarker to help inform the decision of whether to commence or withdraw ICS, but do not specify measuring BEC at a time of clinical stability.

Decisions regarding changes to management are often made in the acute setting. Eosinophils transiently drop to very low levels in half of patients who are admitted to hospital with exacerbations of COPD. Measuring BEC during an acute illness risks incorrectly identifying all patients who may benefit from the introduction of an ICS. In the current BEC COPD study, reliance on admission and discharge BEC inappropriately denied ICS to 47% and 33% of patients respectively compared to a confirmed stable-state measure.

There are co-primary aims for this study. Firstly, the investigators wish to determine when BEC will recover to stable state following a hospital admission for exacerbation of COPD. Determining this will inform healthcare professionals of the optimum time to measure BEC for use as a biomarker when making decisions related to management escalation. Based on the results of BEC COPD, it is likely that an increased number of patients will be identified as being above the BEC threshold and therefore likely to benefit from ICS when time is allowed for BEC to recover to stable state. Appropriate introduction of ICS in this patient group will reduce exacerbation and hospital re-admission rates and thus may reduce overall mortality within this high-risk group. This should reduce the burden of COPD on patient's health, quality of life and the NHS.

Eosinopenia during severe exacerbation of COPD is associated with increased in-hospital and one year mortality. Treatment with oral corticosteroids does not fully explain the mechanism behind the development of eosinopenia, with the phenomenon being less common on discharge compared to admission despite inpatient oral corticosteroid treatment. The investigators other co-primary aim is to identify demographic, physiological and clinical factors independently associated with admission eosinopenia in patients with a severe exacerbation of COPD, providing useful mechanistic information regarding the relationship between BEC and short-term mortality.

The hypothesis for this study is that 90% of participants who are admitted to hospital with a severe exacerbation of COPD and eosinopenia will have recovery of their BEC to baseline stable state within 4 weeks. The investigators also hypothesize that there are demographic, physiological and clinical factors independently associated with admission eosinopenia other than prior systemic corticosteroid use.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: July 2026
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years and older

Eligibility

Inclusion Criteria:

• Admitted to hospital with primary clinical diagnosis of exacerbation of COPD*

• Smoking history of at least 10 pack years

• Airflow obstruction: FEV1/FVC ratio < 0.7 confirmed on historic or inpatient spirometry

• Capacity to give informed consent to participate

Exclusion Criteria:

• Parasitic infection, systemic fungal infection (excluding infection limited to nails or skin), eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome or other conditions associated with a high eosinophil count#

• Active malignancy

• Maintenance oral prednisolone or other systemic steroids, anti-interleukin 5 therapy or other medication known to influence eosinophils

• Patients with poor venous access

• Investigator confirmed history of asthma

• Non-COPD related health problems which in the view of the primary investigator may compromise the conduct and completion of the study

ADDITIONAL CRITERIA FOR THE TIME TO RECOVERY FROM EOSINOPENIA ANALYSIS ONLY

Inclusion criteria:

• Eosinopenia on admission

• Uneventful recovery*

• Eosinopenia on admission who do not receive a further course of systemic corticosteroids or require emergency hospital admission for an acute illness in the six weeks following admission to hospital with a severe exacerbation of COPD.

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Diagnostic Test:
• Blood eosinophil count
To determine the time it takes for blood eosinophil count to recover to baseline stable state following severe exacerbation of COPD associated with admission eosinopenia and to explore independent factors associated with admission eosinopenia.

Locations

Country	Name	City	State
United Kingdom	Northumbria Healthcare NHS Foundation Trust	North Shields

Sponsors (4)

Lead Sponsor	Collaborator
Northumbria Healthcare NHS Foundation Trust	Chiesi UK, GlaxoSmithKline, Newcastle University

Country where clinical trial is conducted

United Kingdom, 

References & Publications (9)

Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, Fageras M. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. 2018 Feb;6(2):117-126. doi: 10.1016/S2213-2600(18)30006-7. Epub 2018 Jan 10. — View Citation

Echevarria C, Steer J, Prasad A, Quint JK, Bourke SC. Admission blood eosinophil count, inpatient death and death at 1 year in exacerbating patients with COPD. Thorax. 2023 Nov;78(11):1090-1096. doi: 10.1136/thorax-2022-219463. Epub 2023 Jul 24. — View Citation

Global Strategy for Prevention, Diagnosis and Management of COPD: 2023 Report. Global Initiative for Chronic Obstructive Lung Disease, 2023.

Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, Dransfield MT, Halpin DMG, Han MK, Jones CE, Kilbride S, Lange P, Lomas DA, Martinez FJ, Singh D, Tabberer M, Wise RA, Pascoe SJ; IMPACT Investigators. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. N Engl J Med. 2018 May 3;378(18):1671-1680. doi: 10.1056/NEJMoa1713901. Epub 2018 Apr 18. — View Citation

Lipson DA, Crim C, Criner GJ, Day NC, Dransfield MT, Halpin DMG, Han MK, Jones CE, Kilbride S, Lange P, Lomas DA, Lettis S, Manchester P, Martin N, Midwinter D, Morris A, Pascoe SJ, Singh D, Wise RA, Martinez FJ. Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2020 Jun 15;201(12):1508-1516. doi: 10.1164/rccm.201911-2207OC. — View Citation

Prasad A, Echevarria C, Steer J, Bourke S C. Blood eosinophil counts during severe exacerbations do not reflect stable state inflammatory phenotype in COPD. European Respiratory Journal 2022 60: 1870.

Singh D, Agusti A, Martinez FJ, Papi A, Pavord ID, Wedzicha JA, Vogelmeier CF, Halpin DMG. Blood Eosinophils and Chronic Obstructive Pulmonary Disease: A Global Initiative for Chronic Obstructive Lung Disease Science Committee 2022 Review. Am J Respir Crit Care Med. 2022 Jul 1;206(1):17-24. doi: 10.1164/rccm.202201-0209PP. No abstract available. — View Citation

Steer J, Gibson J, Bourke SC. The DECAF Score: predicting hospital mortality in exacerbations of chronic obstructive pulmonary disease. Thorax. 2012 Nov;67(11):970-6. doi: 10.1136/thoraxjnl-2012-202103. Epub 2012 Aug 15. — View Citation

Suissa S, Ernst P. Precision Medicine Urgency: The Case of Inhaled Corticosteroids in COPD. Chest. 2017 Aug;152(2):227-231. doi: 10.1016/j.chest.2017.05.020. No abstract available. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Indices independently associated with eosinopenia on admission in patients with a severe exacerbation of COPD.	Candidate indices will be identified by both univariate analysis (inclusion of indices related to eosinopenia at the 0.1 threshold) and domain knowledge (inclusion of indices thought likely to be related to eosinopenia even if no association on univariate analysis). Summary indices will also be created to reduce the number of variables (e.g. evidence of bacterial infection will include positive blood culture, sputum culture or antigens). Once candidate indices have been identifed, collinearity will be addressed and then independent associates of eosinopenia will be identified by logistic regression using backwards stepwise elimination.	On admission date
Primary	The time taken for BEC to recover to stable state following a severe exacerbation of COPD.		1, 2, 3, 4 and 6 weeks from admission date
Secondary	Level of agreement between the index admission eosinophil phenotype and prior admissions for exacerbations of COPD since May 2019.		On admission date
Secondary	Change from baseline cytokine levels at day 28m stratified by intercurrent exacerbation or other acute illness status, including sub-group analysis (eosinopenic cohort vs non-eosinopenic cohort)		On admission date and 4 weeks from admission date
Secondary	The proportion of patients whose BEC reaches 100 cell/uL or higher at each visit.		1, 2, 3, 4 and 6 weeks from admission date
Secondary	The time taken to reach peak BEC after a severe exacerbation of COPD.		1, 2, 3, 4 and 6 weeks from admission date
Secondary	Exploratory analysis looking for patient and treatment associations with rate of recovery of BEC.	Patient and treatment variables associated with rate of recovery of BEC will be identified using univariate analysis.	1, 2, 3, 4 and 6 weeks from admission date
Secondary	Comparison of the rate of recovery of BEC in patients who had further exacerbations of COPD within the study period and patients who have not had further exacerbations.		1, 2, 3, 4 and 6 weeks from admission date