Mepolizumab for COPD Hospital Eosinophilic Admissions Pragmatic Trial

University of Leicester238 enrolled

Overview

This is a single-centre, double-blinded, randomised, placebo controlled trial comparing mepolizumab 100mg versus placebo in patients with eosinophilic COPD, started following their index admission to hospital.

Patients admitted to hospital with an exacerbation of COPD are at high risk of readmission, of which a proportion are driven by eosinophilic inflammation. Whilst oral corticosteroids are beneficial in exacerbations, a considerable proportion of patients experience treatment failure, with 50% of patients readmitted within 3 months (www.RCPLondon.ac.uk). Therapy, such as mepolizumab, reduces eosinophil count and has been shown to reduce exacerbation frequency when given in the stable state in both eosinophilic asthma (Papi et al. 2018) and COPD (Yousef, in press). The investigators hypothesise that starting mepolizumab at the time of a hospitalisation for an exacerbation of COPD in patients with significant eosinophilia will result in a reduction in readmission to hospital in a high risk population. Therefore, 238 participants will be recruited over an 18-month period and will be randomised into a 48-week treatment period in which they will receive monthly subcutaneous injections of either 100 mg mepolizumab or placebo. Secondary outcomes will be measured at baseline (week 0), 4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks and 48 weeks.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

238

Conditions

COPD Eosinophilia

Interventions

MepolizumabDRUG

Mepolizumab 100mg subcutaneous injection

PlaceboDRUG

Saline solution for subcutaneous injection

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Symptoms typical of COPD when stable (baseline eMRC dyspnoea grade 2 or more). 2. A clinician defined exacerbation of COPD requiring admission to hospital. 3. Serum eosinophil count of ≥ 300 cells/μL either at time of admission or at any one time in the preceding 12 months. 4. Smoking pack years ≥10 years. 5. Age ≥ 40 years. 6. Established on inhaled corticosteroids (ICS) prior to this admission. 7. Willing and able to consent to participate in trial. 8. Able to understand written and spoken English. Exclusion Criteria: 1. COPD patients without eosinophilia (defined as persistently \< 300 cells/μL within the last 12 months). 2. Other conditions that may be the cause of eosinophilia (such as hypereosinophilic syndrome, eosinophilic granulomatosis, eosinophilic oesophagitis or parasitic infection). 3. Patients whose treatment is considered palliative (life expectancy \< 6 months). 4. Other respiratory conditions including active lung cancer, interstitial lung disease, primary pulmonary hypertension or any other conditions that in the view of the investigator will affect the trial. 5. Known history of anaphylaxis or hypersensitivity to mepolizumab or any of the excipients (sucrose, sodium phosphate dibasic heptahydrate, polysorbate 80). 6. Unstable or life-threatening cardiac disease including myocardial infarction or unstable angina in the last 6 months, unstable or life-threatening cardiac arrhythmia requiring intervention in the last 3 months and New York Heart Association (NYHA) Class IV heart failure. 7. Decompensated liver disease or cirrhosis. 8. Pregnant, breastfeeding, or lactating women. Women of child-bearing potential must agree to use appropriate methods of birth control and have a negative blood serum pregnancy test performed after randomisation but prior to first dosing with randomised treatment.\* 9. Participation in an interventional clinical trial within 3 months of visit 1 or receipt of any investigational medicinal product within 3 months or 5 half-lives. 10. Known blood born infection (e.g. HIV, hepatitis B or C). * Women of child bearing potential (WOCBP) - A woman is defined as being of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal, unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

Locations (1)

NIHR Biomedical Research Centre, Respiratory

Leicester, Leicestershire, United Kingdom

Outcomes

Primary Outcomes

Time From Randomisation to Next Hospital Readmission or Death (All Cause)

To evaluate the efficacy of mepolizumab initiated following hospitalisation on future hospital readmission or death (all cause) compared with placebo and standard medical therapy in severe exacerbations of eosinophilic COPD.

Time frame: Patients were followed up for up to 48 weeks (an absolute maximum of 49 weeks as the 48 week visit had a visit window of +- 1 week).

Secondary Outcomes

Total Number of Hospital Readmissions All Cause Over 48 Weeks

The number of hospital readmissions (all cause) in total during the 48 (truncated follow-up minimum 24) weeks corresponding to each participant were calculated. Where no hospital admission have occurred a value of zero was derived.

Time frame: 0-48 weeks

Total Number of Moderate Exacerbations Over 48 Weeks

The severity of a COPD exacerbation was deemed as "Moderate" if the participant required treatment with steroids or antibiotics and was not hospitalised . The number of moderate exacerbations each participant had over the course of 48 (truncated follow-up minimum 24) weeks were calculated.

Time frame: 48 weeks

Total Number of Severe Exacerbations Over 48 Weeks

The severity of a COPD exacerbation was deemed as "Severe" if the participant required hospitalisation. The number of severe exacerbations each participant had over the course of 48 (truncated follow-up minimum 24) weeks were calculated.

Time frame: 48 weeks

Total Number of Exacerbations Over 48 Weeks

The number of exacerbations each participant had over the course of 48 (truncated follow-up minimum 24) weeks were calculated.

Time frame: 48 weeks

Data from ClinicalTrials.gov

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Time From Randomisation to Next Hospital Readmission or Death Due to a Respiratory Cause

The time from randomisation to next hospital readmission or death (due to a respiratory cause) is defined as a time to event outcome measured in days. The date of randomisation as well as the date of readmission or death due to respiratory causes (whichever occurs first) were used to calculate time to event. For participants not experiencing an event the time was calculated from randomisation until last known follow-up assessment event-free.

Time frame: Patients were followed up for up to 48 weeks (an absolute maximum of 49 weeks as the 48 week visit had a visit window of +- 1 week).

Time From Randomisation to Treatment Failure

Treatment failure is defined as the composite of three endpoints: 1. treatment intensification with systemic corticosteroids and/or antibiotics for respiratory reasons; 2. step-up in hospital care for respiratory reasons including transfer to the intensive care unit or readmission; or 3. all-cause mortality)

Time frame: Patients were followed up for up to 48 weeks (an absolute maximum of 49 weeks as the 48 week visit had a visit window of +- 1 week).

Hospital Readmission (Respiratory Cause)

Hospital readmission (respiratory cause). Number of individuals that readmitted during follow up is reported. Hospital readmission due to respiratory cause was analysed as a time to event outcome.

Time frame: Patients were followed up for up to 48 weeks (48 week visit had a window of +/- 1 week).

Time From Randomisation to Next Hospital Readmission (All Cause)

The time from randomisation to next hospital readmission (all cause) is defined as a time to event outcome measured in days. The date of randomisation and the date of next hospital readmission following randomisation was used to calculate time to event. Where hospital readmission doesn't occur during follow-up, time was measured until the participant's last known follow-up assessment.

Time frame: Patients were followed up for up to 48 weeks (an absolute maximum of 49 weeks as the 48 week visit had a visit window of +/- 1 week).

Death (All Cause)

All cause death. Number of individuals that died during follow up is reported. Death was analysed as a time to event outcome.

Time frame: Patients were followed up for up to 48 weeks (48 week visit had a window of +/- 1 week).

Death (Respiratory Cause)

Respiratory cause death. Number of individuals that died during follow up is reported. Death due to respiratory cause was analysed as a time to event outcome.

Time frame: Patients were followed up for up to 48 weeks (48 week visit had a window of +/- 1 week).

Extended Medical Research Council Dyspnoea Score (eMRC)

This scale measures perceived respiratory disability. Participants rate their grades of breathlessness on a scale of 1 (least) to 5 (worst). The extension divides the grade 5 rating into 'a' (independent) and 'b' (dependent) to establish dependence on others for washing and dressing.