Mepolizumab for COPD Hospital Eosinophilic Admissions Pragmatic Trial

Overview

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

Full Title of Study: “A Randomised Controlled Trial of Mepolizumab Initiated During Admission to Hospital for a Severe Exacerbation of Eosinophilic COPD”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: April 30, 2022

Detailed Description

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.

Interventions

  • Drug: Mepolizumab
    • Mepolizumab 100mg subcutaneous injection
  • Drug: Placebo
    • Saline solution for subcutaneous injection

Arms, Groups and Cohorts

  • Experimental: Mepolizumab
    • Mepolizumab
  • Placebo Comparator: Placebo
    • Saline solution

Clinical Trial Outcome Measures

Primary Measures

  • Time from randomisation to next hospital readmission or death (all cause)
    • Time Frame: 48 weeks
    • To evaluate the efficacy of mepolizumab initiated during hospitalisation on future hospital readmission or death (all cause) compared with placebo and standard medical therapy in severe exacerbations of eosinophilic COPD.

Secondary Measures

  • Time from randomisation to first hospital readmission or death due to a respiratory cause
    • Time Frame: 48 weeks
  • Total number of hospital readmissions all cause over 48 weeks
    • Time Frame: 48 weeks
    • (adjusted for time minimum 24 weeks of trial treatment)
  • Total number of moderate exacerbations over 48 weeks
    • Time Frame: 48 weeks
    • (adjusted for time minimum 24 weeks of trial treatment)
  • Time from randomisation to treatment failure
    • Time Frame: 48 weeks
    • (defined as readmission, need for further treatment or death)
  • Time from randomisation to death (all cause)
    • Time Frame: 48 weeks
  • Time from randomisation to death (respiratory cause)
    • Time Frame: 48 weeks
  • Time from randomisation to first hospital readmission (all cause)
    • Time Frame: 48 weeks
  • Time from randomisation to first hospital readmission (respiratory cause)
    • Time Frame: 48 weeks
  • Length of index hospital admission
    • Time Frame: 48 weeks
    • Time from admission to discharge of first hospital admission
  • Extended Medical Research Council dyspnoea score (eMRC)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
    • 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.
  • St George’s Respiratory Questionnaire (SGRQ)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
    • This 50-item questionnaire measures health status (quality of life) in patients with diseases of airway obstruction. Scores are broken down into ‘symptoms’ (normal participant range 9-15), ‘activity’ (normal participant range 7-12), ‘impacts’ (normal participant range 1-3), and a total score (normal participant range 5-7). Higher scores indicate poorer health status.
  • COPD Assessment Tool (CAT)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
    • The COPD Assessment Test (CAT) is a questionnaire for people with Chronic Obstructive Pulmonary Disease (COPD). It is designed to measure the impact of COPD on a person’s life, and how this changes over time. Scores range from 0-40, with higher scores indicating greater impact of COPD on a patient’s life.
  • Warwick-Edinburgh Mental wellbeing scale (WEMWBS)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
    • This scale measures mental wellbeing using a 14-item scale. The scoring range for each item is from 1 – 5 and the total score is from 14-70, with higher scores indicating better mental wellbeing.
  • London Chest Activities of Daily Living Questionnaire (LCADL)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
    • This 15-item questionnaire measures dyspnoea during routine daily activities in patients with COPD. It consists of four components: ‘Self-care’, ‘Domestic’, ‘Physical’ and ‘Leisure’. Patients score from 0: ‘I wouldn’t do anyway’, to 5: ‘Someone else does this for me (or helps)’, with higher scores representing maximal disability.
  • Post-bronchodilator lung function – Forced Expiratory Volume in 1 second (FEV1)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
  • Post-bronchodilator lung function – Forced Vital Capacity (FVC)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
  • Lung function – Oscillometry
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
  • Short physical performance battery (SPPB)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
    • This assessment measures lower extremity functioning in older individuals. Lower scores indicate greater impairment.
  • Physical activity using accelerometry
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
  • Handgrip Strength
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
  • Total Serum eosinophil count (inflammatory markers)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
  • Percentage sputum eosinophil count (inflammatory markers)
    • Time Frame: Weeks 0, 4, 8, 12, 24, 36, 48
  • Adverse Events (AEs)
    • Time Frame: 48 weeks
  • Serious Adverse Events (SAEs)
    • Time Frame: 48 weeks
  • Heart Rate (beats per minute)
    • Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48
  • Blood pressure (systolic/diastolic mmHg)
    • Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48
  • Temperature (degrees)
    • Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 40 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Leicester
  • Collaborator
    • Leicester Clinical Trials Unit
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Christopher Brightling, Study Chair, University of Leicester
    • Neil Greening, Principal Investigator, University of Leicester
  • Overall Contact(s)
    • Eleanor Taylor, 01162297247, mepo@leicester.ac.uk

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