Study 117113: Mepolizumab vs. Placebo as add-on treatment for frequently exacerbating COPD patients characterized by eosinophil level

While COPD is generally viewed as a disease driven by neutrophilic inflammation
up to 40% of COPD patients have an inflammatory pattern that includes elevated
sputum eosinophils. Recent studies identified that increased eosinophilic
airway inflammation occurs during COPD exacerbations and that peripheral
eosinophils levels were used successfully as a surrogate to predict response to
corticosteroid therapy.
Mepolizumab is a fully humanized IgG antibody (IgG1, kappa) which binds to and
inhibits the ability of IL-5 to bind to the IL-5 receptor. IL-5 receptors are
primarily expressed on eosinophils. IL-5, through binding to the IL-5 receptor
is a major regulator of eosinophils resulting in accumulation in tissues and
modulation of eosinophil behavior at every stage from maturation to survival.
Mepolizumab reduces eosinophils in the periphery and in tissues.
There is reason to believe that mepolizumab will reduce IL-5 and eosinophils in
a well-defined COPD population. The study target population consists of a
population who despite a history of use of optimal standard of care therapy
continue to be at risk for future exacerbation. Based on extrapolation of the
efficacy findings in severe asthma and the similarities between the severe
asthma and severe COPD patients in terms of eosinophils and IL-5 levels it is
hypothesized that the reduction of eosinophils with mepolizumab in COPD
patients would translate into a reduction of COPD exacerbations.

Primary: To evaluate the efficacy and safety of mepolizumab 100 mg and 300 mg
subcutaneous given every 4 weeks compared to placebo on the frequency of
moderate and severe exacerbations in COPD subjects at high risk of
exacerbations despite the use of optimized standard of care background therapy.
Secondary: Quality of life, health care utilization, and symptoms.

Randomised, double-blind, placebo-controlled, parallel-group phase III study.
Randomisation (1:1:1) to
* Mepolizumab 100 mg s.c. every 4 weeks
* Mepolizumab 300 mg s.c. every 4 weeks
* Placebo every 4 weeks.
Continuation of standard treatment for COPD.
Salbutamol rescue medication.
Treatment phase 52 weeks. Follow-up period 8 weeks.
Approx. 660 patients.
Independent data monitoring committee.

Treatment with mepolizumab or placebo.

Risk: adverse events of study treatment.
Burden: 16 visits in approx. 14 months. Duration 1-3 h.
13 times 3 s.c. injections (1 ml per injection)
Physical examination 6 times.
Blood draws 16 times (approx. 5-50 ml/occasion, approx. 280 ml in total). At
screening testing for op hepatitis B-C.
Pregnancy test 15 times.
Pulmonary function test 9 times. At screening incl. reversibility.
Chest X-ray once (if not performed in the past 3 months).
ECG 6 times.
Questionnaire COPD symptoms (CAT) 14 times.
Other questionnaires 3-5 times.
Paper and electronic diary. Hospital visits, adverse effects, use of medication
(paper) and symptoms, rescue medication and level of exercise (electronic).
Counseling for cessation of smoking, 2 times.
Optional pharmacogenetic testing (1x 6 ml blood)