A randomised, double-blind, placebo-controlled, parallel-group, multi-centre 24-week study to evaluate the efficacy and safety of mepolizumab adjunctive therapy in subjects with severe
eosinophilic asthma on markers of asthma control (study 200862, MUSCA)

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.
Mepolizumab is being developed for the treatment of a.o. severe astma.
The targeted population in this study will be severe refractory asthmatics with
evidence of eosinophilic airway inflammation as assessed by blood eosinophil
levels. This severe, refractory, eosinophilic asthma population, is the subset
of asthmatics most likely to benefit from treatment with mepolizumab.
There are currently no approved therapies for severe eosinophilic asthma and,
therefore, the comparator arm will be standard of care treatment. Standard of
care will consist of high dose ICS and another controller, e.g. LABA, with or
without maintenance oral corticosteroids (OCS).
The primary efficacy endpoint will be improvement in HR-QoL as measured by
SGRQ. Other assessments of asthma control will include lung function and the
asthma control questionnaire. The treatment duration will be 24 weeks. The
optimal duration for HR-QoL assessment is uncertain, but based on the responses
seen in two recently completed trials in the population of interest, the study
duration of 24 weeks will enable an adequate time to assess the impact of
mepolizumab on SGRQ and other study endpoints.

Primary: To evaluate the efficacy of mepolizumab 100 mg subcutaneous (SC) every
4 weeks versus placebo on health-related quality of life (HR-QoL) in adult and
adolescent subjects with severe eosinophilic asthma.
Secondary: To assess the effects of mepolizumab compared to placebo on lung
function, asthma control, tolerability and safety.

Randomised, double-blind, placebo-controlled, parallel-group phase III study.
Randomisation (1:1) to
* Mepolizumab 100 mg s.c. every 4 weeks
* Placebo every 4 weeks.
Continuation of standard treatment for astma.
Salbutamol rescue medication.
Screening 1-4 weeks. Treatment period 24 weeks. Follow-up period 4 weeks.
Dutch centres will not participate in substudies.
Approx. 544 patients.

Treatment with mepolizumab or placebo.

Risk: adverse events of study treatment.
Burden: 8 visits in approx. 6 months. Duration 1-3 h.
6 times 1 s.c. injection (1 ml)
Physical examination 2 times.
Blood draws 6 times (approx. 3-14 ml/occasion). At screening testing for op
hepatitis B-C.
Pregnancy test 8 times.
Pulmonary function test 7 times. At screening incl. reversibility.
ECG 3 times.
Peak expiratory flow daily (1-2 times).
7 times completion of questionnaires (1-5 per visit).
Assessment of (change in) performance 5 times, efficacy of study medication 3
times.
Paper and electronic diary. Asthmatic complaints, rescue medication, other
complaints and medication and level of exercise.
Optional pharmacogenetic testing (1x 6 ml blood)