A Phase IIa Randomized, Placebo-Controlled, Double-Blind (Sponsor Open) Study to Investigate the Clinical Efficacy, Safety, and Tolerability of Nemiralisib (GSK2269557) in Symptomatic COPD Participants with a History of Exacerbations (205739)

The morbidity and mortality of COPD are continuing to increase and worldwide,
by the year 2020, COPD is expected to be the third leading cause of death and
fifth leading cause of disability.
Despite several available therapies that have been shown to reduce COPD
exacerbations and respiratory symptoms, many COPD patients continue to
experience a high burden of respiratory symptoms and COPD exacerbations.
Additionally, there is growing recognition that a high percentage of COPD
patients with mild airflow limitation as well as smokers with preserved lung
function suffer from a high burden of symptoms and COPD exacerbations.
Therapies that effectively further reduce COPD exacerbations and improve
respiratory symptoms could have a substantial impact on healthcare utilization
and most importantly result in an improvement in COPD patients* quality of life.
Phosphoinositide 3-Kinase Delta (PI3Kd) is thought to play a role in a number
of epithelial responses relevant for the development of COPD. Therefore a PI3Kd
inhibitor may be able to suppress a number of these processes. A greater
proportion of macrophages appear to be alternatively activated in COPD and
their ability to phagocytose infective pathogens is reduced as a result of this
alternative activation. PI3Kd is one of the mediators involved in determining
this alternative phenotype in macrophages and therefore it is proposed that
inhibition of PI3Kd might rebalance macrophage activation towards a classic
phagocytic phenotype facilitating clearance of bacteria, a major cause of
exacerbation in COPD. The neutrophil and T cell are the two major inflammatory
cell types involved in the pathogenesis of COPD and both are targeted by PI3Kd
inhibitors.
Nemiralisib is a potent and highly selective inhaled PI3Kd inhibitor being
developed as an anti-inflammatory for the treatment of inflammatory airways
diseases. Nemiralisib will be administered via the ELLIPTA inhaler.
This placebo controlled study is designed to evaluate the clinical efficacy,
safety, and tolerability of a single 500 mcg inhaled daily dose of nemiralisib
for a period of 12 months. Nemiralisib will be added to the prescribed inhaled
maintenance COPD therapy. Participants will be selected for the study on the
basis that they are at an increased risk of exacerbation, having experienced *2
moderate or *1 severe COPD exacerbation(s) in the preceding 12 months despite
the available maintenance therapy and are symptomatic and with COPD Assessment
Test (CAT*10) at screening.

Primary:
To evaluate the clinical efficacy of nemiralisib compared with placebo to
reduce the annual rate of moderate and severe exacerbations in participants
with COPD.
Secondary:
Further efficacy parameters pertaining to exacerbations and aligned with the
primary objective. Symptoms and health related quality of life. Lung function.
Usage of rescue medication. Pharmacokinetics. Safety and tolerability.

Phase IIa, multicenter, randomized, double-blind (sponsor open),
placebo-controlled, parallel-group study.
Study medication (nemiralisib or placebo) on top of standard of care for COPD
exacerbation. Randomization to 2 treatment groups: nemiralisib (500 mcg QD) and
placebo (1:1).
Screening period (2 weeks), treatment period (12 months), follow-up period (up
to 2 weeks).
Approx. 400 subjects.

Treatment with nemiralisib or placebo.

Risk: Adverse events of nemiralisib.
Burden:
9-10 visits in 56 weeks.
Physical examination: 2 times.
Blood draws: 9 times (130 ml blood in total).
Pregnancy test: 9 times.
Pulmonary function tests with reversibility: 6 times.
ECG: 6 times.
Chest X-ray/CT-scan: once (if not performed in the past 3 months).
Entire study period: Electronic diary.
Questionnaires: COPD symptoms and exacerbations, work productivity.
Optional: genetics blood sample (6 ml), PK sampling over 1-6 hrs (twice) 3
blood draws (12 ml in total).