Randomised, Double-Blind(Sponsor Open), Placebo-Controlled, Multicentre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets Administered Twice Daily Compared With Placebo for 24Weeks in Adult Participants With Chronic Obstructive Pulmonary Disease (COPD) (study 205724)

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.
There is much evidence that the CXCR2 chemokine receptor plays a pivotal role
in neutrophil activity in the lung. Danirixin has demonstrated potent
antagonism of CXCR2 activity both in vitro and in vivo in preclinical and
clinical studies. Its potency and duration of action supports its potential use
as an oral, anti-inflammatory agent in the treatment of COPD. In clinical
trials danirixin has been well-tolerated and most adverse events were mild to
moderate.
The primary aim of this study is to evaluate the clinical activity and safety
of 5 doses of danirixin compared with placebo in subjects with COPD.

Primary:
To characterize the dose response of danirixin compared with placebo on the
incidence and severity of respiratory symptoms in subjects with COPD and to
compare the safety of danirixin with placebo.
Secondary:
To assess the annual rate of moderate/severe COPD exacerbations, to further
characterize clinical activity, to characterize the pharmacokinetics of
danirixin.

Double-blind (Sponsor Open), placebo-controlled, parallel group study.
Baseline assessments collected over a 7 day period (i.e. EXACT/E-RS:COPD,
physical activity, and rescue medication use). Thereafter randomization
(1:1:1:1:1:1):
* one of five dose strengths of danirixin (5, 10, 25, 35, 50 mg bid) or
* placebo for 24 weeks.
Three interim analyses are planned for the study: PK after 10 participants in
each treatment group have completed Visit 3, futility analysis based on the
E-RS:COPD after 150 participants have completed 3 months of study treatment,
after 450 participants have completed 6 months of study treatment). The third
interim analysis will be used to support GSK decisions regarding the further
development of danirixin. The last interim analysis will include all clinical
activity assessments and safety assessments.
Estimation 600 subjects (700 to be screened).

Treatment with danirixin or placebo.

Risk: Adverse events of danirixin.
Burden:
11-12 visits in 32 weeks.
Physical examination: 5 times.
Blood draws: max. 11 times (175 ml blood in total).
Pregnancy test: 8 times.
Pulmonary function tests: 4 times.
ECG: 5 times.
Chest X-ray: once.
Entire study period: 1. Daily diary use of rescue medication, adverse events 2.
Daily symptoms questionnaire.
Questionnaires: health resource utilization, symptoms and quality of life.
Optional: genetics blood sample (6 ml), PK sampling over 12 hours 9 blood draws
(2 ml each).