A 64-week treatment, multi-center, randomized, double-blind, parallel-group, active controlled study to evaluate the effect of QVA149 (110/50 *g o.d.) vs NVA237 (50 *g o.d.) and open-label tiotropium (18 *g o.d.) on COPD exacerbations in patients with severe to very severe chronic obstructive pulmonary disease (COPD) (CQVA149A2304)

In patients with COPD, exacerbations of their condition are a common cause of
ill health, hospitalization and deaths. Frequent COPD exacerbations are
associated with impairment in quality of life and increased rate of decline in
lung function. Treatment of COPD exacerbation accounts for a great burden on
the health care system. Therefore effective management of COPD includes both
prevention and treatment of COPD exacerbation. Current data indicates that
long-acting beta agonists (LABAs) combined with corticosteroids or long-acting
muscarinic antagonists (LAMAs, e.g. Spiriva®) reduces the rate of COPD
exacerbations. Both LABAs and LAMAs as monotherapy are effective in providing
long-term bronchodilation in terms of improvement in FEV1 but the possible
beneficial effects of LABAs and LAMAs as fixed-dose combination on COPD
exacerbations has to be demonstrated.
QVA149 is a fixed dose combination of a LABA (indacaterol - QAB149) and a LAMA
(glycopyrronium bromide - NVA237). The selection of QVA149 dose in this study
(110/50 *g once daily) was based on data from the QAB149 and NVA237 monotherapy
programmes. Those programmes identified 150 *g once daily for QAB149, and 50 *g
once daily for NVA237. However, in formulating the QVA149 combination product,
an increase in fine particle (respirable) fraction was observed for the QAB149
component (compared with the monotherapy). As a consequence, to ensure that the
fine particle dose of QAB149 delivered to the lung from the combination matches
that delivered from the monotherapy, the dose for the QAB149 component of
QVA149 has been reduced to 110 *g.
The purpose of this study is to provide data to support regulatory approval
that QVA149 is superior to NVA237 in significantly reducing COPD exacerbations.
Data obtained from this study is intended to be used to support the
registration of QVA149 worldwide.

Primary objective: To demonstrate that QVA149 (110/50 *g o.d.) is superior to
NVA237 (50 *g o.d.) with regard to the rate of moderate to severe COPD
exacerbations during 64 weeks of treatment
Secondary objectives: To demonstrate that QVA149 (110/50 *g o.d.) is superior
to open-label tiotropium (18 *g o.d.) with regard to the rate of moderate to
severe COPD exacerbations during 64 weeks of treatment. To demonstrate that
QVA149 (110/50 *g o.d.) is superior to NVA237 (50 *g o.d.) with regard to the
time to first moderate to severe COPD exacerbation during 64 weeks of
treatment. To demonstrate that QVA149 (110/50 *g o.d.) is superior to
open-label tiotropium (18 *g o.d.) with regard to the time to first moderate to
severe COPD exacerbation during 64 weeks of treatment.

Randomized double blind placebo controlled parallel group phase III study.
Duble blind comparison QVA149-NVA237. Unblinded comparison with tiotropium.
Pre-screening, s.n. adjustment current COPD medication, followed by 2nd
screening and 2 week run-in period. Thereafter randomisation (1:1:1) to
treatment of 64-78 weeks with:
1. QVA149 110/50 mcg o.d.
2. NVA237 50 mcg o.d.
3. tiotropium 18 mcg o.d.
via dry powder inhaler.
Salbutamol rescue medication.
Total study duration approx. 15-18 months.
Approx. 2200 patients.

Treatment with QVA149, NVA237 or tiotropium.

Risk: Adverse effects of study medication. Changes in current COPD medication.
Belasting: 16-18 visits in 15-18 months.
Daily electronic diary (signs, symptoms, rescue medication). Vital signs 7-8x,
physical exam 5-6x, blood tests (safety) 5-6x (ca. 10 ml blood/visit, total
amount 50-60 ml), pregnancy test 3-4x, 1x pulmonary function test with
reversibility, 7-8x 4 pulmonary function tests in 2 hours, 5-6x EKG, 5-6x COPD
questionnaire.