A study to compare the efficacy and safety of once daily QVA149 vs. the once daily concurrent administration of QAB149 plus NVA237 in patients with moderate to severe chronic obstructive pulmonary disease (CQVA149A2326)

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 µg once daily) was based on data from the QAB149 and NVA237 monotherapy
programmes. Those programmes identified 150 µg once daily for QAB149, and 50 µg
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 µg.
The current phase III study is part of the COPD development programme. In this
study the effects of QVA149 are being compared with those of the individual
components. This non-inferiority study is mandatory for the registration
dossier of a combination product. It is expected that the combination product
QVA149 will provide more convenience to the patient and will (tus) enhance
compliance, and that the efficicay will be similar to that of a combination of
both individual products.

Primary objective: To evaluate the non-inferiority of QVA149 110/50 µg qd as
compared to concurrent
administration of QAB149 150 µg qd plus NVA237 50 µg qd in terms of its effect
on trough FEV1 (mean of 23 h 15 min and 23 h 45 min post-dose) following 28
days of blinded treatment in patients with moderate to severe chronic
obstructive pulmonary disease.
Secondary objectives: FEV1, rescue medication, COPD symptoms, safety and
tolerability.

Randomized double blind, parallel group phase III study. Screening, s.n.
adjustment current COPD medication, followed by 2 week run-in period
(indacaterol 150 mcg en NVA237 50 mcg dd). Thereafter randomisation (1:1) to
treatment of 4 weeks with:
• QVA149 110/50 mcg o.d.
• Indacaterol 150 mcg o.d. and NVA237 50 mcg o.d.
via dry powder inhaler.
Salbutamol rescue medication.
Total study duration approx. 6-7 weeks.
Approx. 184 patients.

Treatment with QVA149 or indacaterol plus NVA237.

Risk: Adverse effects of study medication. Changes in current COPD medication.
Belasting: 6 visits and 3 phone calls in 6-7 weeks.
Daily electronic diary (signs, symptoms, rescue medication). Physical exam 3x,
blood tests (safety) 3x (approx. 10 ml blood/visit, total amount 30 ml),
pregnancy test 3x, 1x pulmonary function test with reversibility, 2x 8
pulmonary function tests in 5 hours plus 2 tests next morning, 3x ECG.