A 26-week treatment, randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety and tolerability of NVA237 in patients with chronic obstructive pulmonary disease (CNVA237A2304)

NVA237 is a synthetic quaternary ammonium compound that acts as a competitive
antagonist at muscarinic acetylcholine receptors and is being developed as a
once-daily inhalation treatment to be delivered by the Novartis Single Dose Dry
Powder Inhaler (SDDPI) for patients with COPD. Inhaled anticholinergic drugs
such as ipratrompium bromide (Atrovent®) and Tiotropium bromide (Spiriva®) have
been approved in the US and European Union for the treatment of COPD.
This study is designed to provide pivotal confirmation of efficacy and long
term safety data for the 50µg o.d. dose of NVA237 in patients with moderate to
severe chronic obstructive pulmonary disease (GOLD Guidelines, 2008). Data
obtained from this study is intended to be used to support the registration of
NVA237 worldwide, including the US and the EU.

Primary objectives
To confirm that NVA237 50µg o.d. (delivered via a SDDPI) vs. placebo
significantly increases trough FEV1 (defined as mean evaluation at 23 h 15 min
and 23 h 45 min post dose) following 12 weeks of treatment in patients with
moderate to severe COPD (GOLD Guidelines 2008)
Secondary objectives
Key
• To evaluate the effect of NVA237 (50µg o.d.) vs. placebo on breathlessness
measured using the Transition Dyspnea Index (TDI) after 26 weeks treatment.
• To evaluate the effect of NVA237 (50µg o.d.) vs. placebo on the health status
by measuring the total score of the St George*s Respiratory Questionnaire
(SGRQ) after 26 weeks treatment.
Important secondary objectives/variables
To evaluate the effect of NVA237 (50µg o.d.) vs. placebo on time to
first COPD exacerbation during 26 weeks treatment.
To evaluate the effect of NVA237 (50µg o.d.) vs. placebo on daily
rescue medication use (number of puffs) over 26 weeks.
Additional Secondary Comparisons
To evaluate the effect of NVA237 (50µg o.d.) on lung function (FEV1,
FVC) at all timepoints (including FEV1AUC5min-12h and FEV1AUC5min-24h in a
subset of 250 patients; approximately 167 NVA237: 83 placebo), as compared with
placebo, with respect to the early response, approximate peak response and
trough response.
• To assess the potential effect of NVA237 (50µg o.d.) on cardiovascular safety
using 24 hour Holter monitoring data in a subset of 80 patients.
• To assess safety and tolerability of NVA237 (50µg o.d.) with regard to vital
signs, ECGs, laboratory evaluations and adverse events over 26 weeks.
• To evaluate the effect of NVA237 (50µg o.d.) vs. placebo on rate of COPD
exacerbations during the 26 week randomized treatment period.
• To evaluate the effect of NVA237 (50µg o.d.) vs. placebo on other COPD
symptoms collected via patient diary over the 26 week randomized treatment
period.

The study is a 26 week randomized multi-center, double-blind,
placebo-controlled parallel group design. All study treatments are given in
addition to permitted COPD background therapy as outlined in Section 6.5.7.
At an initial pre-screening visit (Visit 1) informed consent will be obtained,
current COPD medications reviewed and if necessary arrangements made to adjust
prohibited COPD therapy to allowable COPD therapy. At Visit 2 (up to 7 days
after initial visit) screening assessments will be performed including
spirometry and reversibility testing. Between Visit 2 and Visit 3 there is a 14
day run-in period used to assess eligibility of patients for the study and to
collect baseline patient diary data. At Visit 3 patients meeting the
inclusion/exclusion criteria will be randomized to receive double-blind NVA237
50µg o.d. or placebo in a ratio of 2:1, for a 26 week treatment period.
After patients receive their first dose on day 1 (Visit 3) they will remain at
the study site to complete spirometric and safety assessments for up to 4 hours
(up to 12 hours for a subset of patients included in the 24 h serial spirometry
group). Patients will return to the center the following day for spirometric
assessments.
Patients will be required to attend the study center for 10 more visits (total
13). After 12 weeks (assessment of the primary efficacy variable, trough FEV1)
and 26 weeks there are visits on consecutive days to ensure *trough* spirometry
data are accurately collected.
12 hour serial spirometry will be conducted in the clinic, in a subset of
patients (approximately 250 randomized patients) at designated centers, at day
1 (Visit 3). The same subset of patients will perform 24 hour serial spirometry
at week 12 (Visit 8) and at week 26 (Visit 12). All patients will perform
spirometry up to 4 hours post dose at day 1 (Visit 3), week 12 (Visit 8) and
week 26 (Visit 12).
SGRQ and BDI/TDI will be assessed in all patients at day 1 (Visit 3), week 12
(Visit 8) and week 26 (Visit 12).
24 h Holter monitoring will be conducted in a subset of patients (approximately
80 randomized patients) at Visit 2, 3, 8 and 12. Note: baseline Holter
monitoring will begin the day before Visit 2.
PK sampling will be conducted in a subset of patients (approximately 240
randomized patients) at Visit 3, 4, 5, 8, 9, 12 and 13.
During the study patients will be permitted to use allowable COPD medications
described in Section 6.5.7 and will be provided with a salbutamol/albuterol
inhaler to use as rescue medication. Patients will be asked to abstain wherever
possible from using rescue medication during study visits, and in the six hours
prior to attending a study visit.
If a patient experiences a COPD exacerbation during the treatment period he/she
will be treated as deemed appropriate by the Investigator for the exacerbation,
a standardized treatment plan (see section 7.4.4) is provided for reference.
Following treatment for the exacerbation the patient will be expected to
continue in the study if, in the opinion of the investigator, he/she can be
safely returned to their pre-exacerbation concomitant medications. If following
the exacerbation, the patient requires the addition of new concomitant COPD
medications, then he/she should be withdrawn from the study. At the end of an
exacerbation the patient must attend the clinic for assessment of the episode.

Patients will be randomized to treatment with NVA237 50µg o.d., or placebo to
NVA237 in a ratio of 2:1.

Adverse events of study medication. Changes in current COPD medication.
13 visits in 29 weeks, 3 days of extended measurements. Daily diary. Safety
blood 6x. Ca. 10 ml blood per visit, total volume ca. 60 ml. Pregnancy test 4x.
Normal visits: 10x. Vital signs (plus or minus physical exam) all visits.
Pulmonary function tests 1-6x per visit (1x with reversibility). EKG 2 visits.
Extended visits: 3x. Duration 14-24 h. 2x overnight stay in hospital with
nightly measurements. 13-15 pulm. function tests. 3 EKGs en 4x vital signs per
visit.
Optional: PK blood sampling during 7 visits. 1-7 samples of 3 ml per visit.
Total 27 samples, ca. 80 ml.
NB: Holter monitoring and PG blood sampling NOT IN NL.