CQAB149B2401

Novartis Pharma AG

CH-4002, Basel, Switzerland,

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

No

No

No

Final

13 Feb 2014

No

Yes

13 Feb 2014

No

The primary objective of this study was to demonstrate the non-inferiority of indacaterol (150 μg o.d.) to salmeterol 50 μg/fluticasone propionate 500 μg b.i.d. as measured by trough forced expiratory volume in one second (trough FEV1) after 12 weeks (Day 85) of treatment in patients with moderate COPD and having had no exacerbations in the previous year. Trough was defined as the mean of the FEV1 measurements at 23 h 10 min and 23 h 45 min post the Day 84 morning dose.

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. At Visit 1, all patients were provided a SABA (salbutamol) MDI which they were instructed to use throughout the study as rescue medication. Nebulized salbutamol was not allowed as rescue medication. Patients were instructed to abstain from taking rescue medication (salbutamol) within 6 h of the start of each visit where spirometry was being performed unless absolutely necessary.

29 Feb 2012

No

No

Argentina: 254

Colombia: 20

Malaysia: 1

Mexico: 36

Switzerland: 22

Netherlands: 6

Spain: 22

United Kingdom: 8

Italy: 212

581

248

0

0

0

0

0

0

244

332

5

Treatment (overall period)

Randomised - controlled

This was a double-blind, double-dummy study. The identity of the salmeterol/fluticasone and indacaterol treatments was concealed by double-dummy blinding. A double-dummy design was used because the identity of the study drugs could not be disguised and made to look identical due to their different inhaler devices.

Yes

Indacaterol

QAB149

Onbrez Breezhaler

Inhalation powder, hard capsule

Inhalation use

Device training packs were provided to study sites following registration of the center in the IRT system after site initiation, and prior to the first patient at the center attending Visit 1. Patients were trained on the use of the SDDPI and MDDPI and were provided illustrated and written instructions on how to use the devices and how to inhale study medication. Instructions were provided on a leaflet by the investigator. Patients were instructed to administer their medication at approximately the same time and in the same order each morning. Patients were carefully instructed to: • take their indacaterol/placebo medication in the morning only (SDDPI) • take their salmeterol/fluticasone/placebo medication in the morning and in the evening (MDDPI) • always take their morning medications in the same order • record the exact time each dose had taken in the eDiary. Patients were contacted by center personnel approximately one day prior to clinic visits to reinforce training.

salmeterol/fluticasone

Seretide Accuhaler

Inhalation powder

Inhalation use

Device training packs were provided to study sites following registration of the center in the IRT system after site initiation, and prior to the first patient at the center attending Visit 1. Patients were trained on the use of the SDDPI and MDDPI and were provided illustrated and written instructions on how to use the devices and how to inhale study medication. Instructions were provided on a leaflet by the investigator. Patients were instructed to administer their medication at approximately the same time and in the same order each morning. Patients were carefully instructed to: • take their indacaterol/placebo medication in the morning only (SDDPI) • take their salmeterol/fluticasone/placebo medication in the morning and in the evening (MDDPI) • always take their morning medications in the same order • record the exact time each dose had taken in the eDiary. Patients were contacted by center personnel approximately one day prior to clinic visits to reinforce training

Indacaterol

Salmeterol/fluticasone propionate

Indacaterol

Salmeterol/fluticasone propionate

Salmeterol/fluticasone Per Protocol Set

The per-protocol set (PPS) included all patients of the FAS without any major protocol deviations or non-protocol deviations

Indacaterol Per Protocol Set

The per-protocol set (PPS) included all patients of the FAS without any major protocol deviations or non-protocol deviations

Salmeterol/fluticisone Modified Full Analysis Set (FAS)

Clinical Team - Please provide information about why the FAS for Table 14.2-1.1 (source for Table 11-5) is 20 less pts than the FAS in Table 11-1. Is it for the following reason in footnote in Table 14.2-1.1. If so, is there a reason why these were not protocol deviations and why excluded from FAS? Please advise where explanation is for this-cannot locate. "FEV1 data taken within 6 h of rescue medication was excluded from this analysis, as done for trough data outside 22-25 h after last morning dose."

Indacterol Modified Full Analysis Set (FAS)

Clinical Team - Please provide information about why the FAS for Table 14.2-1.1 (source for Table 11-5) is 53 less pts than the FAS in Table 11-1. Is it for the following reason in footnote in Table 14.2-1.1. If so, is there a reason why these were not protocol deviations and why excluded from FAS? Please advise where explanation is for this-cannot locate. "FEV1 data taken within 6 h of rescue medication was excluded from this analysis, as done for trough data outside 22-25 h after last morning dose."

Spirometry conducted to internationally accepted standards. Trough FEV1 defined as the mean of the FEV1 measurements at 23 h 10 min and 23 h 45 min post the Day 84 morning dose. The primary variable (imputed with last observation carried forward) will be analysed using a mixed model for the Per Protocol Set (PPS). The model will contain treatment as a fixed effect with the baseline FEV1 measurement, FEV1 prior to inhalation and FEV1 10-15 min post inhalation of salbutamol (components of reversibility at Visit 1) as covariates. Analysis Population Description: full analysis set

Primary

12 weeks

The primary variable (imputed with LOCF) will be analyzed using a mixed model for the Per Protocol Set (PPS). The model will contain treatment as a fixed effect with the baseline FEV1 measurement, FEV1 prior to inhalation and FEV1 10-15 min post inhalation of salbutamol (components of reversibility at Visit 1) as covariates. To reflect the randomization scheme the model will also include smoking status.

Indacaterol Per Protocol Set v Salmeterol/fluticasone Per Protocol Set

462

Pre-specified

-0.009

2-sided

Standard error of the mean

0.0179

If non-inferiority of indacaterol with respect to trough FEV1 after 12 weeks treatment is met in the PPS, indacaterol will then be tested for superiority using the FAS. Non-inferiority of indacaterol to salmeterol/fluticasone propionate will be demonstrated if the 95% confidence interval for the mean FEV1 difference of indacaterol minus salmeterol/fluticasone propionate lies entirely to the right of -60 mL. The analysis used for the PPS will be repeated for the Full Analysis Set (FAS).

Indacterol Modified Full Analysis Set (FAS) v Salmeterol/fluticisone Modified Full Analysis Set (FAS)

528

Pre-specified

-0.014

2-sided

Standard error of the mean

0.0165

Trough FEV1 ( L ) a t We ek 26 (imputed with LOCF): treatment comparisons. Trough FEV1 is defined as the average of the 23 h 10 min and the 23 h 45 min values taken in the clinic at Visit 11.

Secondary

26 weeks

FEV1 at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group. Full analysis set was used.

Secondary

12 weeks

FEV1 at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group . Analysis Population Description: Full analysis set

Secondary

26 weeks

FVC at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group. Analysis Population Description: Full analysis set

Secondary

12 and 26 weeks

The standardized (with respect to the length of time) AUC for FEV1 will be calculated between 5 min and 4 h post morning dose as the sum of trapezoids divided by the length of time at Day 84 (Visit 6) and Day 182 (Visit 10). Scheduled (not actual) time points are to be used. FEV1 measurements taken within 6 h of rescue use will be set to missing before the standardized AUC is calculated Analysis Population Description: Full analysis set

Secondary

12 and 26 weeks

The Transition Dyspnea Index (TDI) total score after 12 and 26 weeks of treatment will be analyzed using the same mixed model as specified for the primary analysis with the Baseline Dyspnea Index (BDI) total score as the baseline.Total score ranging - 9 to + 9. The lower the score, the more deterioration in severity of dyspnea. One additional option in each category, which does not contribute to the score, allows for circumstances in which impairment is due to reasons other than dyspnea.

Secondary

12 and 26 weeks

The number of exacerbations during the 26 week treatment period will be analyzed using a generalized linear model assuming a negative binomial distribution.

Secondary

26 weeks

The mean daily number of puffs of rescue medication taken by the patient will be derived. If the number of puffs is missing for part of the day (either morning or evening) then a half day will be used in the denominator. Rescue medication data recorded during the 14 day run-in period will be used to calculate the baseline. The mean change from baseline in the daily number of puffs of rescue medication will be analyzed using the same mixed model as specified for the primary analysis, with the baseline FEV1 replaced with the baseline daily rescue use.

Secondary

26 weeks

A ‘day with no rescue use’ is defined from diary data as any day where the patient has taken no puffs of rescue medication. The percentage of ‘days with no rescue use’ will be derived and analyzed as for the percentage of ‘nights with no nighttime awakenings’. Analysis Population Description: Full Analysis Set

Secondary

26 weeks

A Total and three component scores are calculated: Symptoms; Activity; Impacts. Each component of the questionnaire is scored separately:The score for each component is calculated separately by dividing the summed weights by the maximum possible weight for that component and expressing the result as a percentage: Score = 100 x Summed weights from all positive items in that component divided by Sum of weights for all items in that component The Total score is calculated in similar way: Score = 100 x Summed weights from all positive items in the questionnaire divided by Sum of weights for all items in the questionnaire Sum of maximum possible weights for each component and Total: Symptoms 566.2 Activity 982.9 Impacts 1652.8 Total (sum of maximum for all three components) 3201.9 The proportion of patients who achieve a clinically important improvement of at least 4 units in the total SGRQ will be analyzed. The higher the score the more symptoms of disease are present. Analysis Populati

Secondary

12 and 26 weeks

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

16.1

Salmeterol/Fluticasone 50mcg/500mcg

Indacaterol 150 mcg