Pulmonary Disease, Chronic Obstructive, COPD, Lung Diseases, Obstructive
Conditions
Keywords
indacaterol, long acting beta-2 agonist
Brief summary
Stage 1 of the study is designed to provide data about the risk-benefit of 4 dose regimens of indacaterol (75, 150, 300 & 600 µg o.d.) in order to select two doses to carry forward into study Stage 2. Study Stage 2 will provide pivotal confirmation of efficacy, safety, and tolerability of the selected indacaterol doses in patients with COPD
Interventions
DRUGIndacaterol
In the morning, Indacaterol once daily (o.d.) orally inhaled via a single dose dry powder inhaler (SDDPI).
DRUGFormoterol (12 µg b.i.d.)
Formoterol 12 µg twice daily (b.i.d.) in the morning and in the evening via an aerolizer.
DRUGTiotropium (18 µg o.d.)
Tiotropium 18 µg once daily (o.d.) dry powder capsules delivered via a SDDPI.
DRUGPlacebo to Indacaterol
In the morning, Placebo to Indacaterol once daily (o.d.) orally inhaled via a single dose dry powder inhaler (SDDPI).
In the morning and in the evening, placebo to formoterol delivered via Aerolizer.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male and female adults aged ≥ 40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure * Co-operative outpatients with a diagnosis of COPD (moderate to severe as classified by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) Guidelines, 2005) and: * Smoking history of at least 20 pack years * Post-bronchodilator FEV1 \< 80% and ≥ 30% of the predicted normal value. * Post-bronchodilator FEV1/FVC \< 70% (Post refers to within 30 min of inhalation of 400 µg of salbutamol)
Exclusion criteria
* Pregnant or lactating females * Patients who have been hospitalized for a COPD exacerbation in the 6 weeks prior to Visit 1 or during the run-in period * Patients requiring long term oxygen therapy (\> 15 h a day) * Patients who have had a respiratory tract infection 6 weeks prior to V1 (with further criteria) * Patients with concomitant pulmonary disease, pulmonary tuberculosis, or clinically significant bronchiectasis * Patients with a history of asthma (with further criteria) * Patients with Type I or uncontrolled Type II diabetes * Patients with contraindications for tiotropium * Patients who have clinically relevant laboratory abnormalities or a clinically significant abnormality * Any patient with active cancer or a history of cancer with less than 5 years disease free survival time * Patients with a history of long QT syndrome or whose QTc interval is prolonged * Patients with a hypersensitivity to any of the study drugs or drugs with similar chemical structures * Patients who have had treatment with the investigational drug (with further criteria) * Patients who have had live attenuated vaccinations within 30 days prior to visit 1, or during run-in period * Patients with known history of non compliance to medication * Patients unable to satisfactorily use a dry powder inhaler device or perform spirometry measurements Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 12 Weeks of Treatment | after 12 weeks of treatment | FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Days of Poor Control Reported Over the 26 Week Treatment Period | up to 26 weeks | A Chronic Obstructive Pulmonary Disease (COPD) day of poor control was defined as any day in the participant's diary with a score ≥2 (moderate or severe) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness). Score for each symptom ranges from 0-3; a higher number indicates a more severe symptom. The model contained baseline percentage of days of poor control as well as FEV1 reversibility components as covariates. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | Day 15, After 2 Weeks of treatment in Stage 1 | Interim Analysis: Stage 1. Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates. |
| Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | Day 14, After 2 Weeks of treatment in Stage 1 | Interim Analysis: Stage 1. Spirometry was conducted according to internationally accepted standards. Standardized with respect to time (AUC 1h-4h) for FEV1 measurements taken from 1 hour to 4 hour post morning dose on Day 14. Standardized FEV1 AUC was calculated by the trapezoidal rule. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates. |
Countries
Argentina, Canada, Germany, India, Italy, Puerto Rico, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
This study consisted of two stages: a dose selection stage (Stage 1, 2 weeks) from which 2 out of 4 Indacaterol doses were selected following interim analysis to continue into Stage 2 for comparisons of efficacy, safety, and tolerability for total treatment of up to 26 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Indacaterol 150 µg (Continued Into Stage 2) In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1.
Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study. | 416 |
| Indacaterol 300 µg (Continued Into Stage 2) In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1.
Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study. | 416 |
| Tiotropium 18 µg (Continued Into Stage 2) Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2.
Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study. | 415 |
| Placebo (Continued Into Stage 2) In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1.
Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study. | 418 |
| Indacaterol 75 µg (Not Continued Into Stage 2) In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2.
Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study. | 127 |
| Indacaterol 600 µg (Not Continued Into Stage 2) In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2.
Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study. | 122 |
| Formoterol 12 µg (Not Continued Into Stage 2) In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2.
Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study. | 122 |
| Total | 2,036 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Abnormal lab value(s) | 1 | 1 | 2 | 1 | 1 | 0 | 0 |
| Overall Study | Abnormal test procedure result(s) | 1 | 1 | 6 | 2 | 0 | 2 | 0 |
| Overall Study | Administrative problems | 5 | 3 | 6 | 9 | 3 | 2 | 2 |
| Overall Study | Adverse Event | 29 | 26 | 17 | 46 | 10 | 10 | 4 |
| Overall Study | Death | 1 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 4 | 9 | 9 | 17 | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 12 | 6 | 13 | 8 | 1 | 1 | 1 |
| Overall Study | Protocol Deviation | 13 | 9 | 14 | 11 | 1 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 29 | 22 | 20 | 37 | 6 | 5 | 1 |
Baseline characteristics
| Characteristic | Total | Indacaterol 150 µg (Continued Into Stage 2) | Indacaterol 300 µg (Continued Into Stage 2) | Tiotropium 18 µg (Continued Into Stage 2) | Placebo (Continued Into Stage 2) | Indacaterol 75 µg (Not Continued Into Stage 2) | Indacaterol 600 µg (Not Continued Into Stage 2) | Formoterol 12 µg (Not Continued Into Stage 2) |
|---|---|---|---|---|---|---|---|---|
| Age, Customized ≥65 years | 988 participants | 202 participants | 186 participants | 200 participants | 203 participants | 69 participants | 62 participants | 66 participants |
| Age, Customized Between 40 and 64 years | 1048 participants | 214 participants | 230 participants | 215 participants | 215 participants | 58 participants | 60 participants | 56 participants |
| Sex: Female, Male Female | 770 Participants | 157 Participants | 153 Participants | 146 Participants | 163 Participants | 51 Participants | 48 Participants | 52 Participants |
| Sex: Female, Male Male | 1266 Participants | 259 Participants | 263 Participants | 269 Participants | 255 Participants | 76 Participants | 74 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 159 / 416 | 159 / 416 | 156 / 415 | 155 / 418 | 39 / 127 | 44 / 122 | 31 / 122 |
| serious Total, serious adverse events | 35 / 416 | 32 / 416 | 34 / 415 | 35 / 418 | 9 / 127 | 5 / 122 | 4 / 122 |
Outcome results
Primary
Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 12 Weeks of Treatment
FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.
Time frame: after 12 weeks of treatment
Population: Participants from the Intent to Treat Population of Stage 2 of the study who received at least one dose of study drug and for whom data was available for FEV1 at 12 weeks. Imputed with last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 12 Weeks of Treatment | 1.46 Liters | Standard Error 0.015 |
| Indacaterol 300 µg (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 12 Weeks of Treatment | 1.46 Liters | Standard Error 0.015 |
| Tiotropium 18 µg (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 12 Weeks of Treatment | 1.42 Liters | Standard Error 0.015 |
| Placebo (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 12 Weeks of Treatment | 1.28 Liters | Standard Error 0.015 |
Secondary
The Percentage of Days of Poor Control Reported Over the 26 Week Treatment Period
A Chronic Obstructive Pulmonary Disease (COPD) day of poor control was defined as any day in the participant's diary with a score ≥2 (moderate or severe) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness). Score for each symptom ranges from 0-3; a higher number indicates a more severe symptom. The model contained baseline percentage of days of poor control as well as FEV1 reversibility components as covariates.
Time frame: up to 26 weeks
Population: Intent to Treat population consisting of all participants in Stage 2 of the study who received at least one dose of study drug. Eligible participants for the analysis were those with ≥7 evaluable diary days in the baseline period and ≥30% evaluable diary days (at least 20 days) in total.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg (Continued Into Stage 2) | The Percentage of Days of Poor Control Reported Over the 26 Week Treatment Period | 31.5 Percentage of days | Standard Error 1.51 |
| Indacaterol 300 µg (Continued Into Stage 2) | The Percentage of Days of Poor Control Reported Over the 26 Week Treatment Period | 30.8 Percentage of days | Standard Error 1.51 |
| Tiotropium 18 µg (Continued Into Stage 2) | The Percentage of Days of Poor Control Reported Over the 26 Week Treatment Period | 31.0 Percentage of days | Standard Error 1.5 |
| Placebo (Continued Into Stage 2) | The Percentage of Days of Poor Control Reported Over the 26 Week Treatment Period | 34.0 Percentage of days | Standard Error 1.53 |
Other Pre-specified
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment
Interim Analysis: Stage 1. Spirometry was conducted according to internationally accepted standards. Standardized with respect to time (AUC 1h-4h) for FEV1 measurements taken from 1 hour to 4 hour post morning dose on Day 14. Standardized FEV1 AUC was calculated by the trapezoidal rule. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.
Time frame: Day 14, After 2 Weeks of treatment in Stage 1
Population: Interim Intent-to-treat (ITT) population included participants in Stage 1 of the study who received at least one dose of study drug and for whom data were available for AUC 1h-4h FEV1 at Day 14. Missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg (Continued Into Stage 2) | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | 1.53 Liters | Standard Error 0.034 |
| Indacaterol 300 µg (Continued Into Stage 2) | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | 1.58 Liters | Standard Error 0.034 |
| Tiotropium 18 µg (Continued Into Stage 2) | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | 1.49 Liters | Standard Error 0.034 |
| Placebo (Continued Into Stage 2) | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | 1.30 Liters | Standard Error 0.033 |
| Indacaterol 75 µg | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | 1.50 Liters | Standard Error 0.034 |
| Indacaterol 600 µg | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | 1.53 Liters | Standard Error 0.034 |
| Formoterol 12 µg | Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment | 1.52 Liters | Standard Error 0.035 |
Other Pre-specified
Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment
Interim Analysis: Stage 1. Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.
Time frame: Day 15, After 2 Weeks of treatment in Stage 1
Population: Interim Intent-to-treat (ITT) population included participants in Stage 1 of the study who received at least one dose of study drug and for whom data were available for Trough FEV1 at Day 15. Missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol 150 µg (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | 1.49 Liters | Standard Error 0.024 |
| Indacaterol 300 µg (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | 1.52 Liters | Standard Error 0.024 |
| Tiotropium 18 µg (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | 1.45 Liters | Standard Error 0.023 |
| Placebo (Continued Into Stage 2) | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | 1.31 Liters | Standard Error 0.024 |
| Indacaterol 75 µg | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | 1.46 Liters | Standard Error 0.024 |
| Indacaterol 600 µg | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | 1.51 Liters | Standard Error 0.024 |
| Formoterol 12 µg | Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment | 1.42 Liters | Standard Error 0.024 |