Chronic Obstructive Pulmonary Disease
Conditions
Brief summary
To demonstrate the free combination of budesonide and indacaterol is as efficacious as fluticasone and salmeterol in patients with COPD
Interventions
DRUGBudesonide
Budesonide 400 mcg twice a day via Breezhaler® device
DRUGFluticasone
Fluticasone 250 mcg twice daily via Accuhaler® device
DRUGIndacaterol
Indacaterol 150 mcg once daily via Breezhaler® device
DRUGSalmeterol
Salmeterol 50 mcg twice daily via Diskus® device
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed * Outpatients with stable COPD groups C and D according to the 2011 GOLD Guidelines. * Current or ex-smokers who have a smoking history of at least 10 pack years * Patients with a history of at least one exacerbation. * Patients able to read and complete
Exclusion criteria
* Use of other investigational drugs within 30 days * Patients with a history of hypersensitivity to any of the study drugs * History or current diagnosis of ECG abnormalities * Patients with diabetes Type I or uncontrolled diabetes Type II including patients with a history of blood glucose levels consistently outside the normal range * Patients who have not achieved an acceptable spirometry result at Visit 1 * Patients with a body mass index (BMI) of more than 40 kg/m2 * Patients with lung cancer or a history of lung cancer * Patients with a history of malignancy of any organ system * Pregnant or nursing (lactating) women * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment * Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers) * Patients that are uncontrolled or unstable on permitted therapy, who in the opinion of the investigator, have clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or haematological abnormalities which could interfere with the assessment of the efficacy and safety of the study treatment * Patients requiring oxygen therapy for chronic hypoxemia * Patients who have had a respiratory tract infection within 6 weeks prior to Visit 1 * Patients with concomitant pulmonary disease, e.g. pulmonary tuberculosis, bronchiectasis, sarcoidosis, interstitial lung disorder or pulmonary hypertension * Patients with a known diagnosis of Alpha-1 Antitrypsin deficiency. * Patients with history of lung surgery * Patients who are participating in the active phase of a supervised pulmonary rehabilitation program. * Patients with a history of asthma Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (Non-inferiority Analysis). | Baseline and week 12 | Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Health Status - mMRC | Baseline, week 12 and week 24 | Modified Medical Research Council scale (mMRC) questionnaire will be completed by participants. 0 Not troubled with breathlessness except with strenuous exercise; 1 Troubled by shortness of breath when hurrying on the level or walking up a slight hill; 2 Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level; 3 Stops for breath after walking about 100 yards or after a few minutes on the level; 4 Too breathless to leave the house or breathless when dressing or undressing |
| Change From Baseline in Mean Daily Number of Puffs of Rescue Medication Used Over the 24 Week Treatment | 24 weeks | A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours. |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second at Week 24 (Analysis of Superiority) | Baseline and week 24 | Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. |
| Change in Health Status - SGRQ-C | Baseline, week 12 and week 24 | St George's Respiratory Questionnaire short version questionnaire will be completed by participants. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life) |
Countries
Argentina, Brazil, Chile, Dominican Republic, Ecuador, Honduras, Mexico, Panama
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Budesonide/Indacaterol Participants will receive a fixed combination of fluticasone and salmeterol during 4 weeks followed by a free combination of budesonide and indacaterol for the remainig of study. | 109 |
| Fluticasone / Salmeterol Fixed combination of fluticasone and salmeterol | 113 |
| Total | 222 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | AE, study drug would be detrimental | 1 | 3 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Non-eligible | 0 | 1 |
| Overall Study | Patient decision | 1 | 1 |
| Overall Study | Poor compliance | 1 | 1 |
| Overall Study | Reason unknown | 1 | 5 |
| Overall Study | Use of prohibited treatment | 0 | 3 |
| Overall Study | Withdrawal of informed consent | 1 | 0 |
Baseline characteristics
| Characteristic | Budesonide/Indacaterol | Fluticasone / Salmeterol | Total |
|---|---|---|---|
| Age, Continuous | 67.1 Years STANDARD_DEVIATION 9 | 67.3 Years STANDARD_DEVIATION 8.45 | 67.2 Years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 41 Participants | 54 Participants | 95 Participants |
| Sex: Female, Male Male | 68 Participants | 59 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 109 | 39 / 113 |
| serious Total, serious adverse events | 10 / 109 | 9 / 113 |
Outcome results
Primary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (Non-inferiority Analysis).
Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.
Time frame: Baseline and week 12
Population: Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Budesonide/Indacaterol | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (Non-inferiority Analysis). | 0.080 Liters | Standard Error 0.027 |
| Fluticasone / Salmeterol | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (Non-inferiority Analysis). | 0.019 Liters | Standard Error 0.028 |
p-value: 0.004Mixed effects General linear model
Secondary
Change From Baseline in Mean Daily Number of Puffs of Rescue Medication Used Over the 24 Week Treatment
A day with no rescue medication use is defined from the diary data as any day where the patient recorded no rescue medicine use during the previous 12 hours.
Time frame: 24 weeks
Population: Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients that were not discontinued before Visit 3 (day 28±3).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Budesonide/Indacaterol | Change From Baseline in Mean Daily Number of Puffs of Rescue Medication Used Over the 24 Week Treatment | 10.5 Puffs | Standard Deviation 9.53 |
| Fluticasone / Salmeterol | Change From Baseline in Mean Daily Number of Puffs of Rescue Medication Used Over the 24 Week Treatment | 12.9 Puffs | Standard Deviation 12.34 |
Secondary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second at Week 24 (Analysis of Superiority)
Forced Expiratory Volume in 1 second (FEV1) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing.
Time frame: Baseline and week 24
Population: Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Budesonide/Indacaterol | Change From Baseline in Trough Forced Expiratory Volume in 1 Second at Week 24 (Analysis of Superiority) | 0.063 Liters | Standard Error 0.033 |
| Fluticasone / Salmeterol | Change From Baseline in Trough Forced Expiratory Volume in 1 Second at Week 24 (Analysis of Superiority) | 0.020 Liters | Standard Error 0.034 |
Secondary
Change in Health Status - mMRC
Modified Medical Research Council scale (mMRC) questionnaire will be completed by participants. 0 Not troubled with breathlessness except with strenuous exercise; 1 Troubled by shortness of breath when hurrying on the level or walking up a slight hill; 2 Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level; 3 Stops for breath after walking about 100 yards or after a few minutes on the level; 4 Too breathless to leave the house or breathless when dressing or undressing
Time frame: Baseline, week 12 and week 24
Population: Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Budesonide/Indacaterol | Change in Health Status - mMRC | Week 12 | 1.452 Score on a scale | Standard Error 0.111 |
| Budesonide/Indacaterol | Change in Health Status - mMRC | Week 24 | 1.315 Score on a scale | Standard Error 0.112 |
| Fluticasone / Salmeterol | Change in Health Status - mMRC | Week 12 | 1.623 Score on a scale | Standard Error 0.113 |
| Fluticasone / Salmeterol | Change in Health Status - mMRC | Week 24 | 1.414 Score on a scale | Standard Error 0.115 |
Secondary
Change in Health Status - SGRQ-C
St George's Respiratory Questionnaire short version questionnaire will be completed by participants. The SGRQ ranges from 0 (no impairment of quality of life) to 100 (highest impairment of quality of life)
Time frame: Baseline, week 12 and week 24
Population: Per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Major protocol deviations were defined in the validation analysis plan prior to database lock and the unblinding of the study. Patients were analyzed according to the treatment they are randomized to
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Budesonide/Indacaterol | Change in Health Status - SGRQ-C | Week 12 | -8.703 Score on a scale | Standard Error 2.006 |
| Budesonide/Indacaterol | Change in Health Status - SGRQ-C | Week 24 | -7.787 Score on a scale | Standard Error 2.308 |
| Fluticasone / Salmeterol | Change in Health Status - SGRQ-C | Week 12 | -2.334 Score on a scale | Standard Error 2.053 |
| Fluticasone / Salmeterol | Change in Health Status - SGRQ-C | Week 24 | -2.523 Score on a scale | Standard Error 2.384 |