Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
QVA, Indacaterol, Glycopyrrolate, Concept1, COPD, cross over study, safety and efficacy, trough FEV1
Brief summary
This study will evaluate the safety and efficacy of QVA149 in patients with moderate to severe COPD.
Interventions
Inhalation capsule indacaterol/glycopyrrolate 300/50 μg inhaled once daily via a single dose dry powder inhaler for 7 days.
DRUGindacaterol
Inhalation capsule indacaterol supplied as 300 μg capsules inhaled once daily via a single dose dry powder inhaler for 7 days.
DRUGplacebo
Placebo inhalation capsules inhaled once daily via a single dose dry powder inhaler for 7 days.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female adults aged ≥40 years, who have signed an Informed Consent Form prior to initiation of any study-related procedure. 2. Patients with moderate to severe stable Chronic Obstructive Pulmonary Disease (COPD) according to the Global Initiative for Obstructive Lung Disease (GOLD) Guidelines 2006. 3. Patients who have smoking history of at least 10 pack years. 4. Patients with a post-bronchodilator Forced Expiratory Volume in 1 second (FEV1) ≥30% and \< 80% of the predicted normal and post-bronchodilator FEV1/Forced Vital Capacity (FVC) \<0.70.
Exclusion criteria
1. Pregnant or nursing women, or women of child-bearing potential, regardless of whether or not sexually active if they are not using acceptable methods of contraception. 2. Patients requiring long term oxygen therapy (\> 15 hours a day) on a daily basis for chronic hypoxemia, or who have been hospitalized or visited an emergency department for a COPD exacerbation or as result of their airways disease in the 6 weeks prior to screening. 3. Patients who have had a respiratory tract infection within 6 weeks prior to screening. 4. Patients with concomitant pulmonary disease, pulmonary tuberculosis (unless confirmed by chest x-ray to be no longer active) or clinically significant bronchiectasis. 5. Patients with any history of asthma indicated by (but not limited to) a blood eosinophil count \> 400/mm3. 6. Patients who, in the judgment of the investigator or the responsible Novartis personnel, have a clinically relevant laboratory abnormality or a clinically significant condition. 7. Patients with uncontrolled Type I and Type II diabetes. 8. History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years. 9. Patients who are contraindicated for or who have shown an untoward reaction to inhaled anticholinergic agents. 10. Patients with a history of long QT syndrome or whose QTc interval (Fridericia method) measured at screening is prolonged (\>450 ms for males or \>470 ms for females). 11. Patients with a history of untoward reactions to sympathomimetic amines, inhaled medication or any component thereof, or any of the study drugs or drugs with similar chemical structures. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 7 | Baseline, Day 7 | Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 was defined as the average of the 23 hour 15 minute and 23 hour 45 minute measurements post dosing. Baseline FEV1 is the mean of the 45 minute and 15 minute pre-dose FEV1 values at day 1 of each period. Least square means are based on the Analysis of Covariance Trough FEV1 at day 7 = sequence effect + patient(sequence) + period effect + treatment effect + (period) baseline FEV1 + error. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve (AUC) 5 Minutes-12 Hours at Day 7 | Day 7 | Spirometry testing was performed in accordance with American Thoracic Society standards. FEV1 was assessed at 5, 15, 30 minutes, 1, 2, 3, 4, 5, 6, 8, 10 and 12 hours post dose on Day 7. Standardized (with respect to time) AUC (5 minutes-12 hours) for FEV1 on day 7 was calculated using the trapezoidal rule. Least square means are based on the Analysis of Covariance: FEV1 AUC = sequence effect + patient (sequence) + period + treatment + baseline FEV1 (period) + error. |
| Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | 47 days | Additional information about adverse events can be found in the Adverse Event Section. |
Countries
Belgium, Canada, Germany, Netherlands, United States
Participant flow
Pre-assignment details
This was 4 arm crossover study. There was a 7 day washout period between each treatment period. 154 patients were randomized, 153 participants received study drug. 5 patients were excluded from the Modified Intent-to-treat population (MITT). 4 patients for protocol violations and 1 patient was randomized but did not receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Overall Population Participants were randomized and received the following 4 treatments: 1-Two placebo capsules inhaled once daily via a SDDPI for 7 days, 2-One indacaterol/glycopyrrolate (Ind/Glyc) 300/50 μg and one placebo capsule inhaled once daily via a SDDPI for 7 days, 3-One Indacaterol (Ind) 300 μg capsule and one placebo capsule inhaled once daily via a SDDPI for 7 days and 4-Two Indacaterol 300 μg capsules inhaled once daily via a SDDPI for 7 days. There was a 7 day washout period between the four treatment periods. | 153 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Abnormal test procedure | 1 | 0 | 0 | 0 |
| Overall Study | Adverse Event | 0 | 1 | 4 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Protocol deviation | 2 | 1 | 2 | 2 |
| Overall Study | Subject no longer requires study drug | 0 | 1 | 0 | 0 |
| Overall Study | Subject withdrew consent | 0 | 1 | 0 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Population |
|---|---|
| Age, Continuous | 61.7 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 59 Participants |
| Sex: Female, Male Male | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 142 | 14 / 141 | 15 / 141 | 15 / 143 |
| serious Total, serious adverse events | 2 / 142 | 0 / 141 | 0 / 141 | 0 / 143 |
Outcome results
Primary
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 7
Spirometry testing was performed in accordance with American Thoracic Society standards. Trough FEV1 was defined as the average of the 23 hour 15 minute and 23 hour 45 minute measurements post dosing. Baseline FEV1 is the mean of the 45 minute and 15 minute pre-dose FEV1 values at day 1 of each period. Least square means are based on the Analysis of Covariance Trough FEV1 at day 7 = sequence effect + patient(sequence) + period effect + treatment effect + (period) baseline FEV1 + error.
Time frame: Baseline, Day 7
Population: Participants from the Modified Intent-to-treat population (includes all participants who received study drug) with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol/Glycopyrrolate 300/50 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 7 | 1.512 Liters | Standard Error 0.0143 |
| Indacaterol 300 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 7 | 1.389 Liters | Standard Error 0.0144 |
| Indacaterol 600 μg | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 7 | 1.395 Liters | Standard Error 0.0143 |
| Placebo | Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 7 | 1.286 Liters | Standard Error 0.0145 |
Secondary
Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events
Additional information about adverse events can be found in the Adverse Event Section.
Time frame: 47 days
Population: Safety population includes all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Indacaterol/Glycopyrrolate 300/50 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Serious Adverse Events | 2 Participants |
| Indacaterol/Glycopyrrolate 300/50 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Discontinuations Due to Adverse Events | 3 Participants |
| Indacaterol/Glycopyrrolate 300/50 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Adverse Events | 39 Participants |
| Indacaterol 300 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Serious Adverse Events | 0 Participants |
| Indacaterol 300 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Discontinuations Due to Adverse Events | 0 Participants |
| Indacaterol 300 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Adverse Events | 31 Participants |
| Indacaterol 600 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Adverse Events | 37 Participants |
| Indacaterol 600 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Serious Adverse Events | 0 Participants |
| Indacaterol 600 μg | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Discontinuations Due to Adverse Events | 2 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Serious Adverse Events | 0 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Discontinuations Due to Adverse Events | 0 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | Adverse Events | 31 Participants |
Secondary
Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve (AUC) 5 Minutes-12 Hours at Day 7
Spirometry testing was performed in accordance with American Thoracic Society standards. FEV1 was assessed at 5, 15, 30 minutes, 1, 2, 3, 4, 5, 6, 8, 10 and 12 hours post dose on Day 7. Standardized (with respect to time) AUC (5 minutes-12 hours) for FEV1 on day 7 was calculated using the trapezoidal rule. Least square means are based on the Analysis of Covariance: FEV1 AUC = sequence effect + patient (sequence) + period + treatment + baseline FEV1 (period) + error.
Time frame: Day 7
Population: Participants from the Modified Intent-to-treat population (includes all participants who received study drug) with data available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Indacaterol/Glycopyrrolate 300/50 μg | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve (AUC) 5 Minutes-12 Hours at Day 7 | 1.610 Liters | Standard Error 0.018 |
| Indacaterol 300 μg | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve (AUC) 5 Minutes-12 Hours at Day 7 | 1.473 Liters | Standard Error 0.0181 |
| Indacaterol 600 μg | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve (AUC) 5 Minutes-12 Hours at Day 7 | 1.457 Liters | Standard Error 0.018 |
| Placebo | Standardized Forced Expiratory Volume in 1 Second (FEV1) Area Under Curve (AUC) 5 Minutes-12 Hours at Day 7 | 1.317 Liters | Standard Error 0.0185 |