QVA vs. Salmeterol/Fluticasone, 52-week Exacerbation Study, FLAME (EFfect of Indacaterol Glycopyronium Vs Fluticasone Salmeterol on COPD Exacerbations)

A 52-week Treatment, Multi-center, Randomized, Double-blind, Double Dummy, Parallel-group, Active Controlled Study to Compare the Effect of QVA149 (Indacaterol Maleate / Glycopyrronium Bromide) With Salmeterol/Fluticasone on the Rate of Exacerbations in Subjects With Moderate to Very Severe COPD. (FLAME).

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01782326

Enrollment

3362

Registered

2013-02-01

Start date

2013-07-31

Completion date

2015-09-30

Last updated

2016-05-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Obstructive Pulmonary Disease (COPD)

Keywords

COPD, QVA149, FLAME( EFfect of Indacaterol Glycopyronium Vs Fluticasone salmeterol on COPD Exacerbations)

Brief summary

This study will assess the efficacy, safety and tolerability of QVA149 in patients with moderate to very severe COPD.

Interventions

DRUGQVA149

QVA149 will be supplied in a capsule form in blister packs for use in the Novartis Concept 1 SDDPI.

DRUGLong acting B2 agonist (LABA) and inhaled corticosteroid (ICS)

Salmeterol/fluticasone dry inhalation powder delivered via the Accuhaler device.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

40 Years to No maximum

Healthy volunteers

Inclusion criteria

* Written informed consent must be obtained before any assessment is performed * Male or female adults aged ≥40 years * Patients with stable Chronic Obstructive Pulmonary Disease ( COPD) according to the current GOLD strategy (GOLD 2011) * Current or ex-smokers who have a smoking history of at least 10 pack years. (Ten pack-years are defined as 20 cigarettes a day for 10 years, or 10 cigarettes a day for 20 years) * Patients with a post-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥25 and \< 60% of the predicted normal value, and post-bronchodilator FEV1/FVC (Forced Vital Capacity) \< 0.70 at day -28. (Post refers to 1 hour after sequential inhalation of 84 µg (or equivalent dose) of ipratropium bromide and 400 µg of salbutamol) * A documented history of at least 1 COPD exacerbation in the previous 12 months that required treatment with systemic glucocorticosteroids and/or antibiotics * Patients taking stable COPD medication (at least 60 days) prior to day 28 * Patients with an mMRC grade of at least 2 at day 28

Exclusion criteria

* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG (human Chorionic Gonadotropin) laboratory test * 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. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential * Patients with Type I or uncontrolled Type II diabetes * Patients with a history of long QT syndrome or whose QTc measured at day 28 (Fridericia method) is prolonged (\>450 ms for males and females) and confirmed by a central assessor. These patients should not be re-screened * Patients who have a clinically significant ECG abnormality prior to randomization. (These patients should not be re-screened) * Patients who have a clinically significant laboratory abnormality at screening * Patients who have clinically significant renal, cardiovascular (such as but not limited to unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, myocardial infarction), arrhythmia (see below for patients with atrial fibrillation), neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities which could interfere with the assessment of the efficacy and safety of the study treatment * Patients with paroxysmal (e.g. intermittent) atrial fibrillation are excluded * Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at both pre-randomization visits, with a resting ventricular rate \< 100/min. At screening the atrial fibrillation must be confirmed by central reading * Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the following inhaled drugs, drugs of a similar class or any component thereof: anticholinergic agents, long and short acting beta-2 agonists, sympathomimetic amines, lactose or any of the other excipients of trial medication * Patients with a history of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin * Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or moderate to severe renal impairment or urinary retention. Benign Prostatic Hyperplasia (BPH) patients who are stable on treatment can be considered * Patients who have not achieved an acceptable spirometry results at screening in accordance with American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria for acceptability (one retest may be performed for patients that don't meet the acceptability criteria) * Patients who have had a COPD exacerbation that required treatment with antibiotics and/or systemic corticosteroids and/or hospitalization in the 6 weeks prior to screening * Patients who develop a COPD exacerbation of any severity (mild/moderate/severe) between screening and treatment will not be eligible but will be permitted to be re-screened after a minimum of 6 weeks after the resolution of the COPD exacerbation * Patients who have had a respiratory tract infection within 4 weeks prior to screening * Patients who develop a respiratory tract infection between screening and prior to treatment will not be eligible, but will be permitted to be re-screened 4 weeks after the resolution of the respiratory tract infection * Patients requiring long term oxygen therapy prescribed for \>12 hours per day * Patients with any history of asthma * Patients with an onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years * Patients with a blood eosinophil count \> 600/mm3 at screening * Patients with allergic rhinitis who use a H1 antagonist or intra-nasal corticosteroids intermittently (treatment with a stable dose or regimen is permitted) * Patients with concomitant pulmonary disease (e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension) * Patients with clinically significant bronchiectasis * Patients with a diagnosis of α-1 anti-trypsin deficiency * Patients with active pulmonary tuberculosis, unless confirmed by imaging to be no longer active * Patients with pulmonary lobectomy or lung volume reduction surgery or lung transplantation * Patients participating in or planning to participate in the active phase of a supervised pulmonary rehabilitation program during the study. (Maintenance program is permitted.) * Patients receiving any medications in the classes listed in the protocol * Patients receiving any COPD related medications in the classes specified in the protocol must undergo the required washout period prior to screening and follow the adjustment to treatment program * Use of other investigational drugs/devices (approved or unapproved) at the time of enrollment, or within 30 days or 5 half-lives of screening, whichever is longer * Patients unable to use an electronic patient diary and EXACT pro diary * Patients unable to use a dry powder inhaler device, Metered Dose Inhaler (MDI) or a pressurized MDI (rescue medication) or comply with the study regimen.

Design outcomes

Primary

Measure	Time frame	Description
Rate of COPD Exacerbations	52 weeks	COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. As the offset variable log(exposure time in years) was used.

Secondary

Measure	Time frame	Description
Rate of Moderate to Severe COPD Exacerbations.	52 weeks	COPD exacerbations starting between date of first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event with the worst severity. A COPD exacerbation of moderate severity meets the symptoms definition in the protocol and requires treatment with systemic corticosteroids and/or antibiotics. A severe COPD exacerbation requires hospitalization. Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used.
Time to First Moderate to Severe COPD Exacerbation.	52 weeks.	First COPD exacerbations starting between first dose and one day after last treatment are included. Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region.
Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids	52 weeks	COPD exacerbations starting between date of first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event with the worst severity. Estimates are from a generalized linear model assuming a negative binomial distribution with fixed effects of treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used.
Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics	52 weeks	Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used. COPD exacerbations starting between first dose and one day after last treatment are included .
Rate of Moderate to Severe COPD Exacerbations Requiring Hospitalization. COPD Exacerbations Starting Between First Dose and One Day After Last Treatment Are Included.	52 weeks	All exacerbations requiring hospitalization are considered severe according to protocol definitions so this is the rate of severe COPD exacerbations only. Note - an ER visit of longer than 24 hours was considered a hospitalization.
Rate of Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days	52 weeks	Re-hospitalizations are defined as hospitalizations starting within the first 30 days after a severe COPD exacerbation and between first dose and one day after date of last treatment. Generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used. COPD exacerbations starting between first dose and one day after last treatment are included.
Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids	52 weeks	Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.
Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics	52 weeks	Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.
Time to First COPD Exacerbation.	52 weeks	First COPD exacerbations starting between first dose and one day after last treatment are included. Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region.
Time to First Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days	52 weeks	Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.
Forced Expiratory Volume in 1 Second	Baseline, day 1 (30 min and one hour post dose)	Change from baseline. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, region, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.
Change From Baseline in Forced Expiratory Volume in 1 Second AUC (0-12h)	Baseline, 52 weeks	Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 \* visit interaction, and visit, treatment \* visit interaction. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time
Change From Baseline in Total St. George's Respiratory Questionnaire Score	Baseline, 4 weeks	The St. George Respiratory Questionnaire C (SGRQ-C) is a disease-specific measure of health status for use in COPD that was used to provide the health status measurements in this study. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline SGRQ-C total score, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, visit, treatment\visit Interaction, baseline SGRQ-C total score\visit + region. lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. A negative change from baseline indicates improvement.
Change From Baseline in the Number of Puffs of Rescue Medication	Baseline, 52 weeks	A linear mixed model (LMM) was used for this analysis Change from baseline in mean number of puffs. LMM including: treatment, baseline value, smoking status at screening, ICS use at screening, airflow limitation severity, region and random effect of center nested within region.
Change From Baseline in the Safety of QVA149 ((110/50 μg o.d.) vs Fluticasone/Salmeterol (500/50μg Bid) in Terms of HPA Axis Function, as Determined by Collection of 24-hour Urine Cortisol.	Baseline, 52 Weeks	Urine cortisol/creatinine ratio
Change From Baseline in Forced Vital Capacity	4 Weeks, 12 Weeks, 26 Weeks, 38 Weeks, 52 Weeks	Change from baseline in trough value (average of values measured 45 and 15 minutes prior to the morning dose). Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FVC measurements, smoking status at screening, screening inhaled corticosteroid (ICS) use, region, baseline FVC \* visit interaction, and visit, treatment \* visit interaction
Number of Patients With Adverse Events, Serious Adverse Events, and Death	52 weeks of treatment + 30 days	The overall rate of adverse events reported from initiation through 30 days post last dose.
Time to First Moderate to Severe COPD Exacerbations Requiring Hospitalization	52 weeks	Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.

Countries

Argentina, Austria, Belgium, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Guatemala, Hong Kong, Hungary, Iceland, India, Italy, Japan, Latvia, Lithuania, Mexico, Netherlands, Norway, Philippines, Poland, Portugal, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom

Participant flow

Participants by arm

Arm	Count
QVA149 QVA149 (110/50 μg) once daily	1,680
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS) Salmeterol/fluticasone (50/500μg) twice a day	1,682
Total	3,362

Withdrawals & dropouts

Period	Reason	FG000	FG001
Double-blind Treatment	Adverse Event	129	145
Double-blind Treatment	Lack of Efficacy	17	22
Double-blind Treatment	Physician Decision	13	16
Double-blind Treatment	Protocol deviation	8	7
Double-blind Treatment	Subject/guardian decision	111	125
Double-blind Treatment	Technical problems	0	5
Planned Treatment Epoch	Death	29	30
Planned Treatment Epoch	Lost to Follow-up	4	4
Planned Treatment Epoch	Physician Decision	18	16
Planned Treatment Epoch	Protocol deviation	2	3
Planned Treatment Epoch	Subject/guardian decision	149	151
Planned Treatment Epoch	Technical problems	0	4

Baseline characteristics

Characteristic	QVA149	Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Total
Age, Continuous	64.6 Years STANDARD_DEVIATION 7.89	64.5 Years STANDARD_DEVIATION 7.7	64.6 Years STANDARD_DEVIATION 7.79
Sex: Female, Male Female	381 Participants	424 Participants	805 Participants
Sex: Female, Male Male	1299 Participants	1258 Participants	2557 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	1,363 / 1,678	1,424 / 1,680
serious Total, serious adverse events	308 / 1,678	334 / 1,680

Outcome results

Primary

Rate of COPD Exacerbations

COPD exacerbations starting between first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. As the offset variable log(exposure time in years) was used.

Time frame: 52 weeks

Population: The per-protocol set (PPS) included all patients in the FAS without any major protocol deviations. Only PPS patients with non-missing values for all terms in negative binomial model are included.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
QVA149	Rate of COPD Exacerbations	3.59 COPD Exacerbations/year
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Rate of COPD Exacerbations	4.03 COPD Exacerbations/year

95% CI: [0.83, 0.96]Generalized linear model

p-value: 0.00395% CI: [0.83, 0.96]Generalized linear method

Secondary

Change From Baseline in Forced Expiratory Volume in 1 Second AUC (0-12h)

Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, baseline FEV1 \* visit interaction, and visit, treatment \* visit interaction. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time

Time frame: Baseline, 52 weeks

Population: Serial spirometry set - Serial spirometry set includes the patients who performed additional serial spirometry, a subset of FAS. Only patients with non-missing values for all terms in MMRM are included.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in Forced Expiratory Volume in 1 Second AUC (0-12h)	0.078 Liters	Standard Error 0.0174
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Forced Expiratory Volume in 1 Second AUC (0-12h)	-0.032 Liters	Standard Error 0.0176

Secondary

Change From Baseline in Forced Vital Capacity

Change from baseline in trough value (average of values measured 45 and 15 minutes prior to the morning dose). Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FVC was defined as the average of the pre-dose FVC measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FVC measurements, smoking status at screening, screening inhaled corticosteroid (ICS) use, region, baseline FVC \* visit interaction, and visit, treatment \* visit interaction

Time frame: 4 Weeks, 12 Weeks, 26 Weeks, 38 Weeks, 52 Weeks

Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug and had no major GCP violations. Only FAS patients with non-missing values for all terms in MMRM are included

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in Forced Vital Capacity	12 weeks	0.134 Liters	Standard Error 0.0131
QVA149	Change From Baseline in Forced Vital Capacity	38 weeks	0.071 Liters	Standard Error 0.0137
QVA149	Change From Baseline in Forced Vital Capacity	26 weeks	0.088 Liters	Standard Error 0.0135
QVA149	Change From Baseline in Forced Vital Capacity	52 weeks	0.022 Liters	Standard Error 0.0139
QVA149	Change From Baseline in Forced Vital Capacity	4 weeks	0.146 Liters	Standard Error 0.0127
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Forced Vital Capacity	52 weeks	-0.138 Liters	Standard Error 0.014
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Forced Vital Capacity	4 weeks	-0.032 Liters	Standard Error 0.0128
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Forced Vital Capacity	12 weeks	-0.071 Liters	Standard Error 0.0131
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Forced Vital Capacity	26 weeks	-0.121 Liters	Standard Error 0.0136
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Forced Vital Capacity	38 weeks	-0.111 Liters	Standard Error 0.0137

Secondary

Change From Baseline in the Number of Puffs of Rescue Medication

A linear mixed model (LMM) was used for this analysis Change from baseline in mean number of puffs. LMM including: treatment, baseline value, smoking status at screening, ICS use at screening, airflow limitation severity, region and random effect of center nested within region.

Time frame: Baseline, 52 weeks

Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Only FAS patients with non-missing values for all terms in LLM are included.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in the Number of Puffs of Rescue Medication	-1.01 Number of puffs per day	Standard Error 0.097
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in the Number of Puffs of Rescue Medication	-0.76 Number of puffs per day	Standard Error 0.097

Secondary

Change From Baseline in the Safety of QVA149 ((110/50 μg o.d.) vs Fluticasone/Salmeterol (500/50μg Bid) in Terms of HPA Axis Function, as Determined by Collection of 24-hour Urine Cortisol.

Urine cortisol/creatinine ratio

Time frame: Baseline, 52 Weeks

Population: Urine cortisol set is the subset of patients who were measured with 24-hour Urine cortisol, a subset of safety set. The safety set included all patients who received at least one dose of study drug. At the post-baseline timepoint only patients with a value at both baseline and the post-baseline timepoint are included.

Arm	Measure	Value (MEDIAN)	Dispersion
QVA149	Change From Baseline in the Safety of QVA149 ((110/50 μg o.d.) vs Fluticasone/Salmeterol (500/50μg Bid) in Terms of HPA Axis Function, as Determined by Collection of 24-hour Urine Cortisol.	5.615 ng/mL	Full Range 26.633
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in the Safety of QVA149 ((110/50 μg o.d.) vs Fluticasone/Salmeterol (500/50μg Bid) in Terms of HPA Axis Function, as Determined by Collection of 24-hour Urine Cortisol.	-10.390 ng/mL	Full Range 54.428

Secondary

Change From Baseline in Total St. George's Respiratory Questionnaire Score

The St. George Respiratory Questionnaire C (SGRQ-C) is a disease-specific measure of health status for use in COPD that was used to provide the health status measurements in this study. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline SGRQ-C total score, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, visit, treatment\*visit Interaction, baseline SGRQ-C total score\*visit + region. lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status. A negative change from baseline indicates improvement.

Time frame: Baseline, 38 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-3.5 Score on a scale	Standard Error 0.4
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-1.7 Score on a scale	Standard Error 0.4

Secondary

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Time frame: Baseline, 26 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-3.5 Score on a scale	Standard Error 0.39
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-2.3 Score on a scale	Standard Error 0.39

Secondary

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Time frame: Baseline, 12 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-3.2 Score on a scale	Standard Error 0.38
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-1.9 Score on a scale	Standard Error 0.38

Secondary

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Time frame: Baseline, 4 weeks

Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Only FAS patients with non-missing values for all terms in MMRM are included.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-2.3 Score on a scale	Standard Error 0.36
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-2.3 Score on a scale	Standard Error 0.36

Secondary

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Time frame: Baseline, 52 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-3.1 Score on a scale	Standard Error 0.41
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Change From Baseline in Total St. George's Respiratory Questionnaire Score	-1.9 Score on a scale	Standard Error 0.41

Secondary

Forced Expiratory Volume in 1 Second

Change from baseline in trough value. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, region, airflow limitation severity, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.

Time frame: Baseline, 12 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Forced Expiratory Volume in 1 Second	0.070 Liters	Standard Error 0.0072
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Forced Expiratory Volume in 1 Second	-0.008 Liters	Standard Error 0.0072

Secondary

Forced Expiratory Volume in 1 Second

Change from baseline. Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1. A mixed model for repeated measures (MMRM), used for this analysis, included terms of treatment, baseline FEV1 measurements, smoking status at baseline, baseline inhaled corticosteroid (ICS) use, airflow limitation severity, region, visit, treatment-by-visit interaction, and baseline FEV1-by-visit interaction.

Time frame: Baseline, day 1 (30 min and one hour post dose)

Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug and did not have any major GCP violations. Only FAS patients with non-missing values for all terms in MMRM are included.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Forced Expiratory Volume in 1 Second	Day 1, 30 min post-dose (n=1659, 1663)	0.121 Liters	Standard Error 0.0049
QVA149	Forced Expiratory Volume in 1 Second	Day 1, one hour post-dose (n=1657, 1664)	0.147 Liters	Standard Error 0.0054
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Forced Expiratory Volume in 1 Second	Day 1, 30 min post-dose (n=1659, 1663)	0.076 Liters	Standard Error 0.0049
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Forced Expiratory Volume in 1 Second	Day 1, one hour post-dose (n=1657, 1664)	0.092 Liters	Standard Error 0.0054

Secondary

Forced Expiratory Volume in 1 Second

Time frame: Baseline, 4 weeks

Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug and no major GCP violations. Only FAS patients with non-missing values for all terms in MMRM are included.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Forced Expiratory Volume in 1 Second	0.079 Liters	Standard Error 0.007
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Forced Expiratory Volume in 1 Second	0.006 Liters	Standard Error 0.007

Secondary

Forced Expiratory Volume in 1 Second

Time frame: Baseline, 26 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Forced Expiratory Volume in 1 Second	0.049 Liters	Standard Error 0.0073
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Forced Expiratory Volume in 1 Second	-0.037 Liters	Standard Error 0.0074

Secondary

Forced Expiratory Volume in 1 Second

Time frame: Baseline, 38 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Forced Expiratory Volume in 1 Second	0.034 Liters	Standard Error 0.0074
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Forced Expiratory Volume in 1 Second	-0.039 Liters	Standard Error 0.0075

Secondary

Forced Expiratory Volume in 1 Second

Time frame: Baseline, 52 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
QVA149	Forced Expiratory Volume in 1 Second	0.015 Liters	Standard Error 0.0075
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Forced Expiratory Volume in 1 Second	-0.048 Liters	Standard Error 0.0076

Secondary

Number of Patients With Adverse Events, Serious Adverse Events, and Death

The overall rate of adverse events reported from initiation through 30 days post last dose.

Time frame: 52 weeks of treatment + 30 days

Population: The Safety set:all patients that received at least one dose of study medication and had at least one post-baseline safety assessment. Patients were analyzed according to treatment received. The statement that a patient had no AEs also constituted a safety assessment. Only deaths occurring on treatment + 30 days after end of treatment were included

Arm	Measure	Group	Value (NUMBER)
QVA149	Number of Patients With Adverse Events, Serious Adverse Events, and Death	Patients with at least one SAEs	308 Number of participants
QVA149	Number of Patients With Adverse Events, Serious Adverse Events, and Death	Patients with at least one AE	1459 Number of participants
QVA149	Number of Patients With Adverse Events, Serious Adverse Events, and Death	Death	24 Number of participants
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Number of Patients With Adverse Events, Serious Adverse Events, and Death	Patients with at least one SAEs	334 Number of participants
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Number of Patients With Adverse Events, Serious Adverse Events, and Death	Patients with at least one AE	1498 Number of participants
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Number of Patients With Adverse Events, Serious Adverse Events, and Death	Death	24 Number of participants

Secondary

Rate of Moderate to Severe COPD Exacerbations.

COPD exacerbations starting between date of first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event with the worst severity. A COPD exacerbation of moderate severity meets the symptoms definition in the protocol and requires treatment with systemic corticosteroids and/or antibiotics. A severe COPD exacerbation requires hospitalization. Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used.

Time frame: 52 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)
QVA149	Rate of Moderate to Severe COPD Exacerbations.	0.98 COPD Exacerbation/year
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Rate of Moderate to Severe COPD Exacerbations.	1.19 COPD Exacerbation/year

p-value: <0.00195% CI: [0.75, 0.91]Generalized linear model

Secondary

Rate of Moderate to Severe COPD Exacerbations Requiring Hospitalization. COPD Exacerbations Starting Between First Dose and One Day After Last Treatment Are Included.

All exacerbations requiring hospitalization are considered severe according to protocol definitions so this is the rate of severe COPD exacerbations only. Note - an ER visit of longer than 24 hours was considered a hospitalization.

Time frame: 52 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)
QVA149	Rate of Moderate to Severe COPD Exacerbations Requiring Hospitalization. COPD Exacerbations Starting Between First Dose and One Day After Last Treatment Are Included.	0.15 COPD Exacerbation/year
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Rate of Moderate to Severe COPD Exacerbations Requiring Hospitalization. COPD Exacerbations Starting Between First Dose and One Day After Last Treatment Are Included.	0.17 COPD Exacerbation/year

Secondary

Rate of Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days

Re-hospitalizations are defined as hospitalizations starting within the first 30 days after a severe COPD exacerbation and between first dose and one day after date of last treatment. Generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used. COPD exacerbations starting between first dose and one day after last treatment are included.

Time frame: 52 weeks

Arm	Measure	Value (MEAN)	Dispersion
QVA149	Rate of Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days	0.0 COPD Exacerbation/year	Standard Deviation 0.15
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Rate of Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days	0.0 COPD Exacerbation/year	Standard Deviation 0.12

Secondary

Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics

Estimates are from a generalized linear model assuming a negative binomial distribution with terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used. COPD exacerbations starting between first dose and one day after last treatment are included .

Time frame: 52 weeks

Population: The full analysis set (FAS) included all randomized patients who received at least one dose of study drug. Only FAS patients with non-missing values for all terms in negative binomial model are included.

Arm	Measure	Value (LEAST_SQUARES_MEAN)
QVA149	Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics	0.17 COPD Exacerbation/year
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics	0.22 COPD Exacerbation/year

Secondary

Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids

COPD exacerbations starting between date of first dose and one day after last treatment are included. COPD exacerbations that occurred within 7 days of each other are collapsed as one event with the worst severity. Estimates are from a generalized linear model assuming a negative binomial distribution with fixed effects of treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. The offset variable log(exposure time in years) was used.

Time frame: 52 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)
QVA149	Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids	0.18 COPD Exacerbation/year
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids	0.18 COPD Exacerbation/year

Secondary

Time to First COPD Exacerbation.

First COPD exacerbations starting between first dose and one day after last treatment are included. Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region.

Time frame: 52 weeks

Arm	Measure	Value (MEDIAN)
QVA149	Time to First COPD Exacerbation.	71.0 Days
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Time to First COPD Exacerbation.	51.0 Days

p-value: <0.00195% CI: [0.78, 0.91]Regression, Cox

Secondary

Time to First Moderate to Severe COPD Exacerbation.

Time frame: 52 weeks.

Arm	Measure	Value (MEDIAN)
QVA149	Time to First Moderate to Severe COPD Exacerbation.	NA Days
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Time to First Moderate to Severe COPD Exacerbation.	308.0 Days

p-value: <0.00195% CI: [0.7, 0.86]Regression, Cox

Secondary

Time to First Moderate to Severe COPD Exacerbations Requiring Hospitalization

Cox regression model includes terms for treatment, baseline total symptom score, baseline COPD exacerbation history (i.e. number of COPD exacerbations during the past 12 months prior to study), smoking status at screening, ICS use at screening, airflow limitation severity, and region. COPD exacerbations starting between first dose and one day after date of last treatment are included.

Time frame: 52 weeks

Arm	Measure	Value (MEDIAN)
QVA149	Time to First Moderate to Severe COPD Exacerbations Requiring Hospitalization	NA Days
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Time to First Moderate to Severe COPD Exacerbations Requiring Hospitalization	NA Days

p-value: 0.04695% CI: [0.66, 1]Regression, Cox

Secondary

Time to First Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days

Time frame: 52 weeks

Arm	Measure	Value (MEDIAN)
QVA149	Time to First Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days	NA Days
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Time to First Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days	NA Days

p-value: 0.7995% CI: [0.38, 2.1]Regression, Cox

Secondary

Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics

Time frame: 52 weeks

Arm	Measure	Value (MEDIAN)
QVA149	Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics	NA Days
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics	NA Days

p-value: 0.00895% CI: [0.69, 0.95]Regression, Cox

Secondary

Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids

Time frame: 52 weeks

Arm	Measure	Value (MEDIAN)
QVA149	Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids	NA Days
Long Acting B2 Agonist (LABA) and Inhaled Corticosteroid (ICS)	Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids	NA Days

p-value: 0.25695% CI: [0.74, 1.08]Regression, Cox

Source: ClinicalTrials.gov · Data processed: Mar 1, 2026

QVA vs. Salmeterol/Fluticasone, 52-week Exacerbation Study, FLAME (EFfect of Indacaterol Glycopyronium Vs Fluticasone Salmeterol on COPD Exacerbations)

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Rate of COPD Exacerbations

Change From Baseline in Forced Expiratory Volume in 1 Second AUC (0-12h)

Change From Baseline in Forced Vital Capacity

Change From Baseline in the Number of Puffs of Rescue Medication

Change From Baseline in the Safety of QVA149 ((110/50 μg o.d.) vs Fluticasone/Salmeterol (500/50μg Bid) in Terms of HPA Axis Function, as Determined by Collection of 24-hour Urine Cortisol.

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Change From Baseline in Total St. George's Respiratory Questionnaire Score

Forced Expiratory Volume in 1 Second

Forced Expiratory Volume in 1 Second

Forced Expiratory Volume in 1 Second

Forced Expiratory Volume in 1 Second

Forced Expiratory Volume in 1 Second

Forced Expiratory Volume in 1 Second

Number of Patients With Adverse Events, Serious Adverse Events, and Death

Rate of Moderate to Severe COPD Exacerbations.

Rate of Moderate to Severe COPD Exacerbations Requiring Hospitalization. COPD Exacerbations Starting Between First Dose and One Day After Last Treatment Are Included.

Rate of Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days

Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics

Rate of Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids

Time to First COPD Exacerbation.

Time to First Moderate to Severe COPD Exacerbation.

Time to First Moderate to Severe COPD Exacerbations Requiring Hospitalization

Time to First Moderate to Severe COPD Exacerbations Requiring Re-hospitalization Within 30 Days

Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Antibiotics

Time to First Moderate to Severe COPD Exacerbations Requiring Treatment With Systemic Corticosteroids