Chronic Obstructive Pulmonary Disease, COPD
Conditions
Keywords
QVA149, cardiac function, ventricular enddiastolic volume, hyperinflated COPD patients
Brief summary
This mechanistic study is a single-center, randomized, double-blind, placebo-controlled, cross-over study to evaluate the effect of dual bronchodilation with QVA149 on cardiac and lung function parameters in hyperinflated COPD patients.
Interventions
DRUGQVA149
QVA149 capsules 100/50 µg for inhalation via Concept-1-inhaler, taken once daily
DRUGPlacebo
Placebo to QVA140 capsules 100/50 µg for inhalation via Concept-1-inhaler, taken once daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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
* Patients with airflow limitation indicated by a post-bronchodilator FEV1 \<80% of the predicted normal value and a post-bronchodilator FEV1/FVC\<0.7 * Current or ex-smokers who have a smoking history of at least 10 pack years. * Able and willing to give written informed consent * Hyperinflated patients with RVol\>135% predicted
Exclusion criteria
* Patients on LABA or LAMA treatment at Visit 1. * History of one COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization 3 months prior to Visit 2. * More than one COPD exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization within 6 months prior to Visit 2. * Patients who have clinically significant cardiovascular abnormalities, which could interfere with the assessment of the study treatment (such as but not limited to cardiac arrhythmias, heart failure with left ventricular ejection fraction \<40% as determined by MRI scan, unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, history of myocardial infarction 6 months prior to Visit 2) * Patients with a known history or current atrial fibrillation to be confirmed by ECG. * Patients with pacemaker, bypass or stent. * Patients whose QTcF measured at Visit 3 is \>450 ms for males and \>470 ms for females Additional study-specific inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Left Ventricular End-diastolic Volume (LVEDV) | Baseline, week 2 | Left ventricular enddiastolic volume (LVEDV) is a measurement of the volume of blood in the heart's left ventricular chamber at the end of the chamber's filling with blood and will be determined as measured by MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Forced Vital Capacity (FVC). | Baseline, week 2 | Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC will be assessed via spirometry. |
| Change in Inspiratory Capacity (IC) at Each Time-point | Baseline, week 2 | Inspiratory capacity (IC) was defined as the mean of the maximum IC over 3 values measured by bodyplethysmography according to internationally accepted standards. |
| Change in Total Lung Capacity (TLC) | Baseline, week 2 | Total Lung Capacity (TLC) will be calculated from the mean Functional Residual Capacity (FRC) plus the highest value of the Inspiratory Capacity, both measured by body plethymography according to internationally accepted standards. |
| Change in Residual Volume (RVol) | Baseline, week 2 | Residual Volume (RVol) will be calculated from the value of Total Lung Capacity (TLC) minus the highest value of the Slow Vital Capacity, both measured by body plethymography according to internationally accepted standards. |
| Change in Specific Airway Resistance (sRaw) | Baseline, week 2 | Specific Airway Resistance (sRaw) will be documented as effective resistance (sReff) calculated as the median of five acceptable measurements. Values will be measured by body plethymography according to internationally accepted standards. |
| Change in Forced Expiratory Volume in One Second (FEV1). | Baseline, week 2 | Forced Expiratory Volume in one second (FEV1) will be calculated as the volume of air forcibly exhaled in one second as measured by spirometry. |
| Change in Right Ventricular (RV) and Left Ventricular (LV) Ejection Fraction (EF) | Baseline, week 2 | Right and left ventricular ejection fraction is the fraction of blood (in percent) pumped out of the heart's left and right ventricular chamber, respectively, with each heart beat and will be determined as measured by MRI. |
| Change in Left and Right Ventricular End-systolic Volume | Baseline, week 2 | Right ventricular end-systolic volume (RV-ESV) and left ventricular end-systolic volume (LV-ESV) is a measurement of the volume of blood in the heart's right and left ventricular chamber, respectively, at the end of the heart's contraction and will be determined as measured by MRI. |
| Change in Right Ventricular Enddiastolic Volume | Baseline, week 2 | Right ventricular end-diastolic volume is a measurement of the volume of blood in the heart's right ventricular chamber at the end of the chamber's filling with blood and will be determined as measured by MRI. |
| Cardiac Output at Each Time-point, Left and Right Ventricular Cardiac Output (LVCO and RVCO) | week 2 | Cardiac output is calculated as the heart rate multiplied by the stroke volume (= difference between ventricular enddiastolic volume and endsystolic volume) that will be determined as measured by MRI. |
| Change in Functional Residual Capacity (FRC) | Baseline, week 2 | Functional Residual Capacity (FRC) will be calculated as the mean of three reproducible values as measured by body plethymography according to internationally accepted standards. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence 1 QVA149 from day 1 to day 15 followed by Placebo from day 29 to day 43 | 30 |
| Treatment Sequence 2 Placebo from day 1 to day 15 followed by QVA149 from day 29 to day 43 | 32 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 1 |
| Period 1 | COPD exacerbation | 0 | 1 |
| Period 1 | withdrew consent | 0 | 1 |
| Period 2 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Treatment Sequence 2 | Total | Treatment Sequence 1 |
|---|---|---|---|
| Age, Continuous | 63.8 Years STANDARD_DEVIATION 7.8 | 63.9 Years STANDARD_DEVIATION 7.83 | 64.1 Years STANDARD_DEVIATION 8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 62 Participants | 30 Participants |
| Sex: Female, Male Female | 9 Participants | 17 Participants | 8 Participants |
| Sex: Female, Male Male | 23 Participants | 45 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 61 | 0 / 62 |
| other Total, other adverse events | 27 / 59 | 17 / 61 | 40 / 62 |
| serious Total, serious adverse events | 1 / 59 | 2 / 61 | 2 / 62 |
Outcome results
Primary
Change in Left Ventricular End-diastolic Volume (LVEDV)
Left ventricular enddiastolic volume (LVEDV) is a measurement of the volume of blood in the heart's left ventricular chamber at the end of the chamber's filling with blood and will be determined as measured by MRI.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid LV EDV value at both baseline and post-baseline in a period were included
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Left Ventricular End-diastolic Volume (LVEDV) | 11.873 ML | Standard Deviation 14.3215 |
| Placebo | Change in Left Ventricular End-diastolic Volume (LVEDV) | -0.954 ML | Standard Deviation 12.2463 |
p-value: <0.000195% CI: [6.209, 14.331]ANOVA
Secondary
Cardiac Output at Each Time-point, Left and Right Ventricular Cardiac Output (LVCO and RVCO)
Cardiac output is calculated as the heart rate multiplied by the stroke volume (= difference between ventricular enddiastolic volume and endsystolic volume) that will be determined as measured by MRI.
Time frame: week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Cardiac Output at Each Time-point, Left and Right Ventricular Cardiac Output (LVCO and RVCO) | LVCO | 0.504 Liter/min | Standard Deviation 0.7919 |
| QVA149 | Cardiac Output at Each Time-point, Left and Right Ventricular Cardiac Output (LVCO and RVCO) | RVCO | 0.517 Liter/min | Standard Deviation 0.8063 |
| Placebo | Cardiac Output at Each Time-point, Left and Right Ventricular Cardiac Output (LVCO and RVCO) | RVCO | 0.144 Liter/min | Standard Deviation 0.9523 |
| Placebo | Cardiac Output at Each Time-point, Left and Right Ventricular Cardiac Output (LVCO and RVCO) | LVCO | 0.119 Liter/min | Standard Deviation 0.897 |
Comparison: LVCOp-value: 0.003295% CI: [0.118, 0.555]ANOVA
Comparison: RVCOp-value: 0.018295% CI: [0.05, 0.512]ANOVA
Secondary
Change in Forced Expiratory Volume in One Second (FEV1).
Forced Expiratory Volume in one second (FEV1) will be calculated as the volume of air forcibly exhaled in one second as measured by spirometry.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Forced Expiratory Volume in One Second (FEV1). | 0.42 Liter | Standard Deviation 0.211 |
| Placebo | Change in Forced Expiratory Volume in One Second (FEV1). | -0.01 Liter | Standard Deviation 0.168 |
p-value: <0.000195% CI: [0.36, 0.49]ANOVA
Secondary
Change in Forced Vital Capacity (FVC).
Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC will be assessed via spirometry.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Forced Vital Capacity (FVC). | 0.67 Liter | Standard Deviation 0.434 |
| Placebo | Change in Forced Vital Capacity (FVC). | 0.00 Liter | Standard Deviation 0.293 |
p-value: <0.000195% CI: [0.55, 0.8]ANOVA
Secondary
Change in Functional Residual Capacity (FRC)
Functional Residual Capacity (FRC) will be calculated as the mean of three reproducible values as measured by body plethymography according to internationally accepted standards.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Functional Residual Capacity (FRC) | -0.656 Liters | Standard Deviation 0.4602 |
| Placebo | Change in Functional Residual Capacity (FRC) | -0.015 Liters | Standard Deviation 0.4257 |
p-value: <0.000195% CI: [-0.761, -0.489]ANOVA
Secondary
Change in Inspiratory Capacity (IC) at Each Time-point
Inspiratory capacity (IC) was defined as the mean of the maximum IC over 3 values measured by bodyplethysmography according to internationally accepted standards.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Inspiratory Capacity (IC) at Each Time-point | 0.475 Liters | Standard Deviation 0.3284 |
| Placebo | Change in Inspiratory Capacity (IC) at Each Time-point | 0.014 Liters | Standard Deviation 0.2388 |
p-value: <0.000195% CI: [0.352, 0.541]ANOVA
Secondary
Change in Left and Right Ventricular End-systolic Volume
Right ventricular end-systolic volume (RV-ESV) and left ventricular end-systolic volume (LV-ESV) is a measurement of the volume of blood in the heart's right and left ventricular chamber, respectively, at the end of the heart's contraction and will be determined as measured by MRI.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Change in Left and Right Ventricular End-systolic Volume | LV-ESV | 1.898 ML | Standard Deviation 8.4565 |
| QVA149 | Change in Left and Right Ventricular End-systolic Volume | RV-ESV | 2.183 ML | Standard Deviation 8.7063 |
| Placebo | Change in Left and Right Ventricular End-systolic Volume | LV-ESV | -2.283 ML | Standard Deviation 8.1489 |
| Placebo | Change in Left and Right Ventricular End-systolic Volume | RV-ESV | 0.133 ML | Standard Deviation 9.337 |
Comparison: LV ESVp-value: 0.043795% CI: [0.066, 4.417]ANOVA
Comparison: RV ESVp-value: 0.123695% CI: [-0.591, 4.782]ANOVA
Secondary
Change in Residual Volume (RVol)
Residual Volume (RVol) will be calculated from the value of Total Lung Capacity (TLC) minus the highest value of the Slow Vital Capacity, both measured by body plethymography according to internationally accepted standards.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Residual Volume (RVol) | -0.757 Liters | Standard Deviation 0.5833 |
| Placebo | Change in Residual Volume (RVol) | 0.012 Liters | Standard Deviation 0.5141 |
p-value: <0.000195% CI: [-0.925, -0.577]ANOVA
Secondary
Change in Right Ventricular Enddiastolic Volume
Right ventricular end-diastolic volume is a measurement of the volume of blood in the heart's right ventricular chamber at the end of the chamber's filling with blood and will be determined as measured by MRI.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Right Ventricular Enddiastolic Volume | 12.323 ML | Standard Deviation 13.9683 |
| Placebo | Change in Right Ventricular Enddiastolic Volume | 1.758 ML | Standard Deviation 14.7904 |
p-value: 0.000295% CI: [4.649, 14.065]ANOVA
Secondary
Change in Right Ventricular (RV) and Left Ventricular (LV) Ejection Fraction (EF)
Right and left ventricular ejection fraction is the fraction of blood (in percent) pumped out of the heart's left and right ventricular chamber, respectively, with each heart beat and will be determined as measured by MRI.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QVA149 | Change in Right Ventricular (RV) and Left Ventricular (LV) Ejection Fraction (EF) | LV-EF | 1.893 Percentage | Standard Deviation 5.8486 |
| QVA149 | Change in Right Ventricular (RV) and Left Ventricular (LV) Ejection Fraction (EF) | RV-EF | 2.046 Percentage | Standard Deviation 5.8746 |
| Placebo | Change in Right Ventricular (RV) and Left Ventricular (LV) Ejection Fraction (EF) | LV-EF | 1.313 Percentage | Standard Deviation 5.4261 |
| Placebo | Change in Right Ventricular (RV) and Left Ventricular (LV) Ejection Fraction (EF) | RV-EF | 0.361 Percentage | Standard Deviation 6.1936 |
Comparison: LV EFp-value: 0.14295% CI: [-0.419, 2.836]ANOVA
Comparison: RV EFp-value: 0.173295% CI: [-0.512, 2.774]ANOVA
Secondary
Change in Specific Airway Resistance (sRaw)
Specific Airway Resistance (sRaw) will be documented as effective resistance (sReff) calculated as the median of five acceptable measurements. Values will be measured by body plethymography according to internationally accepted standards.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Specific Airway Resistance (sRaw) | -1.887 kPa*s/L | Standard Deviation 1.0979 |
| Placebo | Change in Specific Airway Resistance (sRaw) | 0.037 kPa*s/L | Standard Deviation 1.0383 |
p-value: <0.000195% CI: [-1.945, -1.332]ANOVA
Secondary
Change in Total Lung Capacity (TLC)
Total Lung Capacity (TLC) will be calculated from the mean Functional Residual Capacity (FRC) plus the highest value of the Inspiratory Capacity, both measured by body plethymography according to internationally accepted standards.
Time frame: Baseline, week 2
Population: Per protocol set (PPS) included all patients in the FAS who did not have any major protocol deviations. Only patients with a valid value for parameter at both baseline and post-baseline in a period are included - Period baseline was defined as the value taken in each period prior to start of study treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QVA149 | Change in Total Lung Capacity (TLC) | -0.181 Liters | Standard Deviation 0.3408 |
| Placebo | Change in Total Lung Capacity (TLC) | -0.001 Liters | Standard Deviation 0.3618 |
p-value: 0.001795% CI: [-0.285, -0.07]ANOVA