Asthma
Conditions
Brief summary
The purpose of the study was to assess the clinical effect of QAW039 in non-atopic asthmatics taking low dose Inhaled Corticosteroid (ICS) as background therapy.
Detailed description
This was a multi-centre, randomised, placebo-controlled, double blind, 3-arm study designed to compare the efficacy and safety of a once daily dose of QAW039 with placebo in non-atopic and atopic asthmatics both inadequately controlled despite receiving a low dose ICS background therapy, over a 12 week treatment period. Efficacy and safety of a once daily dose of QAW039 was also compared with an increased dose of ICS in atopic asthmatics taking low dose ICS as background therapy.
Interventions
DRUGQAW039
QAW039 supplied as hard gelatin capsule in unit dose strength of 150 mg. Patient took 450 mg once daily (3 capsules taken with food in the morning) for the approximate period of the study (12 weeks)
DRUGPlacebo QAW039
Matching placebo for QAW039 supplied as hard gelatin capsule were identical in appearance to their active counterparts. Patients took 3 QAW039 matching placebo capsules once a day ( taken with food in the morning) for the approximate period of the study (12 weeks)
DRUGFluticasone 250 mcg
Fluticasone was supplied in inhalers with dose strength of 250 mcg. Patients took 250 mcg bid (morning and evening approximately 12 hours between doses) for a total dose of 500 mcg daily for the approximate period of the study (12 weeks).
DRUGFluticasone 100 mcg
Background therapy - fluticasone was supplied in inhalers with dose strength of 100 mcg. All patients in the study other than the Atopic Fluticasone 150 mcg arm were given the 100 mcg dose strength inhalers and took fluticasone 100 mcg bid (taken morning and evening with approximately 12 hours between doses) as background therapy for the approximate period of the study (12 weeks).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed * Patients with a diagnosis of persistent asthma (according to Global Initiative for Asthma 2011) for a period of at least 6 months prior to screening * Patients with a pre-bronchodilator Forced Expiratory Volume In One Second (FEV1) value of 40% to 80% of individual predicted value at screening and prior to treatment * An Asthma Control Questionnaire score ≥ 1.5 prior to treatment * Demonstration of reversible airway obstruction
Exclusion criteria
* Pregnant or nursing (lactating) women * Acute illness other than asthma at the start of the study * Patients with clinically significant laboratory abnormalities at screening * Patients with clinically significant condition which may compromise subject safety or interfere with study evaluation * Use of other investigational drugs at the time of enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough FEV1 (L) in Non-atopic Patients at Week 12 - Full Analysis Set | baseline,12 weeks | Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the last available FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set | baseline,12 weeks | Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug. |
| Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | baseline,12 weeks | Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population, treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug. |
| Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set | baseline,12 weeks | ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled.' Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects. |
| Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | baseline,12 weeks | ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled.' Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects. |
Countries
Belgium, Colombia, Czechia, Germany, India, Poland, Romania, South Africa, South Korea, United States
Participant flow
Pre-assignment details
Total of 939 subjects were screened, 679 entered the inhaled corticosteroid (ICS) tapering run-in, 345 subjects were randomized; eleven randomized subjects discontinued the study prior to start of study drug. Patient disposition and baseline characteristics were presented for 334 subjects (received study drug)
Participants by arm
| Arm | Count |
|---|---|
| QAW039 450 mg qd Non-atopic QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo. | 93 |
| Placebo Non-atopic Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Non-atopic patients randomized in ratio of approximately 1:1 to QAW039 or placebo. | 94 |
| QAW039 450 mg qd Atopic QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo. | 51 |
| Fluticasone 150 µg Bid Atopic Fluticasone 150 µg plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo. | 42 |
| Placebo Atopic Placebo to QAW039 450 mg qd plus background ICS (100 μg fluticasone, bid). Atopic patients randomized in ratio of approximately 1:1:1 to QAW039 or fluticasone or placebo. | 54 |
| Total | 334 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 3 | 1 | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Non compliance with tx | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Pregnancy | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 4 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | QAW039 450 mg qd Non-atopic | Total | Placebo Atopic | Fluticasone 150 µg Bid Atopic | QAW039 450 mg qd Atopic | Placebo Non-atopic |
|---|---|---|---|---|---|---|
| ACQ-6 score | 1.70 points STANDARD_DEVIATION 0.762 | 1.63 points STANDARD_DEVIATION 0.728 | 1.72 points STANDARD_DEVIATION 0.675 | 1.68 points STANDARD_DEVIATION 0.749 | 1.55 points STANDARD_DEVIATION 0.665 | 1.53 points STANDARD_DEVIATION 0.745 |
| Age, Continuous | 51.9 years STANDARD_DEVIATION 14.33 | 51.0 years STANDARD_DEVIATION 13.81 | 48.2 years STANDARD_DEVIATION 13.58 | 48.2 years STANDARD_DEVIATION 12.16 | 50.3 years STANDARD_DEVIATION 12.75 | 53.5 years STANDARD_DEVIATION 14.37 |
| Duration of asthma | 14.88 years STANDARD_DEVIATION 12.349 | 18.91 years STANDARD_DEVIATION 15.648 | 24.09 years STANDARD_DEVIATION 16.055 | 27.78 years STANDARD_DEVIATION 18.039 | 24.69 years STANDARD_DEVIATION 17.446 | 12.82 years STANDARD_DEVIATION 12.196 |
| Percentage of predicted FEV1 (%) pre-bronchodilator | 67.5446 Percentage STANDARD_DEVIATION 11.81404 | 66.9849 Percentage STANDARD_DEVIATION 12.56166 | 64.8709 Percentage STANDARD_DEVIATION 12.97729 | 68.7483 Percentage STANDARD_DEVIATION 10.52156 | 69.0662 Percentage STANDARD_DEVIATION 12.16292 | 65.7286 Percentage STANDARD_DEVIATION 13.94056 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 13 participants | 2 participants | 3 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 15 participants | 44 participants | 3 participants | 6 participants | 4 participants | 16 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants | 22 participants | 4 participants | 3 participants | 3 participants | 6 participants |
| Race/Ethnicity, Customized More than one race | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants | 6 participants | 1 participants | 1 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 68 participants | 248 participants | 43 participants | 29 participants | 40 participants | 68 participants |
| Sex: Female, Male Female | 60 Participants | 194 Participants | 25 Participants | 23 Participants | 26 Participants | 60 Participants |
| Sex: Female, Male Male | 33 Participants | 140 Participants | 29 Participants | 19 Participants | 25 Participants | 34 Participants |
| Subject population Atopic | 0 Participants | 147 Participants | 54 Participants | 42 Participants | 51 Participants | 0 Participants |
| Subject population Non-atopic | 93 Participants | 187 Participants | 0 Participants | 0 Participants | 0 Participants | 94 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 36 / 145 | 19 / 42 | 35 / 147 |
| serious Total, serious adverse events | 2 / 145 | 0 / 42 | 3 / 147 |
Outcome results
Primary
Change From Baseline in Trough FEV1 (L) in Non-atopic Patients at Week 12 - Full Analysis Set
Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the last available FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug.
Time frame: baseline,12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QAW039 450 mg qd Non-atopic | Change From Baseline in Trough FEV1 (L) in Non-atopic Patients at Week 12 - Full Analysis Set | 0.05 liter | Standard Error 0.029 |
| Placebo Non-atopic | Change From Baseline in Trough FEV1 (L) in Non-atopic Patients at Week 12 - Full Analysis Set | 0.03 liter | Standard Error 0.029 |
p-value: 0.726990% CI: [-0.5, 0.08]Mixed Models Analysis
Secondary
Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set
ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled.' Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects.
Time frame: baseline,12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QAW039 450 mg qd Non-atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set | -0.05 score | Standard Error 0.077 |
| Placebo Non-atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set | -0.03 score | Standard Error 0.073 |
| Placebo Atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set | -0.25 score | Standard Error 0.096 |
| Fluticasone 150 µg Bid Atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set | -0.35 score | Standard Error 0.104 |
| Placebo Atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic and Atopic Patients at Week 12 - Full Analysis Set | -0.18 score | Standard Error 0.096 |
95% CI: [-0.22, 0.17]
95% CI: [-0.32, 0.19]
95% CI: [-0.16, 0.37]
95% CI: [-0.43, 0.09]
Secondary
Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set
ACQ-6 consists of:5 items on symptoms, 1 item on rescue bronchodilator use, and 1 item on airway caliber (FEV1 % predicted). The ACQ was fully validated, including a minimal important difference (MID) or smallest change that could be considered clinically important (0.5). The ACQ was self-administered at the clinic and patients scored each item on a 7-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled.' Study staff scored question 7 based on % predicted FEV1 (ideally pre-bronchodilator). The total score=average of first 6 questions. Baseline=the ACQ-6 measurement taken prior to first dose of randomized study drug. The single missing score was interpolated by utilizing prior or subsequent completions of the questionnaire. Estimates were from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline ACQ-6 and region as fixed effects and center nested within region as random effects.
Time frame: baseline,12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QAW039 450 mg qd Non-atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | -0.05 score | Standard Error 0.077 |
| Placebo Non-atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | -0.03 score | Standard Error 0.073 |
| Placebo Atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | -0.25 score | Standard Error 0.096 |
| Fluticasone 150 µg Bid Atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | -0.35 score | Standard Error 0.104 |
| Placebo Atopic | Change From Baseline in ACQ-6 Score at Week 12 Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | -0.18 score | Standard Error 0.096 |
p-value: 0.793Mixed Models Analysis
Secondary
Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set
Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population (non-atopic vs. atopic), treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug.
Time frame: baseline,12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QAW039 450 mg qd Non-atopic | Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set | 0.06 liter | Standard Error 0.038 |
| Placebo Non-atopic | Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set | 0.01 liter | Standard Error 0.042 |
| Placebo Atopic | Change From Baseline in Trough FEV1 (L) in Atopic Patients at Week 12 - Full Analysis Set | 0.05 liter | Standard Error 0.037 |
90% CI: [-0.08, 0.09]
90% CI: [-0.04, 0.13]
90% CI: [-0.13, 0.05]
Secondary
Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set
Forced Expiratory Volume in one second (FEV1) is calculated as the volume of air forcibly exhaled in one second as measured by a spirometer. Baseline is defined as the FEV1 measurement taken prior to the first dose of randomized study drug. Data within 6 hr of rescue medication use is excluded from this analysis. For subjects with missing trough FEV1 (L) at Week 12, the last post baseline observation were used (LOCF). Estimates are from a mixed effects model with treatment, subject population, treatment by subject population interaction, baseline trough FEV1 and region as fixed effects and center nested within region as random effects. Full analysis set included all randomized subjects who received at least one dose of study drug.
Time frame: baseline,12 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QAW039 450 mg qd Non-atopic | Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | 0.05 liter | Standard Error 0.029 |
| Placebo Non-atopic | Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | 0.03 liter | Standard Error 0.029 |
| Placebo Atopic | Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | 0.06 liter | Standard Error 0.038 |
| Fluticasone 150 µg Bid Atopic | Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | 0.01 liter | Standard Error 0.042 |
| Placebo Atopic | Change From Baseline in Trough FEV1 (L) in Non-atopic Compared to Atopic Patients at Week 12 - Full Analysis Set | 0.05 liter | Standard Error 0.037 |
p-value: 0.9179Mixed Models Analysis