Asthma
Conditions
Keywords
Asthma, Interleukin, QBX258, QAX576, VAK694
Brief summary
This study is designed to investigate the efficacy and safety of QBX258 in subjects with moderate to severe asthma.
Interventions
DRUGQBX258
QBX258 infusion, a combination of VAK694 and QAX576, was supplied to the Investigator as open label bulk medication. The planned dose of VAK694 (lyophilisate in vial, 150 mg/vial), was 3 mg/kg. The planned dose of QAX576 (lyophilisate in vial, 150 mg/vial), was 6 mg/kg.
DRUGPlacebo
The placebo infusion was an equal volume of 5% dextrose for infusion and was provided by the clinical site.
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Patients with atopic asthma \>1 year duration diagnosed according to the GINA guidelines. * Subjects must weigh at least 50 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 39 kg/m2. * Asthma which is not adequately controlled on current treatment, as demonstrated by an Asthma Control Questionnaire (ACQ) score of \> 1.5. * FEV1 40 to 90% of predicted.
Exclusion criteria
* Diagnosed with COPD as defined by the GOLD guidelines * Subjects who have had a respiratory tract infection within 4 weeks prior to screening. * Women of child-bearing potential must use highly effective methods of contraception during dosing and for at least 18 weeks after last study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Asthma Control Questionnaire (ACQ) Score | Baseline and 12 weeks | The ACQ consists of 7 questions assessing symptoms, rescue medication use and lung function. Except for lung function (FEV1), each question was scored on a 7-point scale where 0 = no impairment and 6 = maximum impairment. Scores ranged between 0 totally controlled to 6 (severely uncontrolled). Participants with a score below 1.0 are considered to have adequately controlled asthma. Participants with a score above 1.0 were considered not to be well controlled. A negative change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Asthma Quality of Life Questionnaire (AQLQ) Score | Baseline and 12 weeks | The AQLQ is a 32-item disease specific questionnaire designed to measure functional impairments that are most important to patients with asthma. It consists of 4 domains: symptoms, emotions., exposure to environmental stimuli and activity limitation. Patients were asked to recall their experiences during the previous 2 weeks and to score each item on a 7-point scale. The scale ranges from 1 to 7. The overall AQLQ score was the mean response to all 32 questions. Higher scores represent better outcomes. |
| Morning and Evening Peak Expiratory Flow (PEF) Rate | Baseline and 12 weeks | Morning and evening PEFs were recorded on an electronic diary (e-diary). PEF was assessed twice daily approximately 12 hours apart and the measurements were recorded in the e-diary. |
| Change From Baseline in Maximum Expiratory Flow | Baseline and 12 weeks | Maximum expiratory flow was assessed using central spirometry according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. |
| Number of Participants With Anti-QAX576 Antibodies or Anti-VAK694 Antibodies | 12 weeks | Anti-QAX576 and anti-VAK694 antibodies in serum were analyzed. |
| Change in Forced Expiratory Volume in One Second (FEV1) | Baseline and 12 weeks | FEV1 was assessed using central spirometry according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. |
| Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the VAK694 Analyte | days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183 | Blood samples were obtained to measure Cmax,ss. |
| Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the QAX576 Analyte | days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183 | Blood samples were obtained to measure Cmin,ss. |
| Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the VAK694 Analyte | days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183 | Blood samples were obtained to measure Cmin,ss. |
| Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) | baseline, 12 weeks | FeNO was assessed as a measure of airway inflammation. An FeNO machine was used to obtain the FeNO measurements. FeNO measurements were obtained prior to the spirometry assessments. |
| Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the QAX576 Analyte | days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183 | Blood samples were obtained to measure Cmax,ss. |
Countries
Germany, United Kingdom, United States
Participant flow
Recruitment details
Participants were assigned to either QBX258 or placebo in a 2:1 ratio. Randomization was done by stratification of Q576R.
Participants by arm
| Arm | Count |
|---|---|
| QBX258 Participants received QBX258 intravenous (iv) infusion every 4 weeks for up to 4 doses total. | 44 |
| Placebo Participants received placebo to QBX258 iv infusion every 4 weeks for up to 4 doses total. | 21 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Protocol deviation | 0 | 1 |
Baseline characteristics
| Characteristic | QBX258 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 42.5 Years STANDARD_DEVIATION 11.71 | 42.8 Years STANDARD_DEVIATION 13.54 | 42.6 Years STANDARD_DEVIATION 12.22 |
| Sex: Female, Male Female | 23 Participants | 11 Participants | 34 Participants |
| Sex: Female, Male Male | 21 Participants | 10 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 44 | 7 / 21 |
| serious Total, serious adverse events | 1 / 44 | 1 / 21 |
Outcome results
Primary
Change From Baseline in Asthma Control Questionnaire (ACQ) Score
The ACQ consists of 7 questions assessing symptoms, rescue medication use and lung function. Except for lung function (FEV1), each question was scored on a 7-point scale where 0 = no impairment and 6 = maximum impairment. Scores ranged between 0 totally controlled to 6 (severely uncontrolled). Participants with a score below 1.0 are considered to have adequately controlled asthma. Participants with a score above 1.0 were considered not to be well controlled. A negative change from baseline indicates improvement.
Time frame: Baseline and 12 weeks
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had both baseline and week 12 values were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBX258 | Change From Baseline in Asthma Control Questionnaire (ACQ) Score | -0.513 score on a scale | Standard Error 0.097 |
| Placebo | Change From Baseline in Asthma Control Questionnaire (ACQ) Score | 0.001 score on a scale | Standard Error 0.1487 |
p-value: 0.00590% CI: [-0.811, -0.217]Mixed Models Analysis
Secondary
Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO)
FeNO was assessed as a measure of airway inflammation. An FeNO machine was used to obtain the FeNO measurements. FeNO measurements were obtained prior to the spirometry assessments.
Time frame: baseline, 12 weeks
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had both baseline and week 12 values were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBX258 | Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) | -3.67 parts per billion (ppb) | Standard Error 3.58 |
| Placebo | Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) | 2.21 parts per billion (ppb) | Standard Error 5.393 |
Secondary
Change From Baseline in Maximum Expiratory Flow
Maximum expiratory flow was assessed using central spirometry according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines.
Time frame: Baseline and 12 weeks
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had both baseline and week 12 values were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| QBX258 | Change From Baseline in Maximum Expiratory Flow | 0.099 L/sec | Standard Deviation 0.427 |
| Placebo | Change From Baseline in Maximum Expiratory Flow | 0.025 L/sec | Standard Deviation 0.3 |
Secondary
Change in Asthma Quality of Life Questionnaire (AQLQ) Score
The AQLQ is a 32-item disease specific questionnaire designed to measure functional impairments that are most important to patients with asthma. It consists of 4 domains: symptoms, emotions., exposure to environmental stimuli and activity limitation. Patients were asked to recall their experiences during the previous 2 weeks and to score each item on a 7-point scale. The scale ranges from 1 to 7. The overall AQLQ score was the mean response to all 32 questions. Higher scores represent better outcomes.
Time frame: Baseline and 12 weeks
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had both baseline and week 12 values were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBX258 | Change in Asthma Quality of Life Questionnaire (AQLQ) Score | 0.580 score on a scale | Standard Error 0.1294 |
| Placebo | Change in Asthma Quality of Life Questionnaire (AQLQ) Score | 0.468 score on a scale | Standard Error 0.1878 |
Secondary
Change in Forced Expiratory Volume in One Second (FEV1)
FEV1 was assessed using central spirometry according to the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines.
Time frame: Baseline and 12 weeks
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had both baseline and week 12 values were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QBX258 | Change in Forced Expiratory Volume in One Second (FEV1) | 0.076 Liters | Standard Error 0.0528 |
| Placebo | Change in Forced Expiratory Volume in One Second (FEV1) | 0.050 Liters | Standard Error 0.077 |
Secondary
Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the QAX576 Analyte
Blood samples were obtained to measure Cmin,ss.
Time frame: days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had week 12 values were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBX258 | Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the QAX576 Analyte | Q576R SNP stratum: QQ (n=21) | 37500 ng/mL | Standard Deviation 11900 |
| QBX258 | Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the QAX576 Analyte | Q576R SNP stratum: RR/QR (n=19) | 32200 ng/mL | Standard Deviation 9930 |
| QBX258 | Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the QAX576 Analyte | QBX258 (n=40) | 35000 ng/mL | Standard Deviation 11200 |
Secondary
Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the VAK694 Analyte
Blood samples were obtained to measure Cmin,ss.
Time frame: days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had week 12 values were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBX258 | Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the VAK694 Analyte | Q576R SNP stratum: QQ (n=21) | 10.7 ug/mL | Standard Deviation 2.69 |
| QBX258 | Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the VAK694 Analyte | Q576R SNP stratum: RR/QR (n=19) | 9.83 ug/mL | Standard Deviation 2.94 |
| QBX258 | Lowest Plasma Concentration Observed During a Dosing Interval at Steady State (Cmin,ss) of the VAK694 Analyte | QBX258 (n=40) | 10.3 ug/mL | Standard Deviation 2.81 |
Secondary
Morning and Evening Peak Expiratory Flow (PEF) Rate
Morning and evening PEFs were recorded on an electronic diary (e-diary). PEF was assessed twice daily approximately 12 hours apart and the measurements were recorded in the e-diary.
Time frame: Baseline and 12 weeks
Population: No analysis was performed on the collected data with the eDiary device due to overall poor data quality (values were obtained that were not physiologically possible) and high variability. Therefore, there is no data to present for this outcome measure.
Secondary
Number of Participants With Anti-QAX576 Antibodies or Anti-VAK694 Antibodies
Anti-QAX576 and anti-VAK694 antibodies in serum were analyzed.
Time frame: 12 weeks
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| QBX258 | Number of Participants With Anti-QAX576 Antibodies or Anti-VAK694 Antibodies | 2 Participants |
| Placebo | Number of Participants With Anti-QAX576 Antibodies or Anti-VAK694 Antibodies | 2 Participants |
Secondary
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the QAX576 Analyte
Blood samples were obtained to measure Cmax,ss.
Time frame: days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had week 12 values were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBX258 | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the QAX576 Analyte | Q576R SNP stratum: QQ (n=21) | 169000 ng/mL | Standard Deviation 47000 |
| QBX258 | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the QAX576 Analyte | Q576R SNP stratum: RR/QR (n=19) | 184000 ng/mL | Standard Deviation 85000 |
| QBX258 | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the QAX576 Analyte | QBX258 (n=40) | 176000 ng/mL | Standard Deviation 67300 |
Secondary
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the VAK694 Analyte
Blood samples were obtained to measure Cmax,ss.
Time frame: days 1 (pre-dose and 2 hours post-dose), 15, 29 (pre-dose and 2 hours post-dose), 43, 57 (pre-dose and 2 hours post-dose), 71, 85 (pre-dose and 2 hours post-dose), 99, 113, 141, 183
Population: Participants from the per-protocol analysis set were considered for the analysis. Only participants who had week 12 values were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QBX258 | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the VAK694 Analyte | Q576R SNP stratum: QQ (n=21) | 56.7 ug/mL | Standard Deviation 8.9 |
| QBX258 | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the VAK694 Analyte | Q576R SNP stratum: RR/QR (n=19) | 58.6 ug/mL | Standard Deviation 14.9 |
| QBX258 | Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of the VAK694 Analyte | QBX258 (n=40) | 57.6 ug/mL | Standard Deviation 12 |