Asthma
Conditions
Keywords
QVM149,, asthma,, allergic asthma,, allergy triggered asthma,, reactive asthma,, asthma attack,, difficulty breathing
Brief summary
This was a randomized, placebo-controlled, double-blind, six-sequence, three-period cross-over study in asthma patients. The study consisted of a 14-day screening period, followed by a 14-day run-in period, and a treatment epoch which consists of three treatment periods, with a minimum duration of 14 days each followed (for the 2 first treatment periods) by a wash-out period. The duration of each treatment period may be extended up to a duration of 18 days if needed for operational reasons. The third treatment period was followed by a Study Completion evaluation at 1-7 days following the last dose. The treatment periods were separated by wash-out periods of 14 to 21 days duration.
Interventions
DRUGTreatment A: Matching placebo (morning dose) and QVM149 150/50/80 μg (evening dose)
Matching placebo (morning dose) and QVM149 150/50/80 μg (evening dose)
DRUGTreatment B: QVM149 150/50/80 μg (morning dose) and matching placebo (evening dose)
QVM149 150/50/80 μg (morning dose) and matching placebo (evening dose)
DRUGTreatment C: Placebo (morning dose) and placebo (evening dose)
Placebo (morning dose) and placebo (evening dose)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind masking.
Intervention model description
This study is to assess the bronchodilator effects of QVM149 dosed once daily either in the morning or in the evening for 2 weeks compared to placebo. It will provide evidence of the comparability of lung function effects of QVM149 irrespective of the administration schedule
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients with a documented physician diagnosis of asthma and who additionally meet the following criteria: * Patients receiving daily treatment with an inhaled corticosteroid at a low or medium daily dose * On a stable regimen for at least 4 weeks prior to screening. * Pre-bronchodilator FEV1 ≥ 60 % and \< 100% of the predicted normal value for the patient during screening. * Patients who demonstrate an increase in FEV1 of ≥ 12 % and ≥ 200 mL after administration of 400 μg salbutamol/360 μg albuterol (or equivalent dose) at Screening. All patients must perform a reversibility test at Screening. * At screening, and baseline (day 1 pre-dose time) of the first treatment period, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position and again in the standing position as outlined in the SOM. Sitting and standing vital signs should be within the following ranges: * oral body temperature between 35.0-37.5 °C * systolic blood pressure, 90-159 mmHg * diastolic blood pressure, 50-99 mmHg * pulse rate, 40-90 bpm * Hypertensive patients must have been on stable antihypertensive therapy for at least 4 weeks prior to screening to be included in the trial. * Patients must weigh at least 50 kg at screening to participate in the study, and must have a body mass index (BMI) within the range of 18 to 40 kg/m2.
Exclusion criteria
* Contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any of the drugs of a similar class * Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 1 year of Screening. * Patients who have had previous intubation for a severe asthma ttack/exacerbation. * Patients with a history of clinically relevant bronchoconstriction upon repeated forced expiratory maneuvers. * History of paradoxical bronchospasm in response to inhaled medicines. * Patients who during the run-in period prior to randomization require the use of ≥12 puffs / 24 hours of rescue medication for 48 hours (over two consecutive days) or who have a decline in PEF from the reference PEFof ≥ 30% for 6 consecutive scheduled PEF readings * Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| FEV1 Standardized Area Under the Curve (AUC 0-24h) After Last Evening Dose of 14-day Treatment Period | At the end of each treatment period day 14 pre-dose to 24 hours post-dose. | Weighted mean forced expiratory volume in 1 second (FEV1) over 24 h (AUC0-24h) following 14 days of treatment with QVM149 dosed in the morning, QVM149 dosed in the evening and placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough FEV1 After 24h | At the end of each treatment period day 14 pre-dose to 24 hours post-dose. | FEV1 at approximately 24 h after the last p.m. or penultimate a.m. dose. Morning and evening trough FEV1 (L) were analyzed by time of day. For morning trough FEV1 (L) assessments this meant that the spirometric assessment was done approximately 24 h after last morning dose and approximately 12 h after last evening dose. |
| Peak Expiratory Flow (PEF) | From treatment period start through study completion (up to 19 weeks). | Peak expiratory flow (PEF) is the maximum flow generated during a forceful exhalation, starting from full lung inflationDaily morning and evening peak expiratory flow rate from Day 2 to Day14 during the three treatment periods. |
Countries
Germany, Netherlands, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants randomized to one of six treatment sequences | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 | Subject/Guardian Decision | 0 | 0 | 0 | 2 | 0 | 0 |
| Period 3 | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 43.5 Years STANDARD_DEVIATION 14.04 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 35 Participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 | 0 / 36 |
| other Total, other adverse events | 11 / 35 | 13 / 35 | 16 / 36 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 | 0 / 36 |
Outcome results
Primary
FEV1 Standardized Area Under the Curve (AUC 0-24h) After Last Evening Dose of 14-day Treatment Period
Weighted mean forced expiratory volume in 1 second (FEV1) over 24 h (AUC0-24h) following 14 days of treatment with QVM149 dosed in the morning, QVM149 dosed in the evening and placebo.
Time frame: At the end of each treatment period day 14 pre-dose to 24 hours post-dose.
Population: The pharmacodynamic (PD) analysis set included all patients with any available PD data, who received any dose of study drug and experienced no protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVM149 am | FEV1 Standardized Area Under the Curve (AUC 0-24h) After Last Evening Dose of 14-day Treatment Period | 3.4305 Liters | Standard Error 0.15242 |
| QVM149 pm | FEV1 Standardized Area Under the Curve (AUC 0-24h) After Last Evening Dose of 14-day Treatment Period | 3.4361 Liters | Standard Error 0.15213 |
| Placebo | FEV1 Standardized Area Under the Curve (AUC 0-24h) After Last Evening Dose of 14-day Treatment Period | 2.8209 Liters | Standard Error 0.15259 |
90% CI: [0.538, 0.6811]Mixed Models Analysis
90% CI: [0.5437, 0.6868]Mixed Models Analysis
90% CI: [-0.076, 0.0647]Mixed Models Analysis
Secondary
Peak Expiratory Flow (PEF)
Peak expiratory flow (PEF) is the maximum flow generated during a forceful exhalation, starting from full lung inflationDaily morning and evening peak expiratory flow rate from Day 2 to Day14 during the three treatment periods.
Time frame: From treatment period start through study completion (up to 19 weeks).
Population: The pharmacodynamic (PD) analysis set included all patients with any available PD data, who received any dose of study drug and experienced no protocol deviations with relevant impact on PD data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| QVM149 am | Peak Expiratory Flow (PEF) | Evening average PEF | 522.0 L/min | Standard Error 19.71 |
| QVM149 am | Peak Expiratory Flow (PEF) | Morning average PEF | 489.6 L/min | Standard Error 19.77 |
| QVM149 pm | Peak Expiratory Flow (PEF) | Morning average PEF | 504.4 L/min | Standard Error 19.78 |
| QVM149 pm | Peak Expiratory Flow (PEF) | Evening average PEF | 507.7 L/min | Standard Error 19.71 |
| Placebo | Peak Expiratory Flow (PEF) | Morning average PEF | 417.5 L/min | Standard Error 19.73 |
| Placebo | Peak Expiratory Flow (PEF) | Evening average PEF | 449.0 L/min | Standard Error 19.67 |
Comparison: Morning average PEF90% CI: [61.3, 82.9]Mixed Models Analysis
Comparison: Morning average PEF90% CI: [76.1, 97.8]Mixed Models Analysis
Comparison: Morning average PEF90% CI: [-25.6, -4.1]Mixed Models Analysis
Comparison: Evening average PEF90% CI: [61.9, 84.2]Mixed Models Analysis
Comparison: Evening average PEF90% CI: [47.5, 69.9]Mixed Models Analysis
Comparison: Evening average PEF90% CI: [3.3, 25.5]Mixed Models Analysis
Secondary
Trough FEV1 After 24h
FEV1 at approximately 24 h after the last p.m. or penultimate a.m. dose. Morning and evening trough FEV1 (L) were analyzed by time of day. For morning trough FEV1 (L) assessments this meant that the spirometric assessment was done approximately 24 h after last morning dose and approximately 12 h after last evening dose.
Time frame: At the end of each treatment period day 14 pre-dose to 24 hours post-dose.
Population: The pharmacodynamic (PD) analysis set included all patients with any available PD data, who received any dose of study drug and experienced no protocol deviations with relevant impact on PD data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| QVM149 am | Trough FEV1 After 24h | 3.3731 Liters | Standard Error 0.15037 |
| QVM149 pm | Trough FEV1 After 24h | 3.4871 Liters | Standard Error 0.15041 |
| Placebo | Trough FEV1 After 24h | 2.7524 Liters | Standard Error 0.1512 |
90% CI: [0.5335, 0.7077]Mixed Models Analysis
90% CI: [0.6469, 0.8225]Mixed Models Analysis
90% CI: [-0.197, -0.0311]Mixed Models Analysis