Asthma
Conditions
Keywords
Asthma, dry powder inhaler, short-acting beta2-agonist, SABA, bronchoconstriction, bronchodilation, bronchodilator, metered dose inhaler, Albuterol Spiromax®
Brief summary
The primary objective of this study is to evaluate the efficacy of Albuterol Spiromax® versus placebo in subjects with persistent asthma.
Interventions
DRUGPlacebo MDPI
Placebo MDPI administered as 2 inhalations 4 times a day (QID) (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for 12 weeks.
DRUGAlbuterol MDPI
Albuterol MDPI administered as 2 inhalations 4 times a day (QID) (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for 12 weeks.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent/assent * At least 12 years of age at screening * General good health * Persistent asthma for ≥3 months, with an FEV1 50-80% predicted and ≥15% reversibility * Taking inhaled corticosteroids at a stable dose (≤ equivalent of 500mcg of fluticasone propionate/day) for at least 4 weeks prior to the Screening Visit. * Ability to perform spirometry in an acceptable manner as per protocol guidelines * Other inclusion criteria apply
Exclusion criteria
* A known hypersensitivity to albuterol or any of the excipients in the formulations. * History of a respiratory infection or disorder that has not resolved within 1 week preceding the Screening Visit (SV). * History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation. * Any asthma exacerbation requiring oral corticosteroids within 3 months of the SV. A subject must not have had any hospitalization for asthma within 6 months prior to the SV. * Hospitalization due to asthma exacerbation 2 or more times in the past year * Initiation of immunotherapy or dose escalation during the study period * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) Over the 12-week Treatment Period | Day 1, Day 8 and Day 85 | FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average (by the trapezoidal rule) over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure (i.e., change from baseline at each timepoint) recorded on days 1, 8 and 85 of the treatment period. The baseline for each study day was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 8 | Day 8 | FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min. |
| Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 85 | Day 85 | FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min. |
| Participants With Adverse Events | Day 1 to Day 93 | Adverse events (AEs) summarized in this table are those that began or worsened after treatment with study drug (treatment-emergent AEs). An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. |
| Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Day 1 (Baseline), Day 85 | Physical exam was recorded as normal or abnormal based on physician assessment. Format for results is: Test Baseline/Endpoint. HEENT = head, eyes, ears, nose, throat. |
| Participants With Clinically Significant Vital Sign Assessments | Days 8 and 85 | For both standard and serial vital signs, participants were seated for at least 5 minutes before vital signs were assessed. Heart rate was obtained prior to the blood pressure measurement. Serial heart rate and blood pressure were conducted in the sitting position prior to the spirometry assessment; baseline measures were taken pre-dose at -30 ± 5 and -5 minutes on Day 1. Day 85 serial vital sign measures were taken in the sitting position prior to spirometry assessments pre-dose at -30 ± 5 and -5 minutes, then post-dose at 30 (±5) minutes, 1hr (± 10 min), 2hr (± 10 min), 3hr (± 10 min), 4hr (± 10 min), 5hr (± 10 min) and 6 hr (± 10 min). Serial heart rate and blood pressure measurements that were elevated to the following criteria were considered clinically significant: Systolic blood pressure: \> 160 beats/minute Diastolic blood pressure: \>100 beats/minute Heart rate: \>120 beats/minute |
| Maximum Observed Plasma Drug Concentration (Cmax) for Albuterol on Days 1 and 8 | Days 1 and 8 | Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). |
| Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 1 | Day 1 | FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min. |
| Area Under the Concentration-time Curve From Time 0 (Pre-dose) up to 6 Hours Post-dose (AUC0-6) for Albuterol on Days 1 and 8 | Days 1 and 8 | Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). AUC0-6 on Day 8 is not from pre-dose but at steady state. |
| Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) for Albuterol on Days 1 and 8 | Days 1 and 8 | Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). AUC0-t on Day 8 is not from pre-dose but at steady state. |
| Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Infinity Post-dose(AUC0-inf) for Albuterol on Day 1 | Day 1 | Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). |
| Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 24 Hours Post-dose(AUC0-24) for Albuterol on Day 8 | Day 8 | Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). |
| Terminal Plasma Half-life (t1/2) for Albuterol on Days 1 and 8 | Days 1 and 8 | Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). |
| Time to Observed Peak Plasma Concentration (Tmax) for Albuterol on Days 1 and 8 | Days 1 and 8 | Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). |
Countries
United States
Participant flow
Pre-assignment details
Of the 361 patients screened, 158 were excluded on the basis of inclusion criteria, 5 on the basis of exclusion criteria, 13 withdrew consent, 1 patient was noncompliant, 2 patients were lost to follow-up before the baseline visit, 7 patients had other reasons, and 15 failed to meet the randomization criteria at the end of the run-in period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo MDPI Placebo multi-dose dry powder inhaler (MDPI) administered as 2 inhalations four times a day for 12 weeks. | 85 |
| Albuterol MDPI Albuterol multi-dose dry powder inhaler (MDPI) at a dose of 720 micrograms per day administered as 2 inhalations of 90 mcg /inhalation four times a day for 12 weeks. | 75 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Inclusion criteria not met | 1 | 0 |
| Overall Study | Noncompliance | 1 | 1 |
| Overall Study | Not treated | 1 | 0 |
| Overall Study | Other | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo MDPI | Albuterol MDPI | Total |
|---|---|---|---|
| Age, Continuous | 36.7 years STANDARD_DEVIATION 15.94 | 40.0 years STANDARD_DEVIATION 18.06 | 38.2 years STANDARD_DEVIATION 16.99 |
| Age, Customized 12-17 years | 17 participants | 14 participants | 31 participants |
| Age, Customized 18-64 years | 67 participants | 58 participants | 125 participants |
| Age, Customized 65+ years | 1 participants | 3 participants | 4 participants |
| Body Mass Index | 28.1 kg/m^2 STANDARD_DEVIATION 6.48 | 27.4 kg/m^2 STANDARD_DEVIATION 5.9 | 27.7 kg/m^2 STANDARD_DEVIATION 6.21 |
| Height | 167.8 cm STANDARD_DEVIATION 9.23 | 169.8 cm STANDARD_DEVIATION 10.93 | 168.7 cm STANDARD_DEVIATION 10.08 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 17 participants | 11 participants | 28 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 participants | 6 participants | 14 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 77 participants | 69 participants | 146 participants |
| Race/Ethnicity, Customized Other | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 66 participants | 59 participants | 125 participants |
| Sex: Female, Male Female | 45 Participants | 36 Participants | 81 Participants |
| Sex: Female, Male Male | 40 Participants | 39 Participants | 79 Participants |
| Weight | 79.8 kg STANDARD_DEVIATION 22.76 | 79.6 kg STANDARD_DEVIATION 20.75 | 79.7 kg STANDARD_DEVIATION 21.77 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 75 | 10 / 84 |
| serious Total, serious adverse events | 2 / 75 | 0 / 84 |
Outcome results
Primary
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) Over the 12-week Treatment Period
FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average (by the trapezoidal rule) over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure (i.e., change from baseline at each timepoint) recorded on days 1, 8 and 85 of the treatment period. The baseline for each study day was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time frame: Day 1, Day 8 and Day 85
Population: Full analysis set included all participants in the intent-to-treat population who received at least 1 dose of study medication and had at least 1 post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) Over the 12-week Treatment Period | 0.38 L*hr | Standard Error 0.114 |
| Albuterol MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) Over the 12-week Treatment Period | 1.30 L*hr | Standard Error 0.12 |
p-value: <0.000195% CI: [0.59, 1.24]mixed-model repeated-measures (MMRM)
Secondary
Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 24 Hours Post-dose(AUC0-24) for Albuterol on Day 8
Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).
Time frame: Day 8
Population: Pharmacokinetic analysis set representing a subset of participants from the Albuterol MDPI treatment arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol MDPI | Area Under the Concentration-time Curve From Time 0 (Pre-dose) to 24 Hours Post-dose(AUC0-24) for Albuterol on Day 8 | 3605 pg*hr/mL | Standard Deviation 1189 |
Secondary
Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Infinity Post-dose(AUC0-inf) for Albuterol on Day 1
Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).
Time frame: Day 1
Population: Pharmacokinetic analysis set representing a subset of participants from the Albuterol MDPI treatment arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Albuterol MDPI | Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Infinity Post-dose(AUC0-inf) for Albuterol on Day 1 | 2278 pg*hr/mL | Standard Deviation 869 |
Secondary
Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) for Albuterol on Days 1 and 8
Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). AUC0-t on Day 8 is not from pre-dose but at steady state.
Time frame: Days 1 and 8
Population: Pharmacokinetic analysis set representing a subset of participants from the Albuterol MDPI treatment arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol MDPI | Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) for Albuterol on Days 1 and 8 | Day 1 | 1747 pg*hr/mL | Standard Deviation 785 |
| Albuterol MDPI | Area Under the Concentration-time Curve From Time 0 (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) for Albuterol on Days 1 and 8 | Day 8 | 2165 pg*hr/mL | Standard Deviation 839 |
Secondary
Area Under the Concentration-time Curve From Time 0 (Pre-dose) up to 6 Hours Post-dose (AUC0-6) for Albuterol on Days 1 and 8
Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min). AUC0-6 on Day 8 is not from pre-dose but at steady state.
Time frame: Days 1 and 8
Population: Pharmacokinetic analysis set representing a subset of participants from the Albuterol MDPI treatment arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol MDPI | Area Under the Concentration-time Curve From Time 0 (Pre-dose) up to 6 Hours Post-dose (AUC0-6) for Albuterol on Days 1 and 8 | Day 1 | 1325 pg*hr/mL | Standard Deviation 646 |
| Albuterol MDPI | Area Under the Concentration-time Curve From Time 0 (Pre-dose) up to 6 Hours Post-dose (AUC0-6) for Albuterol on Days 1 and 8 | Day 8 | 2163 pg*hr/mL | Standard Deviation 825 |
Secondary
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 1
FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time frame: Day 1
Population: Full analysis set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 1 | 0.58 L*hr |
| Albuterol MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 1 | 1.63 L*hr |
p-value: <0.000195% CI: [0.56, 1.55]mixed model repeated measures (MMRM)
Secondary
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 8
FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time frame: Day 8
Population: Full analysis set of participants with data at the time point
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 8 | 0.37 L*hr |
| Albuterol MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 8 | 1.15 L*hr |
p-value: 0.000495% CI: [0.35, 1.19]mixed model repeated measures (MMRM)
Secondary
Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 85
FEV1 AUC 0-6 is the area under the effect-time curve from time 0 (pre-dose) up to 6 hours post-dose. It represents the weighted average over six hours of the FEV1 AUC 0-6 measures adjusted for the baseline measure. The baseline was the average of the 2 pre-dose FEV1 measurements on that study day. FEV1 was measured using spirometry. Spirometry assessments were obtained predose at -30 ± 5, and - 5 minutes, then post dose at 5 ± 2, 15 ± 5, 30 ± 5, 45 ± 5 minutes, and at 1hr ± 5 min, 2hr ± 5 min, 3hr ± 5 min, 4hr ± 5 min, 5hr ± 5 min, and 6hr ± 5 min.
Time frame: Day 85
Population: Full analysis set of participants with data at the time point
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 85 | 0.20 L*hr |
| Albuterol MDPI | Baseline-adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC 0-6) on Day 85 | 1.12 L*hr |
p-value: <0.000195% CI: [0.57, 1.28]mixed model repeated measures (MMRM)
Secondary
Maximum Observed Plasma Drug Concentration (Cmax) for Albuterol on Days 1 and 8
Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).
Time frame: Days 1 and 8
Population: Pharmacokinetic analysis set representing a subset of participants from the Albuterol MDPI treatment arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol MDPI | Maximum Observed Plasma Drug Concentration (Cmax) for Albuterol on Days 1 and 8 | Day 1 | 347.2 pg/mL | Standard Deviation 146.6 |
| Albuterol MDPI | Maximum Observed Plasma Drug Concentration (Cmax) for Albuterol on Days 1 and 8 | Day 8 | 499.1 pg/mL | Standard Deviation 154.3 |
Secondary
Participants With Adverse Events
Adverse events (AEs) summarized in this table are those that began or worsened after treatment with study drug (treatment-emergent AEs). An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time frame: Day 1 to Day 93
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo MDPI | Participants With Adverse Events | Any adverse event | 36 participants |
| Placebo MDPI | Participants With Adverse Events | Severe adverse event | 3 participants |
| Placebo MDPI | Participants With Adverse Events | Treatment-related adverse event | 2 participants |
| Placebo MDPI | Participants With Adverse Events | Deaths | 0 participants |
| Placebo MDPI | Participants With Adverse Events | Other serious adverse event | 0 participants |
| Placebo MDPI | Participants With Adverse Events | Withdrawn from study due to adverse event | 1 participants |
| Albuterol MDPI | Participants With Adverse Events | Other serious adverse event | 2 participants |
| Albuterol MDPI | Participants With Adverse Events | Any adverse event | 22 participants |
| Albuterol MDPI | Participants With Adverse Events | Deaths | 0 participants |
| Albuterol MDPI | Participants With Adverse Events | Severe adverse event | 1 participants |
| Albuterol MDPI | Participants With Adverse Events | Withdrawn from study due to adverse event | 2 participants |
| Albuterol MDPI | Participants With Adverse Events | Treatment-related adverse event | 1 participants |
Secondary
Participants With Clinically Significant Vital Sign Assessments
For both standard and serial vital signs, participants were seated for at least 5 minutes before vital signs were assessed. Heart rate was obtained prior to the blood pressure measurement. Serial heart rate and blood pressure were conducted in the sitting position prior to the spirometry assessment; baseline measures were taken pre-dose at -30 ± 5 and -5 minutes on Day 1. Day 85 serial vital sign measures were taken in the sitting position prior to spirometry assessments pre-dose at -30 ± 5 and -5 minutes, then post-dose at 30 (±5) minutes, 1hr (± 10 min), 2hr (± 10 min), 3hr (± 10 min), 4hr (± 10 min), 5hr (± 10 min) and 6 hr (± 10 min). Serial heart rate and blood pressure measurements that were elevated to the following criteria were considered clinically significant: Systolic blood pressure: \> 160 beats/minute Diastolic blood pressure: \>100 beats/minute Heart rate: \>120 beats/minute
Time frame: Days 8 and 85
Population: Safety analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo MDPI | Participants With Clinically Significant Vital Sign Assessments | Systolic blood pressure - high | 2 participants |
| Placebo MDPI | Participants With Clinically Significant Vital Sign Assessments | Diastolic blood pressure - high | 2 participants |
| Placebo MDPI | Participants With Clinically Significant Vital Sign Assessments | Heart rate - high | 0 participants |
| Albuterol MDPI | Participants With Clinically Significant Vital Sign Assessments | Systolic blood pressure - high | 3 participants |
| Albuterol MDPI | Participants With Clinically Significant Vital Sign Assessments | Diastolic blood pressure - high | 2 participants |
| Albuterol MDPI | Participants With Clinically Significant Vital Sign Assessments | Heart rate - high | 0 participants |
Secondary
Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group
Physical exam was recorded as normal or abnormal based on physician assessment. Format for results is: Test Baseline/Endpoint. HEENT = head, eyes, ears, nose, throat.
Time frame: Day 1 (Baseline), Day 85
Population: Safety population. Only participants with both baseline and endpoint physical examination findings are summarized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Abnormal/Normal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Normal/Abnormal | 2 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Abnormal/Abnormal | 1 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Normal/Normal | 81 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Normal/Normal | 81 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Abnormal/Normal | 3 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Normal/Abnormal | 1 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Abnormal/Abnormal | 2 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Abnormal/Normal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Abnormal/Abnormal | 2 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Abnormal/Abnormal | 1 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Abnormal/Normal | 7 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Normal/Normal | 69 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Normal/Normal | 82 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Normal/Abnormal | 5 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Normal/Normal | 59 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Abnormal/Normal | 2 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Normal/Abnormal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Abnormal/Abnormal | 7 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Normal/Abnormal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Normal/Normal | 83 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Abnormal/Normal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Normal/Abnormal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Abnormal/Abnormal | 16 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Abnormal/Normal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Abnormal/Abnormal | 1 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Abnormal/Abnormal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Normal/Abnormal | 1 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Normal/Normal | 83 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Normal/Normal | 82 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Normal/Abnormal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Normal/Normal | 76 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Abnormal/Normal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Normal/Abnormal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Abnormal/Abnormal | 0 participants |
| Placebo MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Abnormal/Normal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Abnormal/Abnormal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Abnormal/Normal | 5 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Normal/Normal | 72 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Normal/Abnormal | 1 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Abnormal/Normal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | General appearance Abnormal/Abnormal | 1 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Normal/Normal | 52 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Abnormal/Abnormal | 15 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Normal/Normal | 64 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Normal/Abnormal | 3 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Abnormal/Normal | 7 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Chest and Lungs Abnormal/Abnormal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Normal/Normal | 70 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Normal/Abnormal | 1 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Abnormal/Normal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Heart Abnormal/Abnormal | 3 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Normal/Normal | 71 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Normal/Abnormal | 1 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Abnormal/Normal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Abdomen Abnormal/Abnormal | 2 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Normal/Normal | 72 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Normal/Abnormal | 1 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Abnormal/Normal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Musculoskeletal Abnormal/Abnormal | 1 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Normal/Normal | 63 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Normal/Abnormal | 1 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Abnormal/Normal | 4 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Skin Abnormal/Abnormal | 6 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Normal/Normal | 74 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Normal/Abnormal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Abnormal/Normal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Lymph nodes Abnormal/Abnormal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Normal/Normal | 74 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Normal/Abnormal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | Neurological Abnormal/Normal | 0 participants |
| Albuterol MDPI | Physical Examination Findings Shifts From Baseline to Endpoint by Treatment Group | HEENT Normal/Abnormal | 2 participants |
Secondary
Terminal Plasma Half-life (t1/2) for Albuterol on Days 1 and 8
Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).
Time frame: Days 1 and 8
Population: Pharmacokinetic analysis set representing a subset of participants from the Albuterol MDPI treatment arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Albuterol MDPI | Terminal Plasma Half-life (t1/2) for Albuterol on Days 1 and 8 | Day 1 | 4.7 hour | Standard Deviation 1.3 |
| Albuterol MDPI | Terminal Plasma Half-life (t1/2) for Albuterol on Days 1 and 8 | Day 8 | 5.7 hour | Standard Deviation 1.4 |
Secondary
Time to Observed Peak Plasma Concentration (Tmax) for Albuterol on Days 1 and 8
Pharmacokinetic parameters of albuterol were determined on Day 1 after the first dose administration and at steady-state on Day 8. Day 1 serial (10-hr) blood samples for pharmacokinetics pre-dose (within 30 minutes prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5, 6, 8 and 10 hours (±10 minutes). Day 8 serial (6-hr) blood samples for pharmacokinetics pre-dose (within 30 min prior to dosing), and post-dose at the following times: 15 (±5) min, 30 (±5) min, and 1, 2, 3, 4, 5 and 6 hr (±10 min).
Time frame: Days 1 and 8
Population: Pharmacokinetic analysis set representing a subset of participants from the Albuterol MDPI treatment arm.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Albuterol MDPI | Time to Observed Peak Plasma Concentration (Tmax) for Albuterol on Days 1 and 8 | Day 1 | 0.48 hour |
| Albuterol MDPI | Time to Observed Peak Plasma Concentration (Tmax) for Albuterol on Days 1 and 8 | Day 8 | 0.44 hour |