Asthma
Conditions
Brief summary
The study is to evaluate the chronic-dose efficacy and the safety of Albuterol MDPI compared to placebo in pediatric participants with asthma.
Interventions
DRUGAlbuterol MDPI
90 mcg/actuation of the multidose dry powder inhaler (MDPI).
DRUGPlacebo
Matching Placebo delivered via a multidose dry powder inhaler (MDPI).
DRUGProAir HFA inhaler
Rescue medication, ProAir hydrofluoroalkane (HFA) inhaler, was dispensed at the run-in visit for the relief of asthma symptoms to be administered as needed.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent/assent signed and dated by the patient and/or parent/caregiver/legal guardian (as appropriate) before conducting any study related procedure 2. Male or premenarchal female 4-11 years of age, inclusive, as of the screening visit (SV) 3. Has a documented physician diagnosis of asthma per the EPR-3 Guidelines of a minimum of 6 months duration that has been stable for at least 4 weeks prior to the SV 4. Has the ability to perform spirometry reproducibly consistent with ATS guidelines and protocol-specific guidelines 5. Has FEV1 50-95% predicted for age, height and gender at the SV following a minimum 6-hour period without β2-agonist use. (Note: Predicted values of 49.50-49.99% may be rounded up to 50% and values of 95.01-95.49% may be rounded down to 95%.) 6. Demonstrated reversible bronchoconstriction as verified by a 15% or greater increase in baseline FEV1 within 30 minutes following inhalation of 180 mcg of albuterol. (Note: Reversibility values of 14.50-14.99% may be rounded up to 15%.) 7. Is maintained on low-dose inhaled corticosteroids (ICS, less than or equal to 200 mcg of fluticasone propionate per day or equivalent), leukotriene modifiers (LTM), or inhaled cromones, and/or on short-acting β2-agonists (SABA); as needed SABA alone is acceptable. The ICS, LTM, and cromone doses must have been stable for at least 4 weeks prior to the SV and should be maintained for the duration of the study 8. Can self-perform peak expiratory flow rate (PEF) measurements with a handheld peak flow meter 9. Can tolerate the withdrawal of applicable medications for qualification at screening 10. Otherwise in general good health, defined as free of any concomitant conditions or treatment that could interfere with study conduct, influence the interpretation of study observations/results, or put the patient at increased risk during the trial, and with a clinically acceptable 6-month medical history, physical examination, 12-lead electrocardiogram (ECG), and vital signs 11. Parents consenting are capable of understanding the requirements, risks and benefits of study participation, and, as judged by the investigator, capable of giving informed consent and being compliant with all study requirements (eg, visits, record-keeping) 12. The patient is able to correctly use the MDPI device, either alone or with assistance by a parent/guardian.
Exclusion criteria
1. Known hypersensitivity to albuterol or any of the excipients in the inhaler formulations (eg, lactose, ethanol) 2. Participation (receiving study medication) in any investigational drug trial within the 30 days preceding the SV or planned participation in another investigational drug trial at any time during this trial 3. History of severe milk protein allergy 4. History of a respiratory infection or disorder (including, but not limited to bronchitis, pneumonia, acute or chronic sinusitis, otitis media, influenza) that has not resolved within 4 weeks preceding the SV 5. Any asthma exacerbation requiring oral corticosteroids within 3 months of the SV. A patient must not have had any hospitalization for asthma within 6 months prior to the SV. 6. Initiation of immunotherapy during the study period or dose escalation during the study period. Patients being treated with immunotherapy prior to the SV must be using a stable (maintenance) dose (90 days or more) to be considered for inclusion. 7. History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest, or hypoxic seizures 8. Use of any prohibited concomitant medications within the washout prescribed per protocol prior to study visits 9. Use of any medication for asthma or allergic rhinitis that is prohibited per the protocol as described in the protocol 10. The dosage of any required LTM, ICS, or inhaled cromones, has not been stable for at least 4 weeks. Intranasal corticosteroid and/or cromones have not been stable for at least two weeks prior to the SV. Allowed corticosteroid, LTM, and cromone asthma and allergy medications should be continued at the same doses during the conduct of the study. 11. Presence of any non-asthmatic acute or chronic condition, including but not limited to bronchitis, emphysema, active tuberculosis, bronchiectasis, cystic fibrosis, clinically significant cardiovascular disease (including but not limited to cardiac arrhythmias and uncontrolled hypertension), clinically significant hepatic, renal, or endocrine dysfunction, stroke, uncontrolled diabetes mellitus, hyperthyroidism, convulsive disorder, and malignancy other than basal cell carcinoma. Significant is defined as any condition that, in the opinion of the investigator, would put the safety of the patient at risk through participation, or which could affect the safety or efficacy analyses 12. Any other medical or psychological condition that in the investigator's opinion should preclude study enrollment 13. Previous participation (received MDPI study medication) in an Albuterol MDPI study 14. Study participation by clinical investigator site employees and/or their immediate relatives 15. Study participation by related or non-related individuals living in the same household, ie, only one subject per household may participate in the study at the same time. 16. Require continuous treatment with β-blockers, MAO inhibitors, tricyclic antidepressants, anticholinergics, and/or systemic corticosteroids 17. Treated with oral or injectable corticosteroids within the 6 weeks prior to SV 18. Hospitalization for acute asthma exacerbation \>2 times in 12 months prior to screening and/or received emergency room treatment other than nebulized albuterol or been hospitalized for asthma exacerbations within 6 months prior to SV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Adjusted Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks | 30 ±5 and 5 ±2 minutes prior to dosing, and at 5 ±2, 15 ±5, 30 ±5, 45 ±5, 60 ±10, 120 ±10, 240 ±10, and 360 ±10 minutes after completion of dosing on Days 1 and 22 | Following measurement of the baseline FEV1 and dose administration on Days 1 and 22, FEV1 values (highest of 3 acceptable maneuvers) will be obtained at 5 (±2), 15 (±5), 30 (±5), 45 (±5), 60 (±10), 120 (±10), 240 (±10), and 360 (±10) minutes after the completion of dosing. Predicted FEV1 values were computed and adjusted for age, height, and gender according to Eigen et al (Eigen et al 2001) for participants 4 to 5 years of age and to Quanjer et al (Quanjer et al 1995) for participants aged 6 to 11 years using ATS criteria (American Thoracic Society/European Respiratory Society Statement 2007). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Adjusted Peak Expiratory Flow (PEF) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks | 30 ±5 and 5 ±2 minutes prior to dosing, and at 5 ±2, 15 ±5, 30 ±5, 45 ±5, 60 ±10, 120 ±10, 240 ±10, and 360 ±10 minutes after completion of dosing on Days 1 and 22 | Serial PEF measurements were obtained via spirometry. PEF measures for purpose of serial PEF assessment (pre and postdose) were collected from the spirometer assessed PEF, utilizing the values from the efforts selected based on the highest of 3 acceptable FEV1 maneuvers. |
| Summary of Participants With Adverse Events | 6 Months | 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 as mild (no limitation of usual activities), moderate, or severe (inability to carry out usual 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. |
Countries
Thailand, United States
Participant flow
Pre-assignment details
The run-in period (days -14 to Day -1) was conducted in a single blind manner with respect to the Placebo MDPI treatment (2 inhalations QID at approximately 7:00 AM, 12:00 PM, 5:00 PM, and bedtime), so that the patient did not know which treatment was administered.
Participants by arm
| Arm | Count |
|---|---|
| Placebo MDPI QID Placebo multidose dry powder inhaler (MDPI) administered as 2 inhalations QID (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for 3 weeks. | 92 |
| Albuterol MDPI 180 mcg QID Albuterol multidose dry powder inhaler (MDPI) 90 mcg/inhalation administered as 2 inhalations QID (at approximately 7:00 AM, 12 noon, 5:00 PM, and bedtime) for a total daily dose of 720 mcgs for 3 weeks. | 94 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Other | 5 | 5 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Sponsor request | 0 | 1 |
| Overall Study | Withdrawal by parent/guardian | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo MDPI QID | Albuterol MDPI 180 mcg QID | Total |
|---|---|---|---|
| Age, Continuous | 8.5 years STANDARD_DEVIATION 1.83 | 8.3 years STANDARD_DEVIATION 1.69 | 8.4 years STANDARD_DEVIATION 1.76 |
| Age, Customized 4-7 years | 23 participants | 30 participants | 53 participants |
| Age, Customized 8-11 years | 69 participants | 64 participants | 133 participants |
| Body Mass Index | 19.5 kg/m^2 STANDARD_DEVIATION 4.96 | 19.4 kg/m^2 STANDARD_DEVIATION 5.34 | 19.4 kg/m^2 STANDARD_DEVIATION 5.14 |
| Ethnicity Hispanic or Latino | 11 participants | 14 participants | 25 participants |
| Ethnicity Not Hispanic or Latino | 81 participants | 80 participants | 161 participants |
| Height | 136.9 cm STANDARD_DEVIATION 12.67 | 135.2 cm STANDARD_DEVIATION 11.59 | 136.0 cm STANDARD_DEVIATION 12.13 |
| Qualifying Airway Reversibility | 22.0 percentage increase from baseline FEV1 STANDARD_DEVIATION 8.14 | 22.9 percentage increase from baseline FEV1 STANDARD_DEVIATION 8.19 | 22.4 percentage increase from baseline FEV1 STANDARD_DEVIATION 8.16 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black | 48 participants | 52 participants | 100 participants |
| Race/Ethnicity, Customized Other | 3 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 41 participants | 40 participants | 81 participants |
| Screening FEV1 | 1.69 liters STANDARD_DEVIATION 0.44 | 1.64 liters STANDARD_DEVIATION 0.35 | 1.66 liters STANDARD_DEVIATION 0.39 |
| Screening PPFEV1 | 87.5 percent of predicted FEV1 STANDARD_DEVIATION 11.46 | 89.0 percent of predicted FEV1 STANDARD_DEVIATION 12.35 | 88.3 percent of predicted FEV1 STANDARD_DEVIATION 11.91 |
| Sex: Female, Male Female | 37 Participants | 42 Participants | 79 Participants |
| Sex: Female, Male Male | 55 Participants | 52 Participants | 107 Participants |
| Weight | 37.2 kg STANDARD_DEVIATION 13.42 | 36.1 kg STANDARD_DEVIATION 13.46 | 36.7 kg STANDARD_DEVIATION 13.42 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 92 | 9 / 93 |
| serious Total, serious adverse events | 0 / 92 | 0 / 93 |
Outcome results
Primary
Baseline Adjusted Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks
Following measurement of the baseline FEV1 and dose administration on Days 1 and 22, FEV1 values (highest of 3 acceptable maneuvers) will be obtained at 5 (±2), 15 (±5), 30 (±5), 45 (±5), 60 (±10), 120 (±10), 240 (±10), and 360 (±10) minutes after the completion of dosing. Predicted FEV1 values were computed and adjusted for age, height, and gender according to Eigen et al (Eigen et al 2001) for participants 4 to 5 years of age and to Quanjer et al (Quanjer et al 1995) for participants aged 6 to 11 years using ATS criteria (American Thoracic Society/European Respiratory Society Statement 2007).
Time frame: 30 ±5 and 5 ±2 minutes prior to dosing, and at 5 ±2, 15 ±5, 30 ±5, 45 ±5, 60 ±10, 120 ±10, 240 ±10, and 360 ±10 minutes after completion of dosing on Days 1 and 22
Population: The full analysis set (FAS) includes all participants in the ITT population who receive at least 1 dose of study medication and have at least 1 postbaseline assessment of the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo MDPI QID | Baseline Adjusted Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks | 18.71 % predicted FEV1/hour | Standard Error 3.19 |
| Albuterol MDPI 180 mcg QID | Baseline Adjusted Percent Predicted Forced Expiratory Volume In 1 Second (FEV1) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks | 43.73 % predicted FEV1/hour | Standard Error 3.2 |
p-value: <0.000195% CI: [16.1, 33.94]mixed model repeated measures analysis
Secondary
Baseline Adjusted Peak Expiratory Flow (PEF) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks
Serial PEF measurements were obtained via spirometry. PEF measures for purpose of serial PEF assessment (pre and postdose) were collected from the spirometer assessed PEF, utilizing the values from the efforts selected based on the highest of 3 acceptable FEV1 maneuvers.
Time frame: 30 ±5 and 5 ±2 minutes prior to dosing, and at 5 ±2, 15 ±5, 30 ±5, 45 ±5, 60 ±10, 120 ±10, 240 ±10, and 360 ±10 minutes after completion of dosing on Days 1 and 22
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo MDPI QID | Baseline Adjusted Peak Expiratory Flow (PEF) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks | 71.52 Liters/min*hour | Standard Error 10.201 |
| Albuterol MDPI 180 mcg QID | Baseline Adjusted Peak Expiratory Flow (PEF) Area Under The Concentration Time Curve Up From Time Zero up to 6 Hours (AUC0-6) Over 3 Weeks | 147.85 Liters/min*hour | Standard Error 10.245 |
p-value: <0.000195% CI: [47.76, 104.91]mixed model repeated measures
Secondary
Summary of 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 as mild (no limitation of usual activities), moderate, or severe (inability to carry out usual 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: 6 Months
Population: Safety Analysis set includes all participants who receive at least 1 dose of study drug. In this population, treatment is assigned based upon the treatment participants actually receive, regardless of the treatment to which they were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo MDPI QID | Summary of Participants With Adverse Events | Any adverse event | 21 participants |
| Placebo MDPI QID | Summary of Participants With Adverse Events | Severe adverse event | 0 participants |
| Placebo MDPI QID | Summary of Participants With Adverse Events | Treatment-related adverse event | 0 participants |
| Placebo MDPI QID | Summary of Participants With Adverse Events | Deaths | 0 participants |
| Placebo MDPI QID | Summary of Participants With Adverse Events | Other serious AE | 0 participants |
| Placebo MDPI QID | Summary of Participants With Adverse Events | Withdrawn from study due to AE | 0 participants |
| Albuterol MDPI 180 mcg QID | Summary of Participants With Adverse Events | Other serious AE | 0 participants |
| Albuterol MDPI 180 mcg QID | Summary of Participants With Adverse Events | Any adverse event | 21 participants |
| Albuterol MDPI 180 mcg QID | Summary of Participants With Adverse Events | Deaths | 0 participants |
| Albuterol MDPI 180 mcg QID | Summary of Participants With Adverse Events | Severe adverse event | 0 participants |
| Albuterol MDPI 180 mcg QID | Summary of Participants With Adverse Events | Withdrawn from study due to AE | 0 participants |
| Albuterol MDPI 180 mcg QID | Summary of Participants With Adverse Events | Treatment-related adverse event | 0 participants |