Efficacy and Safety Comparison of Albuterol Spiromax® and... | NCT01899144

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Albuterol Spiromax 90 mcg	Experimental	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the DPIs contains Albuterol Spiromax 90 mcg; the other three devices contained placebo.	Drug: Albuterol Spiromax Drug: Placebo
Albuterol Spiromax 180 mcg	Experimental	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the DPIs contain Albuterol Spiromax 90 mcg for a total dose of 180 mcg; the MDIs contained placebo.	Drug: Albuterol Spiromax Drug: Placebo
ProAir HFA 90 mcg	Active Comparator	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the MDIs contains ProAir HFA 90 mcg; the other three devices contained placebo.	Drug: ProAir HFA Drug: Placebo
ProAir HFA 180 mcg	Active Comparator	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the MDIs contain ProAir HFA 90 mcg for a total dose of 180 mcg; the DPIs contained placebo.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Albuterol Spiromax	Drug	Albuterol Spiromax® Inhalation Aerosol contains 90 mcg albuterol per actuation orally inhaled in a single dose dry powder inhaler (DPI). Participants took doses at either the 90 or 180 mcg levels. If the higher level, two DPIs filled with Albuterol Spiromax® were used.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Baseline-Adjusted Area-Under-The-Percent-Predicted Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose	Percent predicted FEV1: measured FEV1 as a percent of the "predicted values" for the patients of similar characteristics. Predicted FEV1 values were computed and adjusted for age, height, and gender for patients aged 4-5 years (Eigen et al 2001) and for patients aged 6-11 years (Quanjer et al 1995) using ATS/European Thoracic Society (ERS) criteria applicable to pediatric patients (ATS/ERS 2007). The percent predicted FEV1 (PPFEV1) area under the curve (AUC)0-6 was calculated using the linear trapezoidal rule, and baseline adjustment was made by subtracting the average of the 2 pre-dose PPFEV1 values from each post-dose PPFEV1 determination.	Treatment visits 1-5 (approximately days 1, 6, 11, 16, and 21); -35 and -5 minutes prior to dosing and 5 (±2), 15 (±5), 30 (±5), 45 (±5), 60 (±5), 120 (±5), 180 (±5), 240 (±5), 300 (±5), and 360 (±5) minutes after the completion of study drug administrati

Secondary Outcomes

Measure	Description	Time Frame
Baseline-Adjusted Area-Under-The- Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose (FEV1 AUC0-6)	FEV1 AUC0-6 was calculated using the linear trapezoidal rule, and baseline adjustment was made by subtracting the average of the 2 pre-dose FEV1 values from each post-dose FEV1 determination.	Treatment visits 1-5 (approximately days 1, 6, 11, 16, and 21); -35 and -5 minutes prior to dosing and 5 (±2), 15 (±5), 30 (±5), 45 (±5), 60 (±5), 120 (±5), 180 (±5), 240 (±5), 300 (±5), and 360 (±5) minutes after the completion of study drug administrati

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Written informed consent/assent signed and dated by the patient and/or parent/caregiver/legal guardian (as appropriate) before conducting any study related procedure
Male or pre-menarchal female 4-11 years of age, inclusive, as of the screening visit
Has a documented physician diagnosis of persistent asthma of a minimum of 6 months duration that has been stable for at least 4 weeks prior to the screening visit. The asthma diagnosis must be in accordance with the National Asthma Education and Prevention Program Guidelines Expert Panel Report 3 (EPR3)
Has the ability to self-perform spirometry reproducibly per American Thoracic Society (ATS) guidelines
Has forced expiratory volume in 1 second (FEV1) 60-90% predicted for age, height, and gender at the screening visit based on the pediatric population standards as per protocol.

Notes: (1) Predicted values of 59.50-59.99% may be rounded up to 60% and 90.01-90.49% rounded down to 90%. (2) Patients who at the screening visit fail to meet the predicted spirometry values for study entry may be allowed a single attempt to re-qualify on another day, but they must re-qualify no later than 16 days following the first attempt.
Demonstrates reversible bronchoconstriction as verified by a 15% or greater increase in baseline FEV1 within 30 minutes following inhalation of 180 mcg of albuterol to 200 mcg of fluticasone propionate per day or equivalent), leukotriene modifiers (LTM), inhaled cromones, or on β2-agonists alone as needed. The Inhaled corticosteroid (ICS), LTM, and cromone doses must have been stable for at least 4 weeks prior to the screening visit and are expected to be maintained for the duration of the study
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), inhaled cromones, or on β2-agonists alone as needed. The ICS, LTM, and cromone doses must have been stable for at least 4 weeks prior to the screening visit and are expected to be maintained for the duration of the study
Can self-perform peak expiratory flow rate (PEF) measurements with a handheld peak flow meter
Has the ability to demonstrate acceptable and reproducible inhalation technique with the Spiromax and metered dose inhaler (MDI) devices
- Other inclusion criteria apply.

Exclusion Criteria:

Known hypersensitivity to albuterol or any of the excipients in the inhaler formulations (lactose, ethanol, etc.)
Participation (receiving study medication) in any investigational drug trial within the 30 days preceding the screening visit or planned participation in another investigational drug trial at any time during this trial
History of severe milk protein allergy
History of a respiratory infection or disorder (including, but not limited to bronchitis, pneumonia, acute or chronic sinusitis, otitis media, influenza, etc.) that has not resolved within 4 weeks preceding the screening visit
Any asthma exacerbation requiring oral corticosteroids within 3 months of the screening visit. A patient must not have had any hospitalization for asthma within 6 months prior to the screening visit.
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
Use of any prohibited concomitant medications within the washout period prescribed per protocol prior to the screening visit.
Use of any medication for asthma or allergic rhinitis that is prohibited per the protocol
The dosage of any required intranasal corticosteroid and/or cromone has not been stable for at least 2 weeks prior to the screening visit.
Treated with oral or injectable corticosteroids within the 6 weeks before the screening visit.
Initiation of immunotherapy during the study period or dose escalation during the study period. Patients being treated with immunotherapy prior to the screening visit must be using a stable (maintenance) dose (90 days or more) to be considered for inclusion.

Facility	Status	City	State	ZIP	Country	Contacts
Teva Investigational Site 10598		Birmingham	Alabama		United States
Teva Investigational Site 10593

PubMed Identifier	Type	Citation	Retractions
27657520	Derived	Qaqundah PY, Taveras H, Iverson H, Shore P. Albuterol multidose dry powder inhaler and albuterol hydrofluoroalkane versus placebo in children with persistent asthma. Allergy Asthma Proc. 2016 Sep;37(5):350-8. doi: 10.2500/aap.2016.37.3986.
27523719	Derived	Ratnayake A, Taveras H, Iverson H, Shore P. Pharmacokinetics and pharmacodynamics of albuterol multidose dry powder inhaler and albuterol hydrofluoroalkane in children with asthma. Allergy Asthma Proc. 2016 Sep;37(5):370-5. doi: 10.2500/aap.2016.37.3985. Epub 2016 Aug 12.

ID	Title	Description
FG000	All Participants	Participants were assigned to 1 of 10 possible treatment sequences for five treatments, separated by 2-7 days. Treatments were single inhalations of Albuterol MDPI 90 mcg, Albuterol MDPI 180 mcg, ProAir HFA MDI 90 mcg, ProAir HFA MDI 180 mcg, and placebo.

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Baseline-Adjusted Area-Under-The-Percent-Predicted Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose

Percent predicted FEV1: measured FEV1 as a percent of the "predicted values" for the patients of similar characteristics. Predicted FEV1 values were computed and adjusted for age, height, and gender for patients aged 4-5 years (Eigen et al 2001) and for patients aged 6-11 years (Quanjer et al 1995) using ATS/European Thoracic Society (ERS) criteria applicable to pediatric patients (ATS/ERS 2007).

The percent predicted FEV1 (PPFEV1) area under the curve (AUC)0-6 was calculated using the linear trapezoidal rule, and baseline adjustment was made by subtracting the average of the 2 pre-dose PPFEV1 values from each post-dose PPFEV1 determination.

Full analysis set (FAS) included all participants in the ITT population who received at least 1 dose of study medication, had a baseline assessment, and had at least 1 post baseline assessment.

Posted

Mean

Standard Error

%predicted FEV1*hour

Treatment visits 1-5 (approximately days 1, 6, 11, 16, and 21); -35 and -5 minutes prior to dosing and 5 (±2), 15 (±5), 30 (±5), 45 (±5), 60 (±5), 120 (±5), 180 (±5), 240 (±5), 300 (±5), and 360 (±5) minutes after the completion of study drug administrati

ID	Title	Description
OG000	Albuterol Spiromax 90 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the DPIs contains Albuterol Spiromax 90 mcg; the other three devices contained placebo.
OG001	Albuterol Spiromax 180 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the DPIs contain Albuterol Spiromax 90 mcg for a total dose of 180 mcg; the MDIs contained placebo.
OG002	ProAir HFA 90 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the MDIs contains ProAir HFA 90 mcg; the other three devices contained placebo.
OG003	ProAir HFA 180 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the MDIs contain ProAir HFA 90 mcg for a total dose of 180 mcg; the DPIs contained placebo.
OG004	Placebo	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, all devices contain placebo.

Units	Counts
Participants	OG00058 OG00159 OG00259 OG003

Title

Denominators

Categories

Title	Measurements
	OG00046.6± 6.27 OG00148.0± 6.24 OG00237.9± 6.25 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG001 OG004	The mean difference between each active group and placebo was tested in a sequential manner: Albuterol MDPI 180 mcg to placebo Albuterol MDPI 90 mcg to placebo ProAir HFA 180 mcg to placebo ProAir HFA 90 mcg to placebo Each test was 2 sided and done at the 0.05 level of significance. However, if a test was not significant at this level, no further tests were done. This sequential process assured that the overall alpha level for the entire series was not greater than 0.05.	ANOVA	Mixed effect analysis of variance with fixed effects of sequence, treatment group, and period, and random effect for the patient within sequence	<0.0001		Mean Difference (Final Values)	22.6	Standard Error of the Mean	4.87	2-Sided	95	13.00	32.20

Secondary

Baseline-Adjusted Area-Under-The- Forced Expiratory Volume In 1 Second (FEV1) Versus Time Curve Over 6 Hours Post-Dose (FEV1 AUC0-6)

FEV1 AUC0-6 was calculated using the linear trapezoidal rule, and baseline adjustment was made by subtracting the average of the 2 pre-dose FEV1 values from each post-dose FEV1 determination.

Full analysis set

Posted

Mean

Standard Error

L*hour

ID	Title	Description
OG000	Albuterol Spiromax 90 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the DPIs contains Albuterol Spiromax 90 mcg; the other three devices contained placebo.
OG001	Albuterol Spiromax 180 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the DPIs contain Albuterol Spiromax 90 mcg for a total dose of 180 mcg; the MDIs contained placebo.

Secondary

Participants With Treatment-Emergent 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.

The safety population included all randomized patients who received at least 1 dose of randomized study medication. In this population, treatment was assigned based upon the treatment patients actually receive regardless of the treatment to which they were randomized.

Posted

Number

participants

Day 1 up to Day 35

ID	Title	Description
OG000	Albuterol Spiromax 90 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the DPIs contains Albuterol Spiromax 90 mcg; the other three devices contained placebo.

Arm/Groups

ID	Title	Description	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Albuterol Spiromax 90 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the DPIs contains Albuterol Spiromax 90 mcg; the other three devices contained placebo.	61	0	61
EG001	Albuterol Spiromax 180 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the DPIs contain Albuterol Spiromax 90 mcg for a total dose of 180 mcg; the MDIs contained placebo.	61	0	61
EG002	ProAir HFA 90 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, one of the MDIs contains ProAir HFA 90 mcg; the other three devices contained placebo.	61	3	61
EG003	ProAir HFA 180 mcg	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, both of the MDIs contain ProAir HFA 90 mcg for a total dose of 180 mcg; the DPIs contained placebo.	61	0	61
EG004	Placebo	At each treatment visit, participants receive 1 actuation from each of 4 pre-arranged device combinations comprising 2 dry powder inhalers (DPIs) and 2 metered-dose inhalers (MDIs) in order to maintain the study blind. In this arm, all devices contain placebo.	61	0	61

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012130	Respiratory Hypersensitivity
D006969	Hypersensitivity, Immediate
D006967	Hypersensitivity
D007154	Immune System Diseases

ID	Term
D000420	Albuterol
D017265	Procaterol

ID	Term
D004983	Ethanolamines
D000605	Amino Alcohols
D000438	Alcohols
D009930	Organic Chemicals
D000588	Amines
D010627	Phenethylamines
D005021	Ethylamines
D006912	Hydroxyquinolines
D011804	Quinolines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds