Study to Assess the Efficacy and Safety of Beclomethasone Dipropionate in Adolescent and Adult Patients 12 Years of Age and Older With Persistent Asthma

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02513160
• Collaborator: (none)
• Enrollment: 713
• Locations: 75
• Arms: 4
• Actual Duration (Months): 6
• Patients Per Site: 9.5
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the efficacy of beclomethasone dipropionate administered via BAI at a dose strength of 40 or 80 mcg per oral inhalation (320 or 640 mcg/day, respectively) compared with placebo treatment in patients with persistent asthma as assessed by the standardized baseline-adjusted trough morning (pre-dose and pre-rescue bronchodilator) forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 6 weeks (AUEC[0-6wk]).

Condition or Disease	Intervention/Treatment	Phase
Persistent Asthma	Drug: Beclomethasone Dipropionate 640; Drug: Placebo; Drug: Beclomethasone dipropionate via 320 mcg BAI; Drug: albuterol/salbutamol; Drug: Beclomethasone dipropionate via 320 mcg MDI	Phase 3

Detailed Description

Run-In Period (Days -14 to Day -1): Participants were provided with single-blind placebo breath-actuated inhaler (BAI) or metered-dose inhaler (MDI) device for twice-daily use after appropriate training and demonstration of the proper technique. Participants discontinued their current asthma therapy for the duration of the study.

Treatment Period (Day 0 to Week 6): Participants were randomly assigned to treatment and device type through a qualified randomization service provider (ie, IRT). The interactive response technology (IRT) system stratified patients based on treatment at the time of screening visit, either inhaled corticosteroid (ICS) or non-corticosteroid (NCS). During the study, blinded persons were blinded to treatment (active or placebo) assigned but not device (BAI or MDI) assignment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 713 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 6-Week Clinical Study to Assess the Efficacy and Safety of Beclomethasone Dipropionate Delivered Via Breath-Actuated Inhaler (BAI) at 320 or 640 mcg/Day in Adolescent and Adult Patients 12 Years of Age and Older With Persistent Asthma
• Actual Study Start Date: Sep 30, 2015
• Actual Primary Completion Date: Mar 31, 2016
• Actual Study Completion Date: Mar 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Beclomethasone dipropionate BAI 320 Beclomethasone Dipropionate Delivered via Breath-Actuated Inhaler (BAI) at 320 mcg/day (40 mcg/inhalation, 4 inhalations twice daily) Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Drug: Beclomethasone dipropionate via 320 mcg BAI; Beclomethasone dipropionate treatment administered via breath-actuated inhaler (BAI) (320 mcg/day).; Drug: albuterol/salbutamol; Each patient's current rescue medication was replaced with study-supplied albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent during the run-in and double-blind study periods.; Other Names: ProAir®
Experimental: Beclomethasone dipropionate BAI 640 Beclomethasone Dipropionate Delivered via Breath-Actuated Inhaler (BAI) at 640 mcg/day (80 mcg/inhalation, 4 inhalations twice daily) Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Drug: Beclomethasone Dipropionate 640; Beclomethasone Dipropionate 640 mcg BAI; Drug: albuterol/salbutamol; Each patient's current rescue medication was replaced with study-supplied albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent during the run-in and double-blind study periods.; Other Names: ProAir®
Active Comparator: Beclomethasone dipropionate MDI 320 Beclomethasone dipropionate Metered Dose Inhaler (MDI) 320 mcg/day (40 mcg/inhalation, 4 inhalations twice daily) Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Drug: albuterol/salbutamol; Each patient's current rescue medication was replaced with study-supplied albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent during the run-in and double-blind study periods.; Other Names: ProAir® ; Drug: Beclomethasone dipropionate via 320 mcg MDI; Beclomethasone dipropionate treatment administered via metered-dose inhaler (MDI) (320 mcg/day).; Other Names: QVAR® Inhalation Aerosol
Placebo Comparator: Placebo Pooled breath-actuated inhaler (BAI) or metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Drug: Placebo; Placebo, taken in the morning and evening each day, was provided in matching BAI and MDI devices. The placebo devices were identical to the devices used to deliver active drug.; Drug: albuterol/salbutamol; Each patient's current rescue medication was replaced with study-supplied albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent during the run-in and double-blind study periods.; Other Names: ProAir®

Outcome Measures

Primary Outcome Measures

1. Standardized Baseline-Adjusted Trough Morning Forced Expiratory Volume in One Minute (FEV1) Area Under the Effect Curve From Time Zero to 6 Weeks (AUEC(0-6wk)) [Baseline (Day 0 of Treatment Period), weeks 2, 4, 6]

   The primary efficacy variable was the standardized baseline-adjusted trough morning (pre-dose and pre-rescue bronchodilator) FEV1 AUEC(0-6wk). Pulmonary function measurements such as FEV1 were obtained electronically by spirometry at the randomization visit, each treatment visit (Weeks 2, 4 and 6) and any unscheduled visit (such as the early termination visit). The highest FEV1 value from 3 acceptable and 2 repeatable maneuvers (maximum of 8 attempts) was used. The least-square (LS) means, difference of LS means and its 95% confidence interval (CI), and p-value represent the results obtained from the analysis of covariance with covariate adjustment for baseline, sex, age, current asthma therapy, and treatment.

Secondary Outcome Measures

1. Change From Baseline in Weekly Average of Daily Trough Morning Peak Expiratory Flow (PEF) Rate Over the 6-Week Treatment Period [Timeframes: Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks]

   Change from baseline in the weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) PEF by handheld spirometer over the 6-week treatment period. PEF were determined twice daily, in the morning and in the evening, before administration of study drug or rescue medications. A handheld spirometer was provided to patients and used to determine the morning and evening PEF throughout the study. The spirometer was programmed to record the highest PEF obtained from 3 valid attempts. Baseline was defined as the average of recorded trough morning PEF assessments over the 7 days prior to the first dose of double-blind study treatment, including the morning assessment at the randomization visit. The LS means, difference of LS means and its 95% confidence interval, and p value are obtained from the mixed model for repeated measures analysis with covariate adjustment for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.

2. Change From Baseline in Weekly Average of Daily Trough Morning Forced Expiratory Volume in One Minute (FEV1) Rate Over the 6-Week Treatment Period [Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks]

   Change from baseline in the weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) FEV1 by handheld spirometer over the 6-week treatment period. FEV1 were determined twice daily, in the morning and in the evening, before administration of study drug or rescue medications. A handheld spirometer was provided to patients and used to determine the morning and evening FEV1 throughout the study. The spirometer was programmed to record the highest FEV1 obtained from 3 valid attempts. Baseline was defined as the average of recorded trough morning FEV1 assessments over the 7 days prior to the first dose of double-blind study treatment, including the morning assessment at the randomization visit. The LS means, difference of LS means and its 95% confidence interval, and p value are obtained from the mixed model for repeated measures analysis with covariate adjustment for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.

3. Change From Baseline in Weekly Average of Total Daily (24-Hour) Rescue Medication Use Over the 6-Week Treatment Period [Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks]

   Change from baseline in the weekly average of total daily (24-hour) use of albuterol/salbutamol inhalation aerosol over weeks 1 through 6. Patients recorded the number of inhalations (puffs used) of rescue medication (albuterol/salbutamol HFA MDI [90 mcg ex-actuator] or equivalent) each morning and evening in the diary. The average number of daily inhalations over the 7 days before the randomization visit was the baseline value and was compared with the rescue medication use during the 6-week treatment period.

4. Change From Baseline in Weekly Average of Total Daily Asthma Symptom Score Over the 6-Week Treatment Period [Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks]

   Asthma symptom scores were recorded in the patient's diary each morning and evening before determining FEV1 and PEF and before administration of study or rescue medications. The Daytime Symptom Score was recorded in the evening on a scale of 0 (No symptoms during the day) to 5 (Symptoms so severe that I could not go to work or perform normal daily activities) plus the Nighttime Symptom Score in the morning on a scale of 0 (No symptoms during the night) to 4 (Symptoms so severe that I did not sleep at all) for a total score range of 0-9. Baseline was defined as the average of recorded daily asthma symptom scores (average of daytime and nighttime score) over the 7 days prior to the first dose of double-blind study treatment, including the morning assessment at the randomization visit. The LS means, difference of LS means and its 95% CI, and p value are obtained from the mixed model for repeated measures analysis with covariate adjustment for baseline, sex, age, current asth

5. Count of Participants Withdrawn From Study Drug Treatment Due to Meeting Stopping Criteria for Worsening Asthma [Day 0 to Week 6]

   Number of participants who were withdrawn from study drug due to worsening asthma. Alert criteria for individual patients with worsening asthma were designed to ensure patient safety. The investigator determined whether the patient's overall clinical picture was consistent with worsening asthma and if the patient should be withdrawn from study drug treatment (but not the study) and be placed on appropriate asthma therapy in the interest of patient safety. An example of an alert criteria is: Morning FEV1 by handheld spirometer as measured at home falls below the FEV1 stability limit (FEV1 <80%) as calculated at the screening visit for the Run-in Period and at the randomization visit (Day 0) for the Treatment Period on 4 or more days out of any 7-day period.

6. Participants With Treatment-Emergent Adverse Events (TEAE) [Day 0 to Week 6]

   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 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/birth defect, or an important medical event that may not result in death, be life-threatening, or require hospitalization, but may jeopardize the patient and may require medical intervention to prevent one of the outcomes listed in this definition.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The patient has a diagnosis of asthma as defined by the NIH. The asthma diagnosis

• has been present for a minimum of 3 months and has been stable (defined as no exacerbations and no changes in medication) for at least 30 days.

• The patient has been maintained on stable doses of :

• non-corticosteroid therapy

• inhaled corticosteroid therapy

• Written informed consent/assent is obtained. For adult patients (18 years of age and older, or as applicable per local regulations), the written informed consent form (ICF) must be signed and dated by the patient before conducting any study-related procedure. For minor patients (ages 12 to 17 years, or as applicable per local regulations), the written ICF must be signed and dated by the parent/legal guardian and the written informed assent form must be signed and dated by the patient before conducting any study-related procedure.

• The patient is a male or female 12 years of age or older as of the visit when informed consent/assent is signed (screening or prescreening visit, as applicable). (Note: Age requirements are as specified or allowed by local regulations.)

• The patient is able to perform acceptable and repeatable spirometry

• The patient is able to use an electronic diary after training.

• The patient is able to use devices properly

• If female, patient is currently not pregnant, not breast feeding, nor attempting to become pregnant (for 30 days before the screening visit (SV) and throughout the duration of the study and for 30 days after patient's last study visit) or, is of childbearing potential and not sexually active, has a negative urine pregnancy test, and is willing to commit to using a consistent and acceptable method of birth control

• If male, the patient is willing to commit to an acceptable method of birth control for the duration of the study, is surgically sterile or exclusively has same-sex partner(s).

• The patient does not have any concomitant conditions or treatments that could interfere with study conduct, influence the interpretation of study observations/results, or put the patient at increased risk during the study as judged by the investigator.

• The patient/parent/legal guardian is capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements (eg, dose schedules, visit schedules, procedures, and record keeping).

• The patient, as judged by the investigator, is able to discontinue all asthma medications at the SV.

• other criteria apply, please contact the investigator for more information

Exclusion Criteria

• Life-threatening asthma, defined as a history of asthma episode(s) requiring intubation and/or associated with hypercapnea, respiratory arrest or hypoxic seizures, asthma-related syncopal episode(s), or hospitalizations within the past year.

• The patient received systemic corticosteroids within 30 days before the SV (for asthma exacerbation or for other indications).

• The patient has participated in any investigational drug study as a randomized patient within the 30 days (starting at the final visit of that study) preceding SV (or prescreening visit, as applicable), or plans to participate in another investigational drug study at any time during this study.

• The patient has previously participated in a beclomethasone dipropionate breath-actuated inhaler (device) (BAI) study as a randomized patient.

• The patient has a known hypersensitivity to any corticosteroid or any of the excipients in the study drug or rescue medication formulation.

• The patient has been treated with any known strong cytochrome inhibitors during the study.

• The patient has been treated with any of the prohibited medications during the prescribed (per protocol) withdrawal periods before the SV.

• The patient currently smokes or has a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). The patient may not have used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco).

• The patient has a suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before the SV.

• The patient has a history of alcohol or drug abuse within 2 years preceding SV.

• The patient has had an asthma exacerbation requiring oral corticosteroids within 1 month before the SV, or has had any hospitalization for asthma within 3 months before SV.

• The patient has initiated immunotherapy (administered by any route) less than 90 days before the SV or had a dose escalation of immunotherapy less than 30 days before the SV.

• The patient is unable to tolerate or unwilling to comply with the required washout periods and withholding of all applicable medications.

• The patient has untreated oral candidiasis at SV. Patients with clinical visual evidence of oral candidiasis and who agree to receive treatment and comply with appropriate medical monitoring may enter the study.

• The patient is either an employee or an immediate relative of an employee of the clinical investigational center.

• A member of the patient's household is participating in the study at the same time. (However, after the enrolled patient completes or discontinues participation in the study, another patient from the same household may be screened).

• The patient has a disease/condition that, in the medical judgment of the investigator, would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study.

• other criteria apply, please contact the investigator for more information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 13415	Peoria	Arizona	United States
2	Teva Investigational Site 13389	Downey	California	United States
3	Teva Investigational Site 13421	Huntington Beach	California	United States
4	Teva Investigational Site 13434	Huntington Beach	California	United States
5	Teva Investigational Site 13427	Los Angeles	California	United States
6	Teva Investigational Site 13386	Mission Viejo	California	United States
7	Teva Investigational Site 13394	Orange	California	United States
8	Teva Investigational Site 13417	Riverside	California	United States
9	Teva Investigational Site 13445	Rolling Hills Estates	California	United States
10	Teva Investigational Site 13420	San Diego	California	United States
11	Teva Investigational Site 13443	San Diego	California	United States
12	Teva Investigational Site 13438	San Jose	California	United States
13	Teva Investigational Site 13397	Centennial	Colorado	United States
14	Teva Investigational Site 13454	Denver	Colorado	United States
15	Teva Investigational Site 13404	Aventura	Florida	United States
16	Teva Investigational Site 13458	Hialeah	Florida	United States
17	Teva Investigational Site 13416	Miami	Florida	United States
18	Teva Investigational Site 13440	Miami	Florida	United States
19	Teva Investigational Site 13455	Miami	Florida	United States
20	Teva Investigational Site 13431	Ormond Beach	Florida	United States
21	Teva Investigational Site 13437	Sarasota	Florida	United States
22	Teva Investigational Site 13425	Tallahassee	Florida	United States
23	Teva Investigational Site 13450	Normal	Illinois	United States
24	Teva Investigational Site 13448	River Forest	Illinois	United States
25	Teva Investigational Site 13408	Lenexa	Kansas	United States
26	Teva Investigational Site 13410	Baltimore	Maryland	United States
27	Teva Investigational Site 13422	Bethesda	Maryland	United States
28	Teva Investigational Site 13435	Wheaton	Maryland	United States
29	Teva Investigational Site 13411	North Dartmouth	Massachusetts	United States
30	Teva Investigational Site 13398	Plymouth	Minnesota	United States
31	Teva Investigational Site 13429	Plymouth	Minnesota	United States
32	Teva Investigational Site 13433	Columbia	Missouri	United States
33	Teva Investigational Site 13432	Rolla	Missouri	United States
34	Teva Investigational Site 13414	Saint Louis	Missouri	United States
35	Teva Investigational Site 13430	Saint Louis	Missouri	United States
36	Teva Investigational Site 13384	Bellevue	Nebraska	United States
37	Teva Investigational Site 13392	Brick	New Jersey	United States
38	Teva Investigational Site 13426	Ocean City	New Jersey	United States
39	Teva Investigational Site 13419	Skillman	New Jersey	United States
40	Teva Investigational Site 13388	Rochester	New York	United States
41	Teva Investigational Site 13441	Hickory	North Carolina	United States
42	Teva Investigational Site 13403	Raleigh	North Carolina	United States
43	Teva Investigational Site 13405	Wilmington	North Carolina	United States
44	Teva Investigational Site 13395	Canton	Ohio	United States
45	Teva Investigational Site 13396	Cincinnati	Ohio	United States
46	Teva Investigational Site 13436	Sylvania	Ohio	United States
47	Teva Investigational Site 13423	Toledo	Ohio	United States
48	Teva Investigational Site 13387	Oklahoma City	Oklahoma	United States
49	Teva Investigational Site 13453	Eugene	Oregon	United States
50	Teva Investigational Site 13439	Lake Oswego	Oregon	United States
51	Teva Investigational Site 13402	Medford	Oregon	United States
52	Teva Investigational Site 13412	Portland	Oregon	United States
53	Teva Investigational Site 13391	Pittsburgh	Pennsylvania	United States
54	Teva Investigational Site 13449	East Providence	Rhode Island	United States
55	Teva Investigational Site 13456	Warwick	Rhode Island	United States
56	Teva Investigational Site 13413	North Charleston	South Carolina	United States
57	Teva Investigational Site 13390	Knoxville	Tennessee	United States
58	Teva Investigational Site 13442	Knoxville	Tennessee	United States
59	Teva Investigational Site 13400	Austin	Texas	United States
60	Teva Investigational Site 13452	Boerne	Texas	United States
61	Teva Investigational Site 13407	Dallas	Texas	United States
62	Teva Investigational Site 13424	Dallas	Texas	United States
63	Teva Investigational Site 13409	El Paso	Texas	United States
64	Teva Investigational Site 13451	Houston	Texas	United States
65	Teva Investigational Site 13399	New Braunfels	Texas	United States
66	Teva Investigational Site 13393	San Antonio	Texas	United States
67	Teva Investigational Site 13444	San Antonio	Texas	United States
68	Teva Investigational Site 13446	San Antonio	Texas	United States
69	Teva Investigational Site 13457	San Antonio	Texas	United States
70	Teva Investigational Site 13459	San Antonio	Texas	United States
71	Teva Investigational Site 13383	Waco	Texas	United States
72	Teva Investigational Site 13401	South Burlington	Vermont	United States
73	Teva Investigational Site 13385	Richmond	Virginia	United States
74	Teva Investigational Site 13447	Richmond	Virginia	United States
75	Teva Investigational Site 13428	Greenfield	Wisconsin	United States

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02513160
• Other Study ID Numbers: BDB-AS-30039; 2015-002510-80
• First Posted: Jul 31, 2015
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Additional relevant MeSH terms: Asthma; Beclomethasone; Albuterol

Study Results

Participant Flow

Recruitment Details	A total of 1089 patients with asthma were screened for enrollment into this study at 67 study centers in the US.
Pre-assignment Detail	Of the screened patients, 376 patients were not enrolled; 312 were excluded on the basis of inclusion/exclusion criteria, 19 patients withdrew consent, 10 patients were lost to follow-up before the baseline visit, 1 patient reported an adverse event before entering run-in and the reason for screen failure was "Other" for 34 patients.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Period Title: Run-In Period (Days -14 to Day -1)
STARTED	713	0	0	0
COMPLETED	425	0	0	0
NOT COMPLETED	288	0	0	0
Period Title: Run-In Period (Days -14 to Day -1)
STARTED	107	108	105	105
COMPLETED	101	104	104	103
NOT COMPLETED	6	4	1	2

Baseline Characteristics

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day	Total
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Total of all reporting groups
Overall Participants	107	108	105	105	425
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.2 (13.33)	41.8 (14.29)	42.6 (14.19)	43.1 (16.04)	41.7 (14.52)
Age, Customized (Count of Participants)
12-17 years	8 7.5%	2 1.9%	4 3.8%	7 6.7%	21 4.9%
18-64 years	98 91.6%	101 93.5%	94 89.5%	85 81%	378 88.9%
>=65 years	1 0.9%	5 4.6%	7 6.7%	13 12.4%	26 6.1%
Sex: Female, Male (Count of Participants)
Female	66 61.7%	68 63%	67 63.8%	59 56.2%	260 61.2%
Male	41 38.3%	40 37%	38 36.2%	46 43.8%	165 38.8%
Race/Ethnicity, Customized (Count of Participants)
White	87 81.3%	92 85.2%	83 79%	84 80%	346 81.4%
Black	15 14%	12 11.1%	19 18.1%	17 16.2%	63 14.8%
Asian	3 2.8%	1 0.9%	0 0%	1 1%	5 1.2%
American Indian or Alaskan Native	1 0.9%	0 0%	0 0%	0 0%	1 0.2%
Native Hawaiian or Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Other	1 0.9%	3 2.8%	3 2.9%	3 2.9%	10 2.4%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	89 83.2%	90 83.3%	93 88.6%	88 83.8%	360 84.7%
Hispanic or Latino	18 16.8%	18 16.7%	12 11.4%	17 16.2%	65 15.3%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	84.06 (25.337)	89.93 (24.719)	85.71 (25.590)	88.56 (23.820)	87.07 (24.987)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	167.34 (10.138)	169.30 (9.457)	167.82 (8.753)	169.14 (8.770)	168.40 (9.308)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.909 (8.4253)	31.315 (8.1551)	30.327 (8.3470)	30.944 (8.1645)	30.625 (8.2624)
Duration of Asthma (Count of Participants)
<3 months	0 0%	0 0%	0 0%	0 0%	0 0%
3 months to <6 months	0 0%	0 0%	0 0%	0 0%	0 0%
6 months to <1 year	0 0%	1 0.9%	0 0%	0 0%	1 0.2%
1 year to <5 years	5 4.7%	8 7.4%	6 5.7%	5 4.8%	24 5.6%
5 years to <10 years	6 5.6%	11 10.2%	7 6.7%	8 7.6%	32 7.5%
10 years to <15 years	12 11.2%	7 6.5%	8 7.6%	12 11.4%	39 9.2%
>=15 years	84 78.5%	81 75%	84 80%	80 76.2%	329 77.4%
Current Asthma Therapy (Count of Participants)
Inhaled corticosteroid	66 61.7%	66 61.1%	65 61.9%	65 61.9%	262 61.6%
Non-corticosteroid	41 38.3%	42 38.9%	40 38.1%	40 38.1%	163 38.4%

Outcome Measures

1. Primary Outcome

Title	Standardized Baseline-Adjusted Trough Morning Forced Expiratory Volume in One Minute (FEV1) Area Under the Effect Curve From Time Zero to 6 Weeks (AUEC(0-6wk))
Description	The primary efficacy variable was the standardized baseline-adjusted trough morning (pre-dose and pre-rescue bronchodilator) FEV1 AUEC(0-6wk). Pulmonary function measurements such as FEV1 were obtained electronically by spirometry at the randomization visit, each treatment visit (Weeks 2, 4 and 6) and any unscheduled visit (such as the early termination visit). The highest FEV1 value from 3 acceptable and 2 repeatable maneuvers (maximum of 8 attempts) was used. The least-square (LS) means, difference of LS means and its 95% confidence interval (CI), and p-value represent the results obtained from the analysis of covariance with covariate adjustment for baseline, sex, age, current asthma therapy, and treatment.
Time Frame	Baseline (Day 0 of Treatment Period), weeks 2, 4, 6

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) analysis set included all patients in the ITT analysis set and included the available data for those patients until they discontinued study drug treatment at treatment visit week 6 or last available study visit.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Measure Participants	105	105	104	103
Least Squares Mean (Standard Error) [milliliters]	62 (23.0)	205 (23.2)	212 (23.3)	210 (23.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 640 mcg/Day
	Comments	A fixed-sequence multiple testing procedure was implemented to interpret the results from the primary analysis while controlling the family-wise error rate at 5%. The 640-mcg/day BAI dose was tested first. If the comparison to placebo resulted in p≤0.05, the 320-mcg/day BAI dose was then tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	ANCOVA
	Comments	Difference of LS means, 95% CI, and p-value represent ANCOVA results adjusted for baseline, sex, age, current asthma therapy, and treatment.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	150
	Confidence Interval	(2-Sided) 95%; 86.8 to 213.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 320 mcg/Day
	Comments	A fixed-sequence multiple testing procedure was implemented to interpret the results from the primary analysis while controlling the family-wise error rate at 5%. The 640-mcg/day BAI dose was tested first. If the comparison to placebo resulted in p≤0.05, the 320-mcg/day BAI dose was then tested.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	ANCOVA
	Comments	Difference of LS means, 95% CI, and p-value represent ANCOVA results adjusted for baseline, sex, age, current asthma therapy, and treatment.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	144
	Confidence Interval	(2-Sided) 95%; 80.7 to 206.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, MDI 320 mcg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05. The p-value was not adjusted.
	Method	ANCOVA
	Comments	Difference of LS means and 95% CI represent ANCOVA results adjusted for baseline, sex, age, current asthma therapy, and treatment.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	148
	Confidence Interval	(2-Sided) 95%; 84.7 to 211.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

2. Secondary Outcome

Title	Change From Baseline in Weekly Average of Daily Trough Morning Peak Expiratory Flow (PEF) Rate Over the 6-Week Treatment Period
Description	Change from baseline in the weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) PEF by handheld spirometer over the 6-week treatment period. PEF were determined twice daily, in the morning and in the evening, before administration of study drug or rescue medications. A handheld spirometer was provided to patients and used to determine the morning and evening PEF throughout the study. The spirometer was programmed to record the highest PEF obtained from 3 valid attempts. Baseline was defined as the average of recorded trough morning PEF assessments over the 7 days prior to the first dose of double-blind study treatment, including the morning assessment at the randomization visit. The LS means, difference of LS means and its 95% confidence interval, and p value are obtained from the mixed model for repeated measures analysis with covariate adjustment for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Time Frame	Timeframes: Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) analysis set included all patients in the ITT analysis set and included the available data for those patients until they discontinued study drug treatment at treatment visit week 6 or last available study visit.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Measure Participants	106	108	105	104
Least Squares Mean (Standard Error) [liters/minute]	-10.0 (4.31)	20.1 (4.30)	11.9 (4.28)	10.9 (4.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 640 mcg/Day
	Comments	Treatment comparisons began with am PEF for BAI 640 mcg/day vs placebo. If the p-value was ≤0.05, the next comparisons of interest were made 1) the next secondary outcome comparison for BAI 640 mcg/day vs placebo 2) the am PEF for BAI 320 mcg/day vs placebo. This procedure allowed for control of the Type I error for comparisons at a particular BAI treatment over the 5 secondary endpoints, as well as comparisons within an endpoint. It did not control the overall Type I error.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	21.9
	Confidence Interval	(2-Sided) 95%; 10.11 to 33.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 320 mcg/Day
	Comments	Sequential order of analyses described in previous analysis.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	30.1
	Confidence Interval	(2-Sided) 95%; 18.33 to 41.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, MDI 320 mcg/Day
	Comments	Comparisons for MDI dose versus placebo for the secondary efficacy endpoints were used for assay sensitivity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	21.0
	Confidence Interval	(2-Sided) 95%; 9.14 to 32.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

3. Secondary Outcome

Title	Change From Baseline in Weekly Average of Daily Trough Morning Forced Expiratory Volume in One Minute (FEV1) Rate Over the 6-Week Treatment Period
Description	Change from baseline in the weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) FEV1 by handheld spirometer over the 6-week treatment period. FEV1 were determined twice daily, in the morning and in the evening, before administration of study drug or rescue medications. A handheld spirometer was provided to patients and used to determine the morning and evening FEV1 throughout the study. The spirometer was programmed to record the highest FEV1 obtained from 3 valid attempts. Baseline was defined as the average of recorded trough morning FEV1 assessments over the 7 days prior to the first dose of double-blind study treatment, including the morning assessment at the randomization visit. The LS means, difference of LS means and its 95% confidence interval, and p value are obtained from the mixed model for repeated measures analysis with covariate adjustment for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Time Frame	Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) analysis set included all patients in the ITT analysis set and included the available data for those patients until they discontinued study drug treatment at treatment visit week 6 or last available study visit.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Measure Participants	106	108	105	104
Least Squares Mean (Standard Error) [milliliters]	-8 (26.0)	162 (25.8)	135 (25.9)	125 (25.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 640 mcg/Day
	Comments	Sequential order of analyses described in Outcome #2, analysis #1.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	143
	Confidence Interval	(2-Sided) 95%; 71.7 to 214.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 320 mcg/Day
	Comments	Sequential order of analyses described in Outcome #2, analysis #1.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	170
	Confidence Interval	(2-Sided) 95%; 98.5 to 240.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, MDI 320 mcg/Day
	Comments	Comparisons for MDI dose versus placebo for the secondary efficacy endpoints were used for assay sensitivity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	133
	Confidence Interval	(2-Sided) 95%; 61.3 to 204.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

4. Secondary Outcome

Title	Change From Baseline in Weekly Average of Total Daily (24-Hour) Rescue Medication Use Over the 6-Week Treatment Period
Description	Change from baseline in the weekly average of total daily (24-hour) use of albuterol/salbutamol inhalation aerosol over weeks 1 through 6. Patients recorded the number of inhalations (puffs used) of rescue medication (albuterol/salbutamol HFA MDI [90 mcg ex-actuator] or equivalent) each morning and evening in the diary. The average number of daily inhalations over the 7 days before the randomization visit was the baseline value and was compared with the rescue medication use during the 6-week treatment period.
Time Frame	Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) analysis set included all patients in the ITT analysis set and included the available data for those patients until they discontinued study drug treatment at treatment visit week 6 or last available study visit.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Measure Participants	106	108	105	104
Least Squares Mean (Standard Error) [number of inhalations]	0.37 (0.140)	-0.73 (0.139)	-0.66 (0.140)	-0.66 (0.139)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 640 mcg/Day
	Comments	Sequential order of analyses described in Outcome #2, analysis #1.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 95%; -1.408 to -0.640
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 320 mcg/Day
	Comments	Sequential order of analyses described in Outcome #2, analysis #1.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-1.10
	Confidence Interval	(2-Sided) 95%; -1.482 to -0.717
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, MDI 320 mcg/Day
	Comments	Comparisons for MDI dose versus placebo for the secondary efficacy endpoints were used for assay sensitivity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-1.03
	Confidence Interval	(2-Sided) 95%; -1.415 to -0.643
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

5. Secondary Outcome

Title	Change From Baseline in Weekly Average of Total Daily Asthma Symptom Score Over the 6-Week Treatment Period
Description	Asthma symptom scores were recorded in the patient's diary each morning and evening before determining FEV1 and PEF and before administration of study or rescue medications. The Daytime Symptom Score was recorded in the evening on a scale of 0 (No symptoms during the day) to 5 (Symptoms so severe that I could not go to work or perform normal daily activities) plus the Nighttime Symptom Score in the morning on a scale of 0 (No symptoms during the night) to 4 (Symptoms so severe that I did not sleep at all) for a total score range of 0-9. Baseline was defined as the average of recorded daily asthma symptom scores (average of daytime and nighttime score) over the 7 days prior to the first dose of double-blind study treatment, including the morning assessment at the randomization visit. The LS means, difference of LS means and its 95% CI, and p value are obtained from the mixed model for repeated measures analysis with covariate adjustment for baseline, sex, age, current asth
Time Frame	Baseline (Day -7 to Day 0 which is part of the Run-in Period); Treatment Period from Day 0 up to 6 weeks

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) analysis set included all patients in the ITT analysis set and included the available data for those patients until they discontinued study drug treatment at treatment visit week 6 or last available study visit.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Measure Participants	106	107	105	104
Least Squares Mean (Standard Error) [units on a scale]	0.06 (0.043)	-0.18 (0.043)	-0.26 (0.043)	-0.24 (0.043)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 640 mcg/Day
	Comments	Sequential order of analyses described in Outcome #2, analysis #1.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.440 to -0.203
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 320 mcg/Day
	Comments	Sequential order of analyses described in Outcome #2, analysis #1.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.365 to -0.128
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, MDI 320 mcg/Day
	Comments	Comparisons for MDI dose versus placebo for the secondary efficacy endpoints were used for assay sensitivity.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	a priori threshold for significance of 0.05.
	Method	mixed model for repeated measures
	Comments	MMRM analysis with covariates for baseline, sex, age, current asthma therapy, treatment, week, and treatment by week interaction.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.423 to -0.185
	Parameter Dispersion	Type: Value:
	Estimation Comments	Active - placebo

6. Secondary Outcome

Title	Count of Participants Withdrawn From Study Drug Treatment Due to Meeting Stopping Criteria for Worsening Asthma
Description	Number of participants who were withdrawn from study drug due to worsening asthma. Alert criteria for individual patients with worsening asthma were designed to ensure patient safety. The investigator determined whether the patient's overall clinical picture was consistent with worsening asthma and if the patient should be withdrawn from study drug treatment (but not the study) and be placed on appropriate asthma therapy in the interest of patient safety. An example of an alert criteria is: Morning FEV1 by handheld spirometer as measured at home falls below the FEV1 stability limit (FEV1 <80%) as calculated at the screening visit for the Run-in Period and at the randomization visit (Day 0) for the Treatment Period on 4 or more days out of any 7-day period.
Time Frame	Day 0 to Week 6

Outcome Measure Data

Analysis Population Description

The modified intent-to-treat (mITT) analysis set included all patients in the ITT analysis set and included the available data for those patients until they discontinued study drug treatment at treatment visit week 6 or last available study visit.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Measure Participants	107	108	105	105
Count of Participants [Participants]	10 9.3%	1 0.9%	0 0%	1 1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 320 mcg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0058
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, BAI 640 mcg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, MDI 320 mcg/Day
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0062
	Comments
	Method	Log Rank
	Comments

7. Secondary Outcome

Title	Participants With Treatment-Emergent Adverse Events (TEAE)
Description	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 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/birth defect, or an important medical event that may not result in death, be life-threatening, or require hospitalization, but may jeopardize the patient and may require medical intervention to prevent one of the outcomes listed in this definition.
Time Frame	Day 0 to Week 6

Outcome Measure Data

Analysis Population Description

The safety analysis set included all randomly assigned patients (ITT analysis set) who received at least 1 dose of study drug. In this analysis set, treatment was assigned based on the treatment patients actually received, regardless of the treatment to which they were randomly assigned.

Arm/Group Title	Placebo	BAI 320 mcg/Day	BAI 640 mcg/Day	MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.	Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for 6 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) (90 mcg ex-actuator) or equivalent was supplied by the sponsor for use as rescue medication during the run-in and double-blind study periods.
Measure Participants	107	108	105	105
>=1 adverse event	20 18.7%	22 20.4%	32 30.5%	32 30.5%
>=1 mild TEAE	10 9.3%	10 9.3%	18 17.1%	20 19%
>=1 moderate TEAE	9 8.4%	11 10.2%	10 9.5%	11 10.5%
>=1 severe TEAE	1 0.9%	1 0.9%	4 3.8%	1 1%
>=1 treatment-related TEAE	1 0.9%	2 1.9%	9 8.6%	4 3.8%
>=1 serious TEAE	0 0%	0 0%	2 1.9%	0 0%
>=1 AE leading to withdrawal of study drug	0 0%	1 0.9%	1 1%	0 0%

Adverse Events

Time Frame	Run-in Period: up to Day -30 to Day 0 Treatment Period: Day 0 to Week 6
Arm/Group Title	Run-in Placebo		Placebo		BAI 320 mcg/Day		BAI 640 mcg/Day		MDI 320 mcg/Day
Arm/Group Description	Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for up to 30 days of the single-blind Run-in Period.		Pooled breath-actuated inhaler (BAI) and metered-dose inhaler (MDI) placebo groups. Participants were instructed to take 4 inhalations twice daily for the 6 weeks of the double-blind Treatment Period.		Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for the 6 weeks of the double-blind Treatment Period.		Beclomethasone dipropionate breath-actuated inhaler (BAI), 4 inhalations (80 mcg/inhalation), twice daily for a total daily dose of 640 mcg for the 6 weeks of the double-blind Treatment Period.		Beclomethasone dipropionate metered-dose inhaler (MDI), 4 inhalations (40 mcg/inhalation), twice daily for a total daily dose of 320 mcg for the 6 weeks of the double-blind Treatment Period.
All Cause Mortality
	Run-in Placebo		Placebo		BAI 320 mcg/Day		BAI 640 mcg/Day		MDI 320 mcg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Run-in Placebo		Placebo		BAI 320 mcg/Day		BAI 640 mcg/Day		MDI 320 mcg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/713 (0.1%)		0/107 (0%)		0/108 (0%)		2/105 (1.9%)		0/105 (0%)
Ear and labyrinth disorders
Vertigo positional	0/713 (0%)	0	0/107 (0%)	0	0/108 (0%)	0	1/105 (1%)	1	0/105 (0%)	0
Infections and infestations
Appendicitis	1/713 (0.1%)	1	0/107 (0%)	0	0/108 (0%)	0	0/105 (0%)	0	0/105 (0%)	0
Injury, poisoning and procedural complications
Intentional overdose	0/713 (0%)	0	0/107 (0%)	0	0/108 (0%)	0	1/105 (1%)	1	0/105 (0%)	0
Psychiatric disorders
Suicidal behaviour	0/713 (0%)	0	0/107 (0%)	0	0/108 (0%)	0	1/105 (1%)	1	0/105 (0%)	0
Other (Not Including Serious) Adverse Events
	Run-in Placebo		Placebo		BAI 320 mcg/Day		BAI 640 mcg/Day		MDI 320 mcg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/713 (0%)		3/107 (2.8%)		5/108 (4.6%)		5/105 (4.8%)		10/105 (9.5%)
Infections and infestations
Upper respiratory tract infection	0/713 (0%)	0	3/107 (2.8%)	3	5/108 (4.6%)	5	5/105 (4.8%)	5	10/105 (9.5%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.