Randomized, Placebo-Controlled, Multidose, Study Comparing Generic Budesonide/Formoterol Fumarate Dihydrate to Symbicort® in Asthmatic Participants

• Sponsor: Actavis Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02495168
• Collaborator: Teva Pharmaceuticals USA (Industry)
• Enrollment: 1,714
• Locations: 17
• Arms: 3
• Actual Duration (Months): 16.5
• Patients Per Site: 100.8
• Patients Per Site Per Month: 6.1

Study Details

Study Description

Brief Summary

This study has a randomized multiple-dose, placebo-controlled, parallel group design consisting of a 2-week open placebo Run-in Period followed by a 6-week Treatment Period with placebo, test product (budesonide 80 microgram [μg]/formoterol fumarate dihydrate 4.5 μg), or reference product (Symbicort® inhalation aerosol).

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Generic Budesonide/Formoterol Fumarate Dihydrate; Drug: Symbicort® (Budesonide/Formoterol Fumarate Dihydrate); Drug: Placebo	Phase 3

Detailed Description

This is a pivotal trial that will examine the therapeutic equivalence of a new generic fixed-dose combination product containing budesonide 80 μg/formoterol fumarate dihydrate 4.5 μg and reference listed drug (RLD) Symbicort® inhalation aerosol in adult participants with chronic but stable asthma as defined in National Asthma Education and Prevention Program Expert Panel Report 3 (NAEPP 3) guidelines. To ensure adequate study sensitivity, the test and reference products should both be statistically superior to placebo (p<0.05) with regard to the bioequivalent study primary endpoints. Participants will be provided a generic placebo pressurized metered-dose inhaler (pMDI) device for use during the 2-week Run-in Period for device training.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1714 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Blinded, Parallel Group, Placebo-Controlled, Multiple Dose, Multicenter, Multinational Study to Compare the Therapeutic Equivalence of a Budesonide 80 μg/Formoterol Fumarate Dihydrate 4.5 μg Inhalation Aerosol (Manufactured by Catalent for Watson Laboratories Inc.) to Symbicort® (Budesonide 80 μg/Formoterol Fumarate Dihydrate 4.5 μg Inhalation Aerosol) (Manufactured by AstraZeneca) in Adolescent and Adult Patients With Asthma
• Actual Study Start Date: Jan 13, 2017
• Actual Primary Completion Date: May 31, 2018
• Actual Study Completion Date: May 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Generic Budesonide/Formoterol Fumarate Dihydrate After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants will administer 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	Drug: Generic Budesonide/Formoterol Fumarate Dihydrate; Oral inhalation, generic formulation of the brand-name product.
Active Comparator: Symbicort (Budesonide/Formoterol Fumarate Dihydrate) After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants will administer 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	Drug: Symbicort® (Budesonide/Formoterol Fumarate Dihydrate); Oral inhalation, brand-name product.; Other Names: Symbicort Turbohaler®
Placebo Comparator: Placebo After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants will administer 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.	Drug: Placebo; Oral inhalation, no active ingredient.

Outcome Measures

Primary Outcome Measures

1. Equivalence Analysis of Area Under the Serial FEV1-Time Effect Curve From Time 0 to 12 Hours (FEV1 Area Under Curve [AUC0-12]) on the First Day of Treatment [0 to 12 hours on Day 1]

   FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Baseline-adjusted area under the serial FEV1-time curve was calculated from Time 0 to 12 hours on the first day of the Treatment Period (Day 1). FEV1 AUC0-12 was calculated from baseline-adjusted values using the linear trapezoidal method. The calculation assumed that at time of dosing (Time 0) the baseline adjusted FEV1 was also 0. The calculation proceeded over all available post-dose FEV1 assessments on Day 1 (including unscheduled time points, if any) using actual elapsed time from dosing. FEV1 baseline defined as the average of predose FEV1 values obtained on Day 1. If some of these values were missing, the average was calculated using the available values, however, a minimum of 2 predose FEV1 values were required; participants who had only 1 or no predose FEV1 measurements on Day 1 would have their FEV1 baseline missing, and the participant was to be excluded from analysis.

2. Superiority Analysis of Area Under the Serial FEV1-Time Effect Curve From Time 0 to 12 Hours (FEV AUC0-12) on the First Day of Treatment [0 to 12 hours on Day 1]

   FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Baseline-adjusted area under the serial FEV1-time curve was calculated from Time 0 to 12 hours on the first day of the Treatment Period (Day 1). FEV1 AUC0-12 was calculated from baseline-adjusted values using the linear trapezoidal method. The calculation assumed that at time of dosing (Time 0) the baseline adjusted FEV1 was also 0. The calculation proceeded over all available post-dose FEV1 assessments on Day 1 (including unscheduled time points, if any) using actual elapsed time from dosing. FEV1 baseline defined as the average of predose FEV1 values obtained on Day 1. If some of these values were missing, the average was calculated using the available values, however, a minimum of 2 predose FEV1 values were required; participants who had only 1 or no predose FEV1 measurements on Day 1 would have their FEV1 baseline missing, and the participant was to be excluded from analysis.

3. Equivalence Analysis of Baseline-Adjusted Average Predose FEV1 at End of Treatment [Day 1 up to Day 50]

   FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Average predose FEV1 at End of Treatment defined as the average of all predose assessments on Day 42. If a participant had no predose assessment on Day 42, the average of all available predose assessments on the last day (for example, Early Termination visit [up to Day 50]) when at least 1 predose FEV1 assessments was available was imputed, if the participant discontinued due to lack of efficacy, otherwise there was no imputation. Baseline was defined as the average of at least 2 predose FEV1 values obtained on Day 1. The endpoint of baseline-adjusted predose FEV1 at end of treatment was calculated as follows: [FEV1 at end of treatment] - [Baseline FEV1].

4. Superiority Analysis of Baseline-Adjusted Average Predose FEV1 at End of Treatment [Day 1 up to Day 50]

   FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Average predose FEV1 at End of Treatment defined as the average of all predose assessments on Day 42. If a participant had no predose assessment on Day 42, the average of all available predose assessments on the last day (for example, Early Termination visit [up to Day 50]) when at least 1 predose FEV1 assessments was available was imputed, if the participant discontinued due to lack of efficacy, otherwise there was no imputation. Baseline was defined as the average of at least 2 predose FEV1 values obtained on Day 1. The endpoint of baseline-adjusted predose FEV1 at end of treatment was calculated as follows: [FEV1 at end of treatment] - [Baseline FEV1].

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Adolescent and adult male or female participants (≥12 and ≤75 years of age).

2. Female participants must not be lactating or pregnant at Screening, as documented by a negative serum pregnancy test with a minimum sensitivity of 25 international unit/liter (IU/L) or equivalent units of beta-human chorionic gonadotropin (β-hCG) at Screening.

3. Women of childbearing potential (WOCBP) and female partners (WOCBP) of male participants participating in the study, must commit to consistent and correct use of an acceptable method of birth control (at the Investigator's discretion) throughout the study and for 30 days after study drug discontinuation.

4. Male participants and male partners of female participants (WOCBP) must commit to consistent and correct use of an acceptable method of birth control (at the Investigator's discretion) throughout the study and for 30 days after the study drug discontinuation.

5. Diagnosed with asthma as defined by the NAEPP 3 at least 6 months prior to Screening. If the participant is new to the study site, the Investigator must confirm the participant's asthma diagnosis. Acceptable means include either medical records or pharmacy records.

6. Moderate to severe asthma with a pre-bronchodilator forced expiratory volume in 1 second (FEV1) of ≥45% and ≤85% of the predicted normal value during measured at least 6 hours after short-acting β agonist (SABA) and at least 24 hours after the last dose of long-acting β agonist (LABA) at Screening and prior to randomization on Day 1.

7. Currently non-smoking, negative for urine cotinine at Screening, having not used tobacco products (that is, cigarettes, cigars, pipe tobacco, and electronic cigarettes) within the past year, and had ≤10 pack-years of historical use.

8. Body mass index (BMI) between 18 to 40 (inclusive) for participants ≥18 years old. For adolescent participants 12 to 17 years old, BMI between 15 to 40 inclusive (in accordance with the BMI range typical for the age).

9. ≥15% and ≥0.20 L reversibility of FEV1 within 30 minutes following 360 μg (4 puffs) of albuterol (400 μg salbutamol) inhalation (pMDI). If the participant achieves <15%, but ≥10% reversibility at the Screening, the site may instruct the participant to hold LABA and/or inhaled corticosteroids (ICS) and return up to 7 days later for a repeat test. Only 1 repeat of the Screening spirometry test (to retest reversibility) is allowed.

10. Able to perform valid and reproducible spirometry results per American Thoracic Society/European Respiratory Society (ATS/ERS) standards at Screening.

11. Able to inhale study drug properly.

12. Willing to discontinue asthma medications (ICS and LABAs) during the Run-in Period and for the remainder of the study.

13. Able to replace current regularly scheduled SABAs with albuterol/salbutamol inhaler for use only on as needed basis for the duration of the study (participants should be able to withhold all inhaled SABAs for at least 6 hours prior to lung function assessments on study visits).

14. Able to continue the following medications without a significant adjustment of dosage, formulation, dosing interval for the duration of the study, and judged able by the Investigator to withhold them for the specified minimum time intervals prior to each clinic visit, if applicable:

15. Short-acting forms of theophylline: 12 hours.

16. Twice-a-day controlled-release forms of theophylline: 24 hours.

17. Once-a-day controlled-release forms of theophylline: 36 hours.

18. Able to discontinue the following medications for the specified minimum time intervals prior to the Run-in Period and for the remainder of the study, if applicable:

19. Oral corticosteroids for 30 days.

20. Parenteral corticosteroids for 30 days.

21. Oral (not inhaled) SABAs for 24 hours.

22. Clinical laboratory tests (clinical chemistry, hematology, and urinalysis) and 12-lead electrocardiogram (ECG) conducted at Screening within normal limits or abnormal but not clinically significant to the Investigator. The QTc should be calculated using Bazett's formula.

23. Willing to give written informed consent/assent, and willing and able to follow the study rules and procedures.

24. Stable on chronic asthma treatment regimen for at least 4 weeks prior to enrollment.

25. Ability to perform forced expiratory assessments according to ATS standards.

Randomization eligibility criteria:

1. Baseline pre-bronchodilator FEV1 should be ≥45% and ≤85% of predicted normal value and not vary by more than ±20% from Screening FEV1 value.

2. Compliance during the Run-in Period of at least 75% based on electronic Diary entries is required for a participant to qualify for randomization. Compliance with the run-in placebo treatment must be between 75% and 125%.

3. Documented total asthma symptom score of ≥1 for at least 2 days during the Run-in Period.

Exclusion criteria:

1. 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 or during the Run-in Period.

2. Exercise-induced asthma as the only asthma-related diagnosis.

3. Evidence or history of clinically significant disease or abnormality including congestive heart failure, uncontrolled hypertension, uncontrolled coronary artery disease, myocardial infarction, or cardiac dysrhythmia. In addition, historical or current evidence of significant hematologic, hepatic, neurologic, psychiatric, renal, or other diseases that in the opinion of the Investigator would put the participant at risk through study participation or would affect the study analyses if the disease exacerbated during the study. Participants with well-controlled hypertension, diabetes or hypercholesterolemia are not excluded as long as their medication does not interfere with the study.

4. Any other clinically significant pulmonary disease except for asthma, including chronic obstructive pulmonary disease (COPD), interstitial lung disease, cystic fibrosis, bronchiectasis, chronic bronchitis, emphysema, active pulmonary tuberculosis, pulmonary carcinoma, pulmonary fibrosis, or pulmonary hypertension. In addition, obstructive sleep apnea warranting a prescription for continuous or biphasic positive airway pressure (continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]).

5. Participants who required systemic corticosteroids (for any reason) within the past 4 weeks.

6. Participants with hypersensitivity to any sympathomimetic drug (for example, formoterol, albuterol/salbutamol, or salmeterol) or any inhaled, intranasal, or systemic corticosteroid therapy.

7. Participants taking medication(s) (either daily or as needed) with the potential to affect the course of asthma or to interact with sympathomimetic amines, for example:

8. Oral β-blockers.

9. Strong cytochrome P450 3A4 inhibitors (for example, ritonavir).

10. Monoclonal antibodies/Biologic agents which may affect the course of asthma (such as mepolizumab, reslizumab, lebrikizumab, and others).

11. Viral or bacterial, upper or lower respiratory tract infection or sinus or middle ear infection within 2 weeks prior to Screening or during the Run-in Period.

12. Factors (for example, infirmity, disability or geographic location) that the Investigator feels would likely limit the participant's compliance with the study protocol or scheduled clinic visits.

13. Anti-Immunoglobulin E (IgE) (such as omalizumab) use within the 6 months prior to screening.

14. History of alcohol or drug abuse within the last 6 months.

15. A positive urine drug screen at Screening. Exceptions are made for a positive urine drug screen at Screening for opiates or stimulants if there is a documented prescription with supporting medical history and diagnosis, and the Principal Investigator assesses there are no safety concerns with participant participation. Screened participants with a urine drug screen positive for marijuana/tetrahydrocannabinol are not eligible for study participation, without exceptions. Repeat drug screening is not allowed.

16. Have received any other investigational treatment within 30 days (or within 5 terminal half-lives of the investigational drug whichever is longer) of Screening or plans to receive investigational treatment within 30 days after the study is completed.

17. Be an Investigator, employee, or otherwise be directly affiliated with the study site, Watson Laboratories Inc. and affiliates, or service provider involved in the study including being an immediate family member of an Investigator or site employee (that is, spouse, parent, child, or sibling), whether biological or legally adopted or in foster care.

18. Non-compliance with the study requirements, rules, and procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 100	Surprise	Arizona	United States
2	Site 101	Huntington Beach	California	United States
3	111	San Jose	California	United States
4	114	Centennial	Colorado	United States
5	104	Hialeah	Florida	United States
6	103	Miami	Florida	United States
7	105	Miami	Florida	United States
8	107	Miami	Florida	United States
9	106	Bozeman	Montana	United States
10	113	Bellevue	Nebraska	United States
11	112	Cincinnati	Ohio	United States
12	108	Edmond	Oklahoma	United States
13	115	Eugene	Oregon	United States
14	116	Medford	Oregon	United States
15	110	Rock Hill	South Carolina	United States
16	109	Smyrna	Tennessee	United States
17	102	Waco	Texas	United States

Sponsors and Collaborators

• Actavis Inc.
• Teva Pharmaceuticals USA

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 11, 2018
• Study Protocol - Feb 24, 2017

More Information

Publications

None provided.

• Responsible Party: Actavis Inc.
• ClinicalTrials.gov Identifier: NCT02495168
• Other Study ID Numbers: ACT-2015-075-0AA
• First Posted: Jul 13, 2015
• Last Update Posted: Nov 29, 2019
• Last Verified: Nov 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Asthma; Budesonide; Formoterol Fumarate; Budesonide, Formoterol Fumarate Drug Combination

Study Results

Participant Flow

Pre-assignment Detail	Participants (N=1714) were provided a generic placebo pressurized metered dose inhaler (pMDI) device for use during a 2-week Run-in Period for device training. Then, qualified participants (N=1147) were randomly assigned to treatment on a 4:4:1 ratio of generic budesonide/formoterol fumarate dihydrate, Symbicort, or Placebo, respectively.

Arm/Group Title	Generic Budesonide/Formoterol Fumarate Dihydrate	Symbicort (Budesonide/Formoterol Fumarate Dihydrate)	Placebo
Arm/Group Description	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 microgram [μg]/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.
Period Title: Overall Study
STARTED	504	516	127
Safety Population	501	514	126
Modified Intent-to-Treat Population	468	478	111
Day1 Per-protocol Set (D1PPS) Population	437	437	99
Day 42 (D42PPS) Population	382	383	88
COMPLETED	466	462	110
NOT COMPLETED	38	54	17

Baseline Characteristics

Arm/Group Title	Generic Budesonide/Formoterol Fumarate Dihydrate	Symbicort (Budesonide/Formoterol Fumarate Dihydrate)	Placebo	Total
Arm/Group Description	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.	Total of all reporting groups
Overall Participants	501	514	126	1141
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.7 (15.39)	43.9 (15.56)	41.5 (15.88)	43.1 (15.53)
Sex: Female, Male (Count of Participants)
Female	299 59.7%	292 56.8%	70 55.6%	661 57.9%
Male	202 40.3%	222 43.2%	56 44.4%	480 42.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	171 34.1%	180 35%	48 38.1%	399 35%
Not Hispanic or Latino	330 65.9%	334 65%	78 61.9%	742 65%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 0.4%	0 0%	2 0.2%
Asian	9 1.8%	11 2.1%	5 4%	25 2.2%
Native Hawaiian or Other Pacific Islander	0 0%	2 0.4%	0 0%	2 0.2%
Black or African American	90 18%	86 16.7%	23 18.3%	199 17.4%
White	402 80.2%	410 79.8%	97 77%	909 79.7%
More than one race	0 0%	3 0.6%	1 0.8%	4 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Forced Expiratory Volume in 1 Second (FEV1) (liters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [liters]	2.113 (0.5524)	2.083 (0.5400)	2.136 (0.5975)	2.102 (0.5515)

Outcome Measures

1. Primary Outcome

Title	Equivalence Analysis of Area Under the Serial FEV1-Time Effect Curve From Time 0 to 12 Hours (FEV1 Area Under Curve [AUC0-12]) on the First Day of Treatment
Description	FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Baseline-adjusted area under the serial FEV1-time curve was calculated from Time 0 to 12 hours on the first day of the Treatment Period (Day 1). FEV1 AUC0-12 was calculated from baseline-adjusted values using the linear trapezoidal method. The calculation assumed that at time of dosing (Time 0) the baseline adjusted FEV1 was also 0. The calculation proceeded over all available post-dose FEV1 assessments on Day 1 (including unscheduled time points, if any) using actual elapsed time from dosing. FEV1 baseline defined as the average of predose FEV1 values obtained on Day 1. If some of these values were missing, the average was calculated using the available values, however, a minimum of 2 predose FEV1 values were required; participants who had only 1 or no predose FEV1 measurements on Day 1 would have their FEV1 baseline missing, and the participant was to be excluded from analysis.
Time Frame	0 to 12 hours on Day 1

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, no major inclusion/exclusion violations, enrolled in the study only once, and no major protocol violations that impacted analysis of the Day 1 FEV1 AUC (D1PPS Population).

Arm/Group Title	Generic Budesonide/Formoterol Fumarate Dihydrate	Symbicort (Budesonide/Formoterol Fumarate Dihydrate)	Placebo
Arm/Group Description	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.
Measure Participants	437	437	99
Mean (Standard Deviation) [Liter*hour (Lh)]	3.637 (3.2532)	3.584 (2.9913)	1.460 (3.3183)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Budesonide/Formoterol Fumarate Dihydrate, Symbicort (Budesonide/Formoterol Fumarate Dihydrate)
	Comments
	Type of Statistical Test	Equivalence
	Comments	To show the clinical equivalence, an analysis of covariance (ANCOVA) model was fit on the participants from the generic budesonide/formoterol fumarate and Symbicort groups only, with the endpoint as outcome and treatment, study site and treatment by site interaction as fixed effects and FEV1 baseline value as covariate. If the treatment-by-site interaction factor was not significant at the 0.05 level, the model was to be rerun without the interaction term.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test/Referece LS Mean Ratio
	Estimated Value	101.9
	Confidence Interval	(2-Sided) 90%; 92.7 to 111.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Fieller's formula was applied to calculate the 90% confidence interval (CI) for the generic budesonide/formoterol fumarate and Symbicort LS mean ratio; covariance between treatment means was assumed to be 0.

2. Primary Outcome

Title	Superiority Analysis of Area Under the Serial FEV1-Time Effect Curve From Time 0 to 12 Hours (FEV AUC0-12) on the First Day of Treatment
Description	FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Baseline-adjusted area under the serial FEV1-time curve was calculated from Time 0 to 12 hours on the first day of the Treatment Period (Day 1). FEV1 AUC0-12 was calculated from baseline-adjusted values using the linear trapezoidal method. The calculation assumed that at time of dosing (Time 0) the baseline adjusted FEV1 was also 0. The calculation proceeded over all available post-dose FEV1 assessments on Day 1 (including unscheduled time points, if any) using actual elapsed time from dosing. FEV1 baseline defined as the average of predose FEV1 values obtained on Day 1. If some of these values were missing, the average was calculated using the available values, however, a minimum of 2 predose FEV1 values were required; participants who had only 1 or no predose FEV1 measurements on Day 1 would have their FEV1 baseline missing, and the participant was to be excluded from analysis.
Time Frame	0 to 12 hours on Day 1

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, no major inclusion/exclusion violations, and enrolled in the study only once (mITT Population) and with evaluable FEV1 AUC data.

Arm/Group Title	Generic Budesonide/Formoterol Fumarate Dihydrate	Symbicort (Budesonide/Formoterol Fumarate Dihydrate)	Placebo
Arm/Group Description	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.
Measure Participants	468	478	111
Mean (Standard Deviation) [Lh]	3.630 (3.2528)	3.573 (2.9960)	1.449 (3.3033)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Budesonide/Formoterol Fumarate Dihydrate, Placebo
	Comments	LS means difference and p-value from ANCOVA model with treatment and site as fixed effects, baseline FEV1 as covariate and endpoint as outcome on generic budesonide/formoterol fumarate dihydrate and Placebo participants only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.334
	Confidence Interval	(2-Sided) 95%; 1.673 to 2.996
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Symbicort (Budesonide/Formoterol Fumarate Dihydrate), Placebo
	Comments	LS means difference and p-value from ANCOVA model with treatment and site as fixed effects, baseline FEV1 as covariate and endpoint as outcome on Symbicort and Placebo participants only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.606
	Confidence Interval	(2-Sided) 95%; 1.939 to 3.273
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Equivalence Analysis of Baseline-Adjusted Average Predose FEV1 at End of Treatment
Description	FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Average predose FEV1 at End of Treatment defined as the average of all predose assessments on Day 42. If a participant had no predose assessment on Day 42, the average of all available predose assessments on the last day (for example, Early Termination visit [up to Day 50]) when at least 1 predose FEV1 assessments was available was imputed, if the participant discontinued due to lack of efficacy, otherwise there was no imputation. Baseline was defined as the average of at least 2 predose FEV1 values obtained on Day 1. The endpoint of baseline-adjusted predose FEV1 at end of treatment was calculated as follows: [FEV1 at end of treatment] - [Baseline FEV1].
Time Frame	Day 1 up to Day 50

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, no major inclusion/exclusion violations, enrolled in the study only once, and no major protocol violations that impacted analysis of the Day 42 FEV1 AUC (D42PPS Population).

Arm/Group Title	Generic Budesonide/Formoterol Fumarate Dihydrate	Symbicort (Budesonide/Formoterol Fumarate Dihydrate)	Placebo
Arm/Group Description	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.
Measure Participants	382	383	88
Mean (Standard Deviation) [liters]	0.278 (0.3306)	0.283 (0.3241)	0.094 (0.3298)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Budesonide/Formoterol Fumarate Dihydrate, Symbicort (Budesonide/Formoterol Fumarate Dihydrate)
	Comments
	Type of Statistical Test	Equivalence
	Comments	To show the clinical equivalence, an ANCOVA model was fit on the participants from the generic budesonide/formoterol fumarate and Symbicort groups only, with the endpoint as outcome and treatment, study site and treatment-by site interaction as fixed effects and FEV1 baseline value as covariate. If the treatment-by-site interaction factor was not significant at the 0.05 level, the model was to be rerun without the interaction term.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Test/Reference LS Mean Ratio
	Estimated Value	99.8
	Confidence Interval	(2-Sided) 90%; 87.0 to 114.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Fieller's formula was applied to calculate the 90% CI for the generic budesonide/formoterol fumarate and Symbicort LS mean ratio; covariance between treatment means was assumed to be 0.

4. Primary Outcome

Title	Superiority Analysis of Baseline-Adjusted Average Predose FEV1 at End of Treatment
Description	FEV1 was measured using spirometry in accordance with the ATS/ERS consensus guidelines. Average predose FEV1 at End of Treatment defined as the average of all predose assessments on Day 42. If a participant had no predose assessment on Day 42, the average of all available predose assessments on the last day (for example, Early Termination visit [up to Day 50]) when at least 1 predose FEV1 assessments was available was imputed, if the participant discontinued due to lack of efficacy, otherwise there was no imputation. Baseline was defined as the average of at least 2 predose FEV1 values obtained on Day 1. The endpoint of baseline-adjusted predose FEV1 at end of treatment was calculated as follows: [FEV1 at end of treatment] - [Baseline FEV1].
Time Frame	Day 1 up to Day 50

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug, no major inclusion/exclusion violations, and enrolled in the study only once (mITT Population) and with evaluable baseline-adjusted average predose FEV1 data.

Arm/Group Title	Generic Budesonide/Formoterol Fumarate Dihydrate	Symbicort (Budesonide/Formoterol Fumarate Dihydrate)	Placebo
Arm/Group Description	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.
Measure Participants	468	478	111
Mean (Standard Deviation) [liters]	0.269 (0.3238)	0.277 (0.3156)	0.124 (0.3673)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Generic Budesonide/Formoterol Fumarate Dihydrate, Placebo
	Comments	LS means difference and p-value from ANCOVA model with treatment and site as fixed effects, baseline FEV1 as covariate and endpoint as outcome on generic budesonide/formoterol fumarate dihydrate and Placebo participants only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.159
	Confidence Interval	(2-Sided) 95%; 0.093 to 0.226
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Symbicort (Budesonide/Formoterol Fumarate Dihydrate), Placebo
	Comments	LS means difference and p-value from ANCOVA model with treatment and site as fixed effects, baseline FEV1 as covariate and endpoint as outcome on Symbicort and Placebo participants only.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.164
	Confidence Interval	(2-Sided) 95%; 0.099 to 0.229
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	First day of the Treatment Period (Day 1) up to Day 72
Adverse Event Reporting Description	Randomized participants who received at least 1 dose of study drug during Treatment Period (Safety Population).
Arm/Group Title	Generic Budesonide/Formoterol Fumarate Dihydrate		Symbicort (Budesonide/Formoterol Fumarate Dihydrate)		Placebo
Arm/Group Description	After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.		After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a Symbicort budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pMDI for up to 50 days.		After a 2-week Run-in Period of administering 2 inhalations twice daily via a generic placebo pMDI device, participants administered 2 inhalations twice daily via a generic placebo pMDI for up to 50 days.
All Cause Mortality
	Generic Budesonide/Formoterol Fumarate Dihydrate		Symbicort (Budesonide/Formoterol Fumarate Dihydrate)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/501 (0%)		0/514 (0%)		0/126 (0%)
Serious Adverse Events
	Generic Budesonide/Formoterol Fumarate Dihydrate		Symbicort (Budesonide/Formoterol Fumarate Dihydrate)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/501 (0.6%)		2/514 (0.4%)		1/126 (0.8%)
Blood and lymphatic system disorders
Anaemia	0/501 (0%)		0/514 (0%)		1/126 (0.8%)
Cardiac disorders
Atrial fibrillation	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
General disorders
Non-cardiac chest pain	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Infections and infestations
Upper respiratory tract infection	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	1/299 (0.3%)		0/292 (0%)		0/70 (0%)
Vascular disorders
Hypertensive crisis	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Other (Not Including Serious) Adverse Events
	Generic Budesonide/Formoterol Fumarate Dihydrate		Symbicort (Budesonide/Formoterol Fumarate Dihydrate)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/501 (14%)		79/514 (15.4%)		15/126 (11.9%)
Cardiac disorders
Angina pectoris	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Palpitations	2/501 (0.4%)		0/514 (0%)		0/126 (0%)
Eye disorders
Blepharitis	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Abdominal distension	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Abdominal pain	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Abdominal pain upper	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Diarrhoea	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Gastrooesophageal reflux disease	2/501 (0.4%)		0/514 (0%)		0/126 (0%)
Haematochezia	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Inguinal hernia	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Nausea	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Toothache	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Vomiting	2/501 (0.4%)		1/514 (0.2%)		0/126 (0%)
General disorders
Adverse drug reaction	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Asthenia	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Chest discomfort	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Hernia pain	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Malaise	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Pain	0/501 (0%)		2/514 (0.4%)		0/126 (0%)
Immune system disorders
Hypersensitivity	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Infections and infestations
Sinusitis	0/501 (0%)		5/514 (1%)		1/126 (0.8%)
Upper respiratory tract infection	12/501 (2.4%)		8/514 (1.6%)		3/126 (2.4%)
Viral upper respiratory tract infection	10/501 (2%)		5/514 (1%)		1/126 (0.8%)
Acute sinusitis	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Body tinea	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Bronchitis	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Folliculitis	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Gastroenteritis	0/501 (0%)		2/514 (0.4%)		1/126 (0.8%)
Herpes zoster	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Hordeolum	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Influenza	0/501 (0%)		2/514 (0.4%)		0/126 (0%)
Laryngitis	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Otitis externa	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Pharyngitis	0/501 (0%)		2/514 (0.4%)		0/126 (0%)
Respiratory tract infection	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Tooth abscess	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Tooth infection	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Urinary tract infection	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Viral infection	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Viral pharyngitis	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Vulvovaginal mycotic infection	1/299 (0.3%)		0/292 (0%)		0/70 (0%)
Injury, poisoning and procedural complications
Arthropod sting	2/501 (0.4%)		0/514 (0%)		0/126 (0%)
Foot fracture	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Laceration	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Ligament sprain	0/501 (0%)		2/514 (0.4%)		0/126 (0%)
Neck injury	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Procedural pain	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Investigations
Alanine aminotransferase increased	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Antinuclear antibody positive	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Aspartate aminotransferase increased	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Blood glucose decreased	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Blood glucose increased	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Blood potassium increased	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Glucose urine	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Glucose urine present	2/501 (0.4%)		0/514 (0%)		0/126 (0%)
Liver function test increased	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Protein urine present	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Metabolism and nutrition disorders
Hypercholesterolaemia	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Hypocalcaemia	0/501 (0%)		0/514 (0%)		1/126 (0.8%)
Increased appetite	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Lactic acidosis	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/501 (0%)		6/514 (1.2%)		0/126 (0%)
Arthritis	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Muscle spasms	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Muscular weakness	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Musculoskeletal chest pain	0/501 (0%)		0/514 (0%)		1/126 (0.8%)
Musculoskeletal pain	0/501 (0%)		2/514 (0.4%)		0/126 (0%)
Myalgia	0/501 (0%)		0/514 (0%)		1/126 (0.8%)
Neck pain	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Tendonitis	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Nervous system disorders
Headache	5/501 (1%)		11/514 (2.1%)		3/126 (2.4%)
Dizziness	2/501 (0.4%)		1/514 (0.2%)		0/126 (0%)
Hypoaesthesia	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Migraine	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Paraesthesia	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Sciatica	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Sinus headache	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Syncope	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Psychiatric disorders
Insomnia	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Mood swings	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Renal and urinary disorders
Glycosuria	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Haematuria	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Hydronephrosis	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Nephrolithiasis	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	3/501 (0.6%)		4/514 (0.8%)		2/126 (1.6%)
Dysphonia	3/501 (0.6%)		5/514 (1%)		0/126 (0%)
Bronchospasm	0/501 (0%)		0/514 (0%)		1/126 (0.8%)
Cough	2/501 (0.4%)		2/514 (0.4%)		0/126 (0%)
Dyspnoea	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Epistaxis	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Nasal congestion	0/501 (0%)		2/514 (0.4%)		0/126 (0%)
Nasal discomfort	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Nasal dryness	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Oropharyngeal pain	2/501 (0.4%)		1/514 (0.2%)		0/126 (0%)
Rhinitis allergic	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Rhinorrhoea	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Throat irritation	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Wheezing	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Dermatitis contact	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Pruritus	1/501 (0.2%)		1/514 (0.2%)		0/126 (0%)
Rash	0/501 (0%)		2/514 (0.4%)		0/126 (0%)
Rash erythematous	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Rash maculo-papular	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Urticaria	1/501 (0.2%)		0/514 (0%)		0/126 (0%)
Surgical and medical procedures
Bunion operation	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Tooth extraction	0/501 (0%)		1/514 (0.2%)		0/126 (0%)
Vascular disorders
Hypertension	0/501 (0%)		2/514 (0.4%)		0/126 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The results of the study may be published or presented by the Investigator(s) after the review by, and in consultation and agreement with the Sponsor, and such that confidential or proprietary information is not disclosed.