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

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

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

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

 15. 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:

 1. Oral corticosteroids for 30 days.

 2. Parenteral corticosteroids for 30 days.

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

 16. 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.

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

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

 19. 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:

 1. Oral β-blockers.

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

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

 8. 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.

 9. 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.

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

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

 12. 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.

 13. 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.

 14. 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.

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