Randomized, Placebo-Controlled, Multidose, Study Comparing Generic Budesonide/Formoterol Fumarate Dihydrate to Symbicort® in Asthmatic Participants
Condition: Asthma
MeSH terms: Asthma
Intervention: Generic Budesonide/Formoterol Fumarate Dihydrate; Symbicort® (Budesonide/Formoterol Fumarate Dihydrate); Placebo
Intervention description: Oral inhalation, generic formulation of the brand-name product.; Oral inhalation, brand-name product.; Oral inhalation, no active ingredient.
Intervention MeSH terms: Budesonide; Formoterol Fumarate; Budesonide, Formoterol Fumarate Drug Combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 1714.0
Sex: All
Minimum age: 12 Years
Maximum age: 75 Years
Healthy volunteers: No

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).
    

Eligibility criteria:

        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.