Beclomethasone Dipropionate HFA in Adult and Adolescent Subjects With Persistent Asthma

A Randomized, Parallel Group, Placebo-controlled, Multicenter Phase 3 Study With a PK Sub-group Study With Beclomethasone HFA at 400 μg and 800 μg Daily Doses Compared to Placebo and QVAR in Persistent Asthma.

Approximately 480 (120 per group) would need to complete the 6 weeks of treatments.

This is four arm study. Approximately 480 (120 per group) would need to complete the 6 weeks of treatments.

In order to achieve that number of subjects, approximately 700 subjects will be screened randomized into the study.

A screening visit (Visit 1) will be inclusive of at least the 2-week (14 days) placebo Run-in Period during which asthma subjects will wash out their daily inhaled corticosteroid and other medications and assessed for compliance. Study treatment period will be for a duration of 6 weeks with visits: Visit 2 - Baseline Day 1; Visit 3 Day 21 (± 2 days) and Visit 4 Day 42 (± 2 days). Rescue Therapy: Short-acting beta agonists, Albuterol 90 μg/actuation

Inclusion Criteria

1. Male or female subjects (between ≥ 12 and ≤ 80 years old). Females may be of either childbearing or non-childbearing potential. All females of childbearing potential must be either abstinent from sexual intercourse or using adequate contraception and must also have a negative pregnancy test. Pregnant or nursing females or females intending to become pregnant during the course of the study must be excluded from the study.
2. The subject has persistent asthma as defined by the National Asthma Education a Prevention Program (NAEPP ERP-3 (1)) at least 12 weeks prior to screening.
3. Pre-bronchodilator forced expiratory volume in 1 second (FEV1) on the screening visit and on the baseline visit is >40% of the predicted value according to age, height, race and sex using The global lung function 2012 equations: Report of the Global Lung Function Initiative (GLI), following abstinence from short-acting β-agonists for a minimum of 6 hours and withholding restricted medications prior to the visits. At Visit 2 the baseline FEV1 and the predicted FEV1 value would be the mean of 2 pre-dose FEV1 measurements taken 30 minutes apart (-30 min and 0).
4. The subject has demonstrated at least 12% reversibility of FEV1 at either the screening or baseline visit within 30 minutes after 4 inhalations (total of 360 μg) of albuterol (pMDI). [Note: Subjects who fail to demonstrate the required reversibility at the Screening Visit (Visit 1) are eligible to enter the Run-in Period and repeat the testing at the End of Run-in Period/Baseline (Visit 2)].
5. If the subject is on inhaled corticosteroids the subject must be on a stable dose of daily-inhaled corticosteroid (ICS) at least 160 μg/day of beclomethasone dipropionate or equivalent for a minimum of 4 weeks before screening visit (Estimated comparative daily doses for ICSs for youths ≥12 years of age and adults per NAEPP ERP-3).
6. Currently nonsmoking; had not used tobacco products (i.e., cigarettes, cigars, pipe tobacco) within the past year, and had ≤ 10 pack years of historical use.
7. A body mass index between 18-35 kg/m2, inclusive.
8. Willingness to give their written informed consent/assent to participate in the study.
9. Subjects must be able to perform acceptable and repeatable spirometry, Peak Flow Meter (twice a day measurements), keep a diary record and to use the inhalation devices as assessed at Screening and Baseline by the study staff.
10. Ability to understand and comply with the protocol requirements, instructions and protocol stated restrictions.

NOTE: At the end of the placebo Run-in period the subject will be stratified into two categories:

• Corticosteroid naïve subjects (Not have taken inhaled corticosteroids (ICSs) at least 3 months prior to screening or systemic corticosteroids at least 6 months before screening)

• Prior corticosteroid users Exclusion criteria

  1. Incidence of asthma exacerbations per NAEPP ERP-3 within the last 3 months.

  2. Respiratory diseases other than asthma or allergic rhinitis.

  3. Uncontrolled asthma defined as having 3 - 4 of the following symptoms: a) Daytime asthma symptoms (> twice/week) b) Night waking due to asthma c) Reliever needed for symptoms more than twice a week (excluding reliever taken before exercise) d) Any activity limitation due to asthma per GINA, Chapter 2, Box 2-2, page 29.

  4. Life threatening asthma, defined as a history of asthma episode(s) requiring intubation, and/or associated with hypercapnia; respiratory arrest or hypoxic seizures, asthma related syncopal episode(s) within the previous 10 years.

  5. The known presence or history of tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, parasitic or viral infections; or ocular herpes simplex.

  6. The presence or history of clinically significant medical condition, other than asthma, including laboratory results abnormalities, that in the opinion of the investigator would put the subject at risk through study participation, or would affect the study analyses if the disease exacerbated during the study. Following conditions should be considered carefully: congestive heart failure, recent myocardial infarction, uncontrolled hypertension, cardiac arrhythmias and diabetes mellitus, epilepsy, glaucoma, cataract, uncontrolled hypothyroidism, liver failure, severe osteoporosis, peptic ulceration and renal impairment.

  7. Hospitalization for asthma or a respiratory condition in the last 12 months.

  8. Need for oral steroids or/and antibiotics for lung disease in last the 3 months.

  9. Current or recent respiratory infection or current oral candida infection.

  10. Participation in another clinical trial or study within 1 month or at least 5 half-lives (whichever is longer) preceding the first dose of trial medication. Previous participation in this study.

  11. Use of any of the following excluded respiratory medications within the indicated time frame prior to screening and throughout the study:

      1. Anti-IgE antibody (e.g. Xolair) and depot corticosteroids 3 months
      2. Systemic (I.V., I.M., oral) corticosteroids 3 months
      3. Inhaled corticosteroids Stop at screening
      4. Long-acting anti-muscarinics (e.g., tiotropium) 48 hours
      5. Short-acting anti-muscarinics (e.g., ipratropium) 24 hours
      6. LABA (e.g., salmeterol, formoterol,etc.) 12 hours
      7. Short-acting β2-adrenergic agonists (SABA), except for study rescue medication (albuterol) (see Section 4.7) 6 hours
      8. Oral β2-adrenergic agonists 1 month
      9. Topical dermatologic corticosteroids of intermediate to high potency such as fluticasone propionate, mometasone furoate 14 days
      10. Oral or nasal antihistamines unless on a stable dose for 30 days prior screening.
      11. Immunologically active biologic medications such as anti-TNFα (tumor necrosis factor) 3 months
      12. Immunosuppressive therapy such as methotrexate, gold, Azathioprine 1 month
      13. Immunotherapy initiation within 3 months or change in dose within 1 month
      14. Over-the-counter bronchodilators 2 weeks
      15. Marijuana 1 month
      16. Inhaled nicotine such as e-cigarettes 1 day

  12. Use of the following medications 30 days before screening:

      n. Non-cardioselective β-blockers (e.g. propranolol, nadolol, carvedilol, labetalol, sotalol) o. Digitalis p. Thiazide diuretics q. Oral decongestants r. Potent Cytochrome P450 3A4 enzyme inhibitors s. Benzodiazepines t. Cyclic antidepressants u. Monoamine oxidase inhibitors v. Diazoxide w. Ketoconazole, itraconazole x. Phenytoin y. Rifampicin z. Mifepristone

  13. Known hypersensitivity to any corticosteroid or any of the excipients in the study drug or rescue medication formulation.

  14. Evidence (as assessed by the Investigator using good clinical judgment) of alcohol or drug abuse or dependency at the time of screening, for the 6 months prior to screening.

  15. Donation or loss of blood or plasma of one unit (about 450 mL whole blood or 220 mL plasma) in the previous 60 days. (Applicable for patients participating in PK arm of the study).

  16. Lived in the same household as currently enrolled subject.

  17. Any other reason which might, in the opinion of the Investigator, interfere with study evaluations or pose a risk to subject safety during the study.