Efficacy of FLUTIFORM ® vs Seretide® in Moderate to Severe Persistent Asthma in Subjects Aged ≥12 Years

A Double Blind, Double Dummy, Randomised, Multicentre, Two Arm Parallel Group Study to Assess the Efficacy and Safety of FLUTIFORM® pMDI (2 Puffs Bid) vs Seretide® pMDI (2 Puffs Bid) in Subjects Aged ≥12 Years With Moderate to Severe Persistent, Reversible Asthma

A double blind, double dummy, randomised, multicentre, two arm parallel group study to assess the efficacy and safety of FLUTIFORM® pMDI (2 puffs bid) vs Seretide® pMDI (2 puffs bid) in subjects aged ≥12 years with moderate to severe persistent, reversible asthma.

The primary objective is to show non-inferiority in the efficacy of FLUTIFORM ® pMDI (2 puffs bid) versus Seretide® pMDI (2 puffs bid) based on the change from the pre-dose forced expiratory volume in the first second (FEV1) at baseline to 2 hours post-dose FEV1 at Week 12.

Inclusion Criteria:

1. Male or female subjects at least aged ≥12 years old.

2. Known history of moderate to severe persistent, reversible asthma for ≥ 6 months prior to the Screening Visit characterized by inadequate asthma control on treatment with an ICS alone OR controlled asthma on treatment with an ICS-LABA combination.

3. Demonstrated a pre-dose FEV1 of ≥ 40% to ≤ 80% for predicted normal values during the Screening Visit (Visit 1) following appropriate withholding of asthma medications (if applicable).

   • No LABA use within 12 hours and/or no SABA use within 6 hours of the PFT.
   • No SAMA (e.g., ipratropium) use within 8 hours and/or no LAMA (e.g., tiotropium) use within 72 hours of the PFT.
   • No use of inhaled ICS-LABA combination asthma therapy within 12 hours of the PFT.
   • Inhaled corticosteroids are allowed on the day of screening.
   • Oral Aminophylline should be withheld for at least 24 hours prior to the PFT.

4. Documented FEV1 reversibility of ≥ 12% (plus ≥ 200ml if the subject is older than 18 years old) within last 12 months which could be accepted by the investigator, or during the screening phase or at Visit 2.

5. Demonstrated satisfactory technique in the use of the study medication.

6. Females of child bearing potential or less than one year post-menopausal must have a negative serum pregnancy test recorded at the screening visit and a negative urine pregnancy test result prior to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasectomised partner.

7. Willing and able to enter information in the diary and attend all study visits.

8. Willing and able to substitute study medication for their pre-study prescribed asthma medication for the duration of the study.

9. Written informed consent obtained, for <18 years old subjects, both parental consent and subjects assent are needed.

Besides The Inclusion/Exclusion Criteria Checking, Additional Randomisation Criteria Required Following Run-In Period:

1. Demonstrated a pre-dose FEV1 of ≥ 40% to ≤ 80% for predicted normal values at Randomisation Visit (Visit 3) following appropriate withholding of asthma medications (if applicable).

2. ACQ score at Visit 3 ≥ 1.0.

3. Subjects with a good compliance with treatment or patient dairy. The definition of good compliance is that the completeness of diary during the last 14 days of the run-in period is at least 80%. The compliance on diary completeness will be assessed from the aspects below and agreed by the investigator and study Medical Monitor:

   1. Diary info has been filled out on ≥80% of the days during the last 14 days before randomization (e.g., at least 11 days with diary filled completed out of the last 14 days prior to randomization).
   2. 80% main items including the study endpoints related ones have been filled out within the last 14 days prior to randomization.
   3. No other significant incompliance judged by the investigator that indicates the potential future incompliance for critical data collection during the study treatment period.

Exclusion Criteria:

1. The adolescent subjects (age ≥ 12 years to <18 years) who are on ICS alone at a dose >250μg bid fluticasone or equivalent OR ICS-LABA combination at a dose of Seretide > 250/50 μg bid or equivalent.
2. Near fatal or life-threatening (including intubation) asthma within the past year.
3. Chest X-ray at the Investigator's discretion from clinical perspective that reveals evidence of clinically significant abnormalities not believed to be due to asthma.
4. Hospitalization or an emergency visit for asthma within the 4 weeks before the screening visit or during the screening visit.
5. Use of systemic (injectable or oral) corticosteroid medication within 1 month of the Screening Visit.
6. Omalizumab use within the past 6 months prior to the Screening Visit.
7. Current evidence or known history of any clinically significant disease or abnormality including uncontrolled coronary artery disease, congestive heart failure, myocardial infarction, or cardiac dysrhythmia. 'Clinically significant' is defined as any disease that, in the opinion of the Investigator, would put the subject at risk through study participation, or which would affect the outcome of the study.
8. In the investigator's opinion a clinically significant upper or lower respiratory infection within 4 weeks prior to the Screening Visit.
9. Significant, non-reversible, active pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, tuberculosis).
10. Subject has a smoking history equivalent to ≥ 10 pack years (i.e., at least 1 pack of 20 cigarettes /day for 10 years or 10 packs/day for 1 year, etc.) or significant history of exposure to biomass fuel combustion which may be considered a plausible contributory cause to the subject's obstructive lung disease.
11. Current smoking history within 12 months prior to the Screening Visit.
12. Current evidence or known history of alcohol and/or substance abuse within 12 months prior to the Screening Visit.
13. Subject has taken B-blocking agents, tricyclic antidepressants, monoamine oxidase inhibitors, astemizole (Hismanal), quinidine type antiarrhythmics, or potent CYP 3A4 inhibitors such as ketoconazole within the past week.
14. Current use of medications other than those allowed in the protocol that will have an effect on bronchospasm and/or pulmonary function.
15. Current evidence or known history of hypersensitivity or contraindications to the investigational products or components, including the history of paradoxical bronchospasm after inhalation therapy as immediate increase in wheezing and shortness of breath.
16. Subject has received an investigational drug within 30 days of the Screening Visit (12 weeks if an oral or injectable steroid).
17. Subject is currently participating in another clinical study or has already been randomized in this study.
18. Mental incapacity, unwillingness, or language barrier precluding adequate understanding, cooperation or any factors might block patients from protocol defined visits and may impact the patient diary completion at the Investigator's discretion.