| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study was to establish the noninferiority of the efficacy of FSC 250/50mcg ROTAHALER compared with FSC 250/50 mcg DISKUS BID in adults and adolescents with asthma. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives were the evaluation of the safety, tolerability, and pharmacodynamics of the two inhalers and their effect on the asthma control of these subjects. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female >=12 and <=80 years of age at the time of signing the informed consent
- A female subject is eligible to participate if she is of:
- Non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea
- Severity of disease: A best prebronchodilator FEV1 of >=40% to <=85% of the predicted normal value at Visit 1
- Reversibility of disease: Demonstrated >=12% and >=200 mL reversibility of FEV1 within 10 to 40 minutes after 2 to 4 inhalations of salbutamol inhalation aerosol (or equivalent nebulised treatment with salbutamol solution) at Visit 1 (Screening and Run-in Visit).
- Current anti-asthma therapy: All subjects must be using an Inhaled Corticosteroid (ICS) with or without long-acting beta-adrenergic agonist (LABA) for at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening and Run-in Visit).
- Ability to withhold LABA therapy: Other than what is provided during the study, LABA therapy is not permitted on the day of Visit 1
SABA: All subjects must be able to replace their current SABA treatment with rescue salbutamol/albuterol at Visit 1 (Screening and Run-in Visit) for use as needed for the duration of the study. Subjects must be able to withhold salbutamol/albuterol for at least 6 hours before each study visit.
- Liver safety criteria: Alanine aminotransferase (ALT) <=2 the upper limit of normal (ULN), Alkaline phosphatase and bilirubin <=1.5 ULN (isolated bilirubin >1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%) at Visit 1 (Screening and Run-in Visit).
- Electrocardiogram (ECG) safety criteria: The subject must have no ECG abnormalities that would, in the opinion of investigator, compromise subject safety, or significantly affect subject’s ability to complete the trial. As such, the investigator will determine the clinical significance of any ECG abnormality and determine if a subject is precluded from entering the study. At Visit 1 (Screening and Run-in Visit), ECG safety criteria must be: QT interval corrected for heart rate (QTc) or QT interval corrected for heart rate according to Fridericia formula (QTcF) <450 msec or QTc <480 msec for subjects with bundle branch block; Investigators will be responsible for ensuring appropriate clinical interpretation of ECGs.
- The subject and/or the subject’s legal guardian (if applicable) must be capable of giving informed consent/assent, which includes compliance with the study requirements and restrictions listed in the consent/assent form.
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| E.4 | Principal exclusion criteria |
History of life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 10 years
- Respiratory infection: Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1
- Asthma exacerbation: Any asthma exacerbation requiring oral corticosteroids within 12 weeks of Visit 1 (Screening and Run-in Visit) or that resulted in overnight hospitalisation requiring additional treatment for asthma within 6 months before Visit 1 (Screening and Run-in Visit)
- Concurrent respiratory disease: A subject must not have current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory abnormalities other than asthma
- Other concurrent diseases/abnormalities: A subject must not have any clinically significant, uncontrolled condition or disease state
- Evidence of a severe exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an in-patient hospitalisation or emergency department
- Oropharyngeal examination: A subject will not be eligible for the Run-in if he/she has clinical visual evidence of candidiasis at Visit 1 (Screening and Run-in Visit)
- Investigational medications: A subject must not have administered any investigational drug within 30 days before Visit
- Allergies: Drug allergy; Any adverse reaction including immediate or delayed hypersensitivity to any beta2 agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the FSC multi-dose inhaler and capsule-based inhaler (i.e., lactose), Milk protein allergy; History of severe milk protein allergy
- Concomitant medications: Administration of prescription or over the counter medication that would significantly affect the course of asthma, or interact with study treatment, such as: anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants; beta-adrenergic blocking agents; phenothiazines; and monoamine oxidase (MAO) inhibitors
- Immunosuppressive medications: A subject must not be using or require use of immunosuppressive medications during the study
- Cytochrome P450 3A4 (CYP3A4) inhibitors: Subjects who have received a potent CYP3A4 inhibitor within 4 weeks of Visit 1(Screening and Run-in Visit) (e.g., ritonavir, ketoconazole, itraconazole)
- Subject is unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John’s wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or five half-lives (whichever is longer) before the first dose of study treatment, - Any subjects that have previously received or are currently receiving omalizumab
- Use of the excluded medications are included in the study protocol
- Compliance: A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, disease, or geographical location that seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol, including visit schedule and completion of the daily diaries
- Tobacco use: Current smoker or a smoking history of ≥10 pack-years (e.g., 20 cigarettes/day for 10 years). A subject must not have used inhaled tobacco products within the past 3 months (e.g., cigarettes, cigars or pipe tobacco). One pack year is defined as 20 manufactured cigarettes (1 pack) smoked per day for 1 year
- Pregnant females as determined by urine test at Visit 1 (Screening and Run-in Visit) or predosing. A confirmatory serum pregnancy test is required if the urine test is questionable or positive
- Lactating females
- A positive hepatitis B surface antigen or positive hepatitis C test result
- Subject is mentally or legally incapacitated
- Child in Care (CiC): A CiC is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The determination of whether a child meets the definition of CiC should be made with the study centre staff in consultation with the responsible institutional review board (IRB)/independent ethics committee (IEC).
- Unwillingness or inability to follow the procedures outlined in the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline in trough morning Forced expiratory volume in 1 second (FEV1) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to Day 85 of each Treatment Period |
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| E.5.2 | Secondary end point(s) |
•Change from Baseline in Asthma Control Test (ACT)
Time Frame: Baseline and upto Day 85 of each Treatment Period
•Estimation of FEV1 area under the curve from 0 to 12 hours (AUC [0-12]) at Day 85
Time Frame: Predose, 15 minutes, 30 minutes, 1, 2, 4, 6, 9, and 12 hours post morning dose on Day 85 at the end of each Treatment Period
•Change from Baseline in morning Peak Expiratory Flow Rate (PEFR) from paper Diary Card
Time Frame: Predose at Visit 1, Baseline and upto Day 85 of each Treatment Period
•Change from Baseline in trough FEV1
Time Frame: Predose, Day 1, Day 28, Day 56 and Day 85 of each Treatment Period
•Change from Baseline in the percentage of symptom-free days from paper Diary Card
Time Frame: Predose at Visit 1, Baseline and upto Day 85 of each Treatment Period
•Change from Baseline in day- and night-time asthma symptoms from paper Diary Card
Time Frame: Predose at Visit 1, Baseline and upto Day 85 of each Treatment Period
•Change from Baseline in rescue medication use from paper Diary Card
Time Frame: Predose at Visit 1, Baseline and upto Day 85 of each Treatment Period
•Estimation of FEV1 area under the curve from 0 to 12 hours (AUC [0-12]) at Day 1
Time Frame: Predose, 15 minutes, 30 minutes, 1, 2, 4, 6, 9, and 12 hours post morning dose on Day 1 at the end of each Treatment Period |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints detailed alongside each secondary end point. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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