| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| 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 |
| To evaluate the efficacy and safety of inhaled fluticasone furoate 50 mcg administered once daily in the evening in adolescent and adult subjects 12 years of age and older with persistent asthma over a 24-week treatment period. |
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| E.2.2 | Secondary objectives of the trial |
| Change compared to baseline in number of days without rescue medication, peakflow, symptom free days, asthma control, healthcare utilization, adverse events, exacerbations. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Informed consent: Subjects must give their signed and dated written informed consent to participate
2. Type of Subject: Outpatients 12 years of age or older at Visit 1 (or ≥18 years of age if local regulations or the regulatory status of study medication permit enrolment of adults only) with a diagnosis of asthma as defined by the National Institutes of Health [NIH, 2007] at least 12 weeks prior to Visit 1.
Note: Target to randomise approximately 12% of subjects aged 12-17years.
3. Gender: Male or eligible Female, defined as non-childbearing potential or childbearing potential using an acceptable method of birth control consistently and correctly, as defined by the following:
• Male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for that female subject
• Implants of levonorgestrel
• Injectable progestogen
• Oral contraceptive (either combined estrogen/progestin or progestin only)
• Any intrauterine device (IUD) with a documented failure rate of less than 1% per year
• Double barrier method – Condom and an occlusive cap (diaphragm or
cervical/vault cap) with a vaginal spermicidal agent (foam/ gel/ film/ cream/suppository)
• Estrogenic vaginal ring
• Percutaneous contraceptive patches
• Females of childbearing potential who are not sexually active must commit to complete abstinence from intercourse throughout the clinical trial and for a period after the trial to account for elimination of the drug (minimum of six days)
• Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. A serum pregnancy test is required for females of childbearing potential at the initial Screening Visit (Visit 1). In addition, a urine pregnancy test will be performed on all females of childbearing potential at Visits 2, 6 and Visit 8/EW. A take-home test will be performed at Visit 9 (Follow up
Visit/Contact).
4. Severity of Disease: A best evening pre-bronchodilator FEV1 of ≥60% of the predicted normal value at the Screening Visit (Visit 1). Predicted values will be based upon NHANES III [Hankinson, 1999]. If a subject is recorded as having Hispanic or Latino ethnicity, then the Mexican-American equations will be used (irrespective of race). If a subject is recorded as being of African- American/African heritage race, then the African-American equations will be used. If a subject is recorded as being of Asian race, then the Asian adjustment will be used. Otherwise, the Caucasian equations will be used [Hankinson, 2010].
5. Reversibility of Disease: Demonstrated ≥12% and ≥200mL evening reversibility of FEV1 within 10 to 40 minutes following 2 to 4 inhalations of albuterol/salbutamol inhalation aerosol (or equivalent nebulised treatment with albuterol/salbutamol solution) at screening (Visit 1).
6. Current Anti-Asthma Therapy: Preceding Visit 1 subjects must have been using:
• non-corticosteroid controller (e.g. leukotriene modifying agent)
AND/OR
• short-acting beta2-agonist (SABA) alone
Subjects must not have used an ICS or LABA for at least 4 weeks prior to Visit 1.
Short-Acting Beta2-Agonists (SABAs): All subjects must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at Visit 1 for use as needed for the duration of the study. Subjects must be capable of withholding albuterol/salbutamol for at least 6 hours prior to study visits |
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. History of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures within the last 10 years.
2. 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 and led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject’s asthma status or the subject’s ability to participate in the study.
3. Asthma Exacerbation: Any asthma exacerbation within 12 weeks of Visit 1 requiring oral corticosteroids or that resulted in overnight hospitalisation requiring additional treatment for asthma within 6 months prior to Visit 1.
4. 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.
5. Other Concurrent Diseases/Abnormalities: A subject must not have any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the patient at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study.
The list of additional excluded conditions/diseases includes, but is not limited to the following:
Congestive heart failure Known aortic aneurysm
Clinically significant coronary heart disease
Clinically significant cardiac arrhythmia
Stroke within 3 months of Visit 1 Uncontrolled hypertension1
Recent or poorly controlled peptic ulcer Hematologic, hepatic, or renal disease
Immunologic compromise Current malignancy2
Tuberculosis (current or untreated)3 Cushing’s disease
Addison’s disease Uncontrolled diabetes mellitus
Uncontrolled thyroid disorder Recent history of drug or alcohol abuse
1. Two or more measurements with systolic BP>160mmHg, or diastolic BP >100mmHg
2. History of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission = no current evidence of malignancy and no treatment for the malignancy in the 12 months
prior to Visit 1)
3. Subjects with a history of tuberculosis infection who have completed an appropriate course of antituberculous treatment may be suitable for study entry provided that there is no clinical suspicion of
active or recurrent disease.
6. Viral Hepatitis: Subjects with chronic stable hepatitis B or C are acceptable provided their screening ALT is < 2x ULN and the subject otherwise meets the entry criteria. Subjects who have chronic co-infection with both hepatitis B and hepatitis C are not eligible.
7. Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has clinical visual evidence of candidiasis at Visit 1.
8. Allergies:
• Drug Allergy: Any adverse reaction including immediate or delayed
hypersensitivity to any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the new powder inhaler (i.e., lactose).
• Milk Protein Allergy: History of severe milk protein allergy.
9. Concomitant Medications:
• Prescription or over the counter medication that would significantly affect the course of asthma, or interact with study drug.
• Immunosuppressive Medications: A subject must not be using or require use of immunosuppressive medications during the study.
Note: Immunotherapy for the treatment of allergies is allowed during the study provided it was initiated 4 weeks prior to Visit 1 and subjects remain in the maintenance phase for the duration of the study.
• Cytochrome P450 3A4 (CYP3A4) inhibitors: Subjects who have received a potent CYP3A4 inhibitor within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconzole, clarithromycin).
10. 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 which 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.
11. Tobacco Use: Current smoker or a smoking history of 10 pack years (e.g., 20 cigarettes/day for 10 years). A subject may not have used inhaled tobacco products within the past 3 months (i.e., cigarettes, cigars or pipe tobacco).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary Efficacy Endpoint: Change from baseline in evening clinic visit (pre-bronchodilator and pre-dose) FEV1 at the end of the 24-week treatment period. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening, Randomisation, and treatment weeks 2, 4, 8, 12, 18 and 24 |
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| E.5.2 | Secondary end point(s) |
• Powered secondary endpoint. Change from baseline in the percentage of rescuefree 24-hour periods during the 24-week treatment period.
• Change from baseline in daily (pre-dose and pre-rescue bronchodilator) PM PEF averaged over the 24-week treatment period.
• Change from baseline in daily AM PEF averaged over the 24-week treatment period.
• Change from baseline in the percentage of symptom-free 24-hour periods during the 24-week treatment period.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Daily entry into patient electronic diary for each of above secondary endpoints |
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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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Mexico |
| Netherlands |
| Peru |
| Poland |
| Russian Federation |
| United States |
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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.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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