| 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 is to evaluate the dose response, efficacy and safety of 4 different doses of fluticasone propionate (50, 100, 200, and 400mcg) delivered as Fluticasone Spiromax® Inhalation Powder (Fp Spiromax) when administered twice daily in subjects 12 years of age and older with severe persistent asthma who are uncontrolled on high dose ICS therapy. |
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent/assent: For adult patients, written informed consent signed and dated by the patient before conducting any study related procedures; for minor patients, written informed consent signed and dated by the parent/legal guardian and written assent signed and dated by the patient before conducting any study related procedure.
2. Male or female 12 years and older, as of the Screening Visit. Male or female 18 years and older, as of the Screening Visit, in countries where local regulations or the regulatory status of study medication permit enrollment of adults only.
3. General good health, free of any concomitant conditions or treatment that could interfere with study conduct, influence the interpretation of study observations/results, or put the subject at increased risk during the study.
4. Asthma Diagnosis: Asthma as defined by the National Institutes of Health.
5. Severity of Disease: A best forced expiratory volume in one second (FEV1) of 40%-85% of the predicted normal value during the Screening Visit. NHANES III predicted values will be used for subjects aged ≥12 years and adjustments to predicted values will be made for African American subjects. American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria for acceptability, repeatability, and end of test must be met for spirometry.
6.Reversibility of Disease: Demonstrated a ≥12% reversibility of FEV1 Page 27/43 within 30 minutes following 2-4 inhalations of albuterol/salbutamol inhalation aerosol (if required, spacers and nebulized albuterol are permitted for reversibility testing only) at the Screening Visit. If subjects fail to demonstrate an increase in FEV1 ≥12% then subjects are not eligible for the study; however, based on investigator judgment, they will be allowed to retest once within 7 days and rescreen once after 7
days. Reversibility values of 11.50 – 11.99 will be rounded to 12. Documented historical reversibility of ≥ 12% within 1 year of the Screening Visit will be accepted.
7. Current Asthma Therapy: Subjects will be required to be on a short acting β2 agonist and inhaled corticosteroid for a minimum of 8 weeks before the Screening Visit and have been maintained on a stable dose of inhaled corticosteroids (either as ICS mono or as ICS/LABA combination therapy) for 4 weeks prior to the Screening Visit at 1 of the following qualifying ICS doses (see protocol for details of qualifying doses).
8. Short-Acting β2-Agonists: All subjects must be able to replace their current short-acting β2-agonists with albuterol/salbutamol inhalation aerosol at the Screening Visit for use as needed for the duration of the study. The use of spacer devices with the metered dose inhaler (MDI) will not be allowed during the study with exception of it’s use during reversibility testing at the Screening Visit. Nebulized albuterol/salbutamol will not be allowed at any time during the study. Subjects must be able to withhold all inhaled short-acting β2 sympathomimetic bronchodilators for at least 6 hours prior to all study visits.
9. If female, is currently not pregnant, breast feeding, or attempting to become pregnant, has a negative serum pregnancy test, and is of
• Non-childbearing potential, defined as:
- Before menarche, or
- ≥1 year post-menopausal, or
- Surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy), or
- Congenital sterility, or
- Diagnosed as infertile & not undergoing treatment to reverse infertility
or is of
• Child-bearing potential, willing to commit to using a consistent and acceptable method of birth control as defined below for the duration of the study:
- Systemic contraception used for ≥1 month prior to screening, including birth control pills, transdermal patch (Ortho Evra®), vaginal ring (NuvaRing®), levonorgesterel (Norplant®), or injectable progesterone (Depo-Provera®), or
- Double barrier methods (condoms, cervical cap, diaphragm, & vaginal contraceptive film with spermicide), or
- Intrauterine device (IUD)
- Monogamous with a vasectomized male partner
or is of
• Child-bearing potential & not sexually active, willing to commit to using a consistent & acceptable method of birth control as defined above for the duration of the study, in the event the subject becomes sexually active
10. Capable of understanding the requirements, risks, and benefits of study participation, &, as judged by the investigator, capable of giving informed consent/assent & being compliant with all study requirements (visits, record-keeping, etc).
See Protocol Document Appendix C (pages 115-133) for complete summary of changes. |
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| E.4 | Principal exclusion criteria |
1. History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation &/or was associated with hypercapnea, respiratory arrest or hypoxic seizures.
2. Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that is not resolved within 2 weeks of the Screening Visit. In addition, the subject must be excluded if such infection occurs between the Screening Visit and the Randomization Visit.
3. Any asthma exacerbation requiring oral corticosteroids within 1 month of the Screening Visit. A subject must not have had an emergency room visit or hospitalization for asthma within 2 months prior to the Screening Visit.
4. Presence of glaucoma, cataracts, ocular herpes simplex, or malignancy other than basal cell carcinoma.
5. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular (e.g congestive heart failure, known aortic aneurysm, clinically significant cardiac arrhythmia or coronary heart disease), hepatic, renal, hematological, neuropsychological, endocrine (e.g uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison’s disease, Cushing’s syndrome), gastrointestinal (e.g poorly-controlled peptic ulcer, GERD), or pulmonary (e.g chronic bronchitis, emphysema, bronchiectasis with the need for treatment, cystic fibrosis, bronchopulmonary dysplasia, chronic obstructive pulmonary disease).
6. Have any of the following conditions that, in the judgment of the investigator, might cause participation in this study to be detrimental to the subject, including, but not limited to:
• Current malignancy excluding basal cell carcinoma; History of malignancy is acceptable only if the subject has been in remission for 1 year prior to the Screening Visit.
• Current or untreated tuberculosis; History of tuberculosis is acceptable only if a subject has received an approved prophylactic treatment regimen or an approved active treatment regimen and has had no evidence of active disease for a minimum of 2 years
• Uncontrolled hypertension (systolic BP ≥160 or diastolic BP >100)
• Stroke within 3 months prior to the Screening Visit
• Immunologic compromise
7. History of a positive test for HIV, hepatitis B or hepatitis C infection.
8. Untreated oral candidiasis at the Screening Visit. Subjects with clinical visual evidence of oral candidiasis and who agree to receive treatment and comply with appropriate medical monitoring may enter the study.
9. History of any adverse reaction to any intranasal, inhaled or systemic corticosteroid therapy. Known/suspected sensitivity to the constituents of the dry powder inhalers used in the study (i.e lactose).
10. History of severe allergy to milk protein.
11. Use of systemic, oral or depot corticosteroids within 4 weeks prior to the Screening Visit
• Use of topical corticosteroids (≤1% hydrocortisone cream) for dermatological disease is permitted
• Use of intranasal corticosteroids or ocular corticosteroids at a stable dose for at least 4 weeks prior to the Screening Visit and throughout the study is permitted
12. Use of immunosuppressive medications within 4 weeks prior to the Screening Visit and during the study.
13. Immunotherapy for the treatment of allergy at a stable maintenance dose for at least 90 days prior to the Screening Visit and which will remain at a stable dose without escalation throughout the study is permitted.
14. Use of Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, ketoconazole, itraconazole) within 4 weeks prior to the Screening Visit. Strong and moderate CYP3A4 inhibitors are prohibited and weak CYP3A4 are allowed
15. History of alcohol or drug abuse within 2 years preceding the Screening Visit.
16. Current smoker or a smoking history of 10 pack years or more. A subject may not have used tobacco products within the past one year (e.g cigarettes, cigars, chewing tobacco, or pipe tobacco).
17. Study participation by clinical investigator site employees &/or their immediate relatives.
18. Study participation by more than 1 subject from the same household at the same time. However, after the study completion or discontinuation by one subject another subject from the same household may be screened.
19. Participation in any investigational drug study within the 30 days (starting at the final follow-up visit) preceding the Screening Visit or planned participation in another investigational drug study at any time during this study.
20. Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for in vitro fertilization during the study period or for 30 days following the subject’s last study related visit (for eligible subjects only – if applicable). Eligible female subjects unwilling to employ appropriate contraceptive measures to ensure that pregnancy will not occur during the study will be excluded. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is:
• Change from baseline in trough (AM pre-dose and pre-rescue bronchodilator) FEV1 over the 12-week Treatment Period
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is:
• Change from baseline in trough (AM pre-dose and pre-rescue bronchodilator) FEV1 over the 12-week Treatment Period |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoint:
• Change from baseline in weekly average of daily trough (pre-dose and pre-rescue bronchodilator) AM PEF over the 12-week Treatment Period
• Change from baseline in weekly average of daily PM PEF over the 12-week Treatment Period
• Time to withdrawal due to meeting stopping criteria for worsening asthma during the 12-week Treatment Period
• Change from baseline in the percentage of rescue-free 24-hour periods during the 12-week Treatment Period
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Change from baseline in weekly average of daily trough (pre-dose and pre-rescue bronchodilator) AM PEF over the 12-week Treatment Period
• Change from baseline in weekly average of daily PM PEF over the 12-week Treatment Period
•Time to withdrawal due to meeting stopping criteria for worsening asthma during the 12-week Treatment Period
• Change from baseline in the percentage of rescue-free 24-hour periods during the 12-week Treatment Period
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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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| The study is double blind for doses of Fp Spiromax vs placebo but the comparator arm is open label |
|
| 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 | No |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Bulgaria |
| Hungary |
| Israel |
| Poland |
| Russian Federation |
| Serbia |
| Spain |
| Ukraine |
| United States |
| Croatia |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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