| 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 | 14.1 |
| 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 |
| The primary objective of the study is to establish the noninferiority of budesonide/formoterol fumarate dihydrate (BF) SPIROMAX 160/4.5 mcg with that of SYMBICORT TURBOHALER 200/6 mcg administered twice daily in patients 12 years of age and older with persistent asthma as assessed by the change from baseline in average of daily trough (predose and pre-rescue bronchodilator) morning (AM) peak expiratory flow rate (PEF) over a 12-week treatment period. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to evaluate patient preference and ease of use of the budesonide/formoterol fumarate dihydrate (BF) SPIROMAX device compared to SYMICORT TURBOHALER.
Safety and tolerability of budesonide/formoterol fumarate dihydrate (BF) SPIROMAX 160/4.5 mcg will also be evaluated by the following:
• incidence of adverse events throughout the 12-week treatment period
• oropharynx examination findings at the screening visit (visit 1) and at the end of the double-blind treatment period (visit 5)
• physical examination findings at the screening visit and the at the end of the double-blind treatment period (visit 5)
• vital sign measurements (including blood pressure (BP), pulse rate, respiratory rate, and temperature) at the screening visit and throughout the study |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Serial spirometry:
- Information regarding the substudy is located in the main protocol for this study, dated 10 December 2012.
- Serial spirometry is planned to be performed for a subset of patients (approximately 30 patients from 3-4 sites) at the baseline visit (visit 2) only.
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| E.3 | Principal inclusion criteria |
a. 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.
b. Male or female patients 12 years and older as of the screening visit. Male or female patients 18 years and older, as of the screening visit, in countries where local regulations or the regulatory status of study medication permit enrollment of adult patients only.
c. General good health, and free of any concomitant conditions or treatment that could interfere with study conduct, influence the interpretation of study observations/results, or put the patient at increased risk during the study.
d. Asthma Diagnosis: The asthma diagnosis must be in accordance with the Global Initiative for Asthma (GINA).
e. Patient has an ACQ score of ≥1.0 at the screening visit.
f. Severity of Disease: Persistent asthma, with an FEV1 40-85% predicted for age, height, gender and race, as per the third National Health and Nutrition Examination Survey (NHANES III) reference values, with adjustments to predicted values for African American patients, for a minimum of 3 months duration, and that has been stable for at least 30 days before the screening visit, as defined by clinical history.
g. Reversibility of Disease: Demonstrated a ≥12% reversibility of FEV1 within 30 minutes after 2-4 inhalations of albuterol/salbutamol (if required, spacers are permitted for reversibility testing) at the screening visit. Documented historical reversibility of ≥12% to a beta-agonist in the 12 months before the screening visit is also acceptable.
h. Current Asthma Therapy: Patients will be required to be on a short-acting β2 agonist (SABA) and inhaled corticosteroid (ICS) for a minimum of 8 weeks before the screening visit and have been maintained on a stable dose of inhaled corticosteroids for 4 weeks before the screening visit at on of the doses specified in the protocol.
i. Short-Acting β2-Agonists: All patients must be able to replace their current SABA with albuterol/salbutamol at the screening visit for use as needed for the duration of the study. Nebulized albuterol/salbutamol will not be allowed at any time during the study. Patients must be able to withhold all inhaled short-acting β2-sympathomimetic bronchodilators for at least 6 hours before all study visits.
j. If female, is currently not pregnant, breast feeding, or attempting to become pregnant, and is of Nonchildbearing potential, defined as:
− Pre-menarche
− ≥1 year post-menopausal
− Surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy)
− Congenital sterility
− Diagnosed as infertile and not undergoing treatment to reverse infertility or is of:
Childbearing potential, must have a negative serum pregnancy test and be 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, vaginal ring, levonorgesterel, or injectable progesterone
− Double barrier methods (condoms, cervical cap, diaphragm, and vaginal contraceptive film with spermicide)
− Intrauterine device (IUD)
Childbearing potential and not sexually active, willing to commit to using a consistent and acceptable method of birth control, as defined above, for the duration of the study, in the event the patient becomes sexually active.
If male, is willing to commit to using 2 consistent and acceptable methods of birth control for the duration of the study, and for a period of 3 months after dosing
k. Capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements (visits, record-keeping, etc.). |
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| E.4 | Principal exclusion criteria |
a. 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.
b. 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 before the screening visit. In addition, the patient must be excluded if such infection occurs between the screening visit and the baseline visit.
c. Any asthma exacerbation requiring oral corticosteroids within one month of the screening visit. A patient must not have been hospitalized for asthma within 6 months before the screening visit.
d. Presence of glaucoma, cataracts, ocular herpes simplex, or malignancy other than basal cell carcinoma.
e. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular conditions (eg, congestive heart failure, known aortic aneurysm, clinically significant cardiac arrhythmia or coronary heart disease), hepatic, renal, hematological, neuropsychological, endocrine conditions (eg, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison’s disease, Cushing’s syndrome), gastrointestinal conditions (eg, poorly-controlled peptic ulcer, gastroesophageal reflux disease [GERD]), or pulmonary conditions (eg, chronic bronchitis, emphysema, bronchiectasis with the need for treatment, cystic fibrosis, bronchopulmonary dysplasia, chronic obstructive pulmonary disease). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the patient at risk through participation, or which could affect the efficacy or safety analysis if the disease/condition became exacerbated during the study.
f. Have any of the following conditions that, in the judgment of the investigator, might cause participation in this study to be detrimental to the patient, including, but not limited to:
- Current malignancy, excluding basal cell carcinoma. History of malignancy is acceptable only if the patient has been in remission for one year prior to the screening visit. (Remission is defined as no current evidence of malignancy and no treatment for the malignancy in the 12 months before the screening visit)
- Current or untreated tuberculosis. History of tuberculosis is acceptable only if a patient 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 blood pressure (BP) ≥160 or diastolic BP >100)
- Stroke within 3 months before the screening visit
- Immunologic compromise
g. History of a positive test for human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection.
h. Clinical visual evidence of oral candidiasis at the screening visit.
i. History of any adverse reaction, including immediate or delayed hypersensitivity to any β2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy.
j. Known or suspected sensitivity to the constituents of the DPIs (SPIROMAX or TURBOHALER) used in the study (eg, lactose).
k. History of severe allergy to milk protein.
l. Use of systemic, oral or depot corticosteroids within 4 weeks before the screening visit
- Use of topical corticosteroids (≤1% hydrocortisone cream) for dermatological disease is permitted
- Use of intranasal corticosteroids at a stable dose or as needed may be used during the study for treatment of allergic rhinitis.
m. Use of immunosuppressive medications within 12 weeks before the screening visit and during the study.
n. Immunotherapy at a stable dose for at least 90 days before the screening visit and throughout the study for the treatment of allergies is permitted.
o. Use of potent Cytochrome P450 3A4 (CYP3A4) inhibitors (eg, ritonavir, ketoconazole, intraconzole) within 4 weeks before the screening visit.
p. Use of any prohibited concomitant non-asthma medications, such as treatment with β2-adrenergic receptor antagonists and non-selective β-receptor blocking agents, such as β-blocking anti-hypertensive products (administered by any route), monoamine oxidase (MAO) inhibitors, and tricyclic antidepressants within 1 week before the screening visit.
q. History of alcohol or drug abuse within 2 years preceding the screening visit.
r. Current smoker or a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). A patient may not have used tobacco products within the past 1 year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco).
s. Patient is a clinical investigator site employee or their immediate relatives.
For exclusion criteria (t) to (v), please refer to the current protocol |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy measure and endpoint for this study is the change from baseline in weekly average of daily trough (predose and pre-rescue bronchodilator) AM PEF over the 12-week treatment period. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PEF will be determined twice daily (AM and PM) |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Measures and Endpoints:
1) change from baseline in weekly average of daily PM PEF over the 12-week treatment period
2) change from baseline in the percentage of symptom-free 24-hour periods during the 12-week treatment period
2) change from baseline in the percentage of rescue-free 24-hour periods during the 12-week treatment period
3) change from baseline in trough (AM predose and pre-rescue bronchodilator) FEV1 over the 12-week treatment period
4) change from baseline in Patient Satisfaction and Preference Questionnaire for Inhalation Devices (PASAPQ) total satisfaction score (Part I), performance and convenience domain scores (Part I), device preference category (Part II), and willingness to continue using the device score (Part II) at week 12
5) change from baseline in overall inhaler quickness satisfaction score at week 12
For all other Efficacy Measures and Endpoints, please refer to the protocol.
Safety Measures and Endpoints
• The safety of BF SPIROMAX will be assessed throughout the study by evaluating adverse events, oropharynx examination results, physical examination results, and vital signs measurements.
For a subset of approximately 30 patients from 3-4 sites the following endpoints will be analyzed:
1) the onset time when patients experience an increase of at least 12% above baseline FEV1 up to 6 hours
2) duration of effect when patients experience an increase of at least 12% above baseline FEV1
3) number of patients who experience at least 12% increase in FEV1 during 6 hours from baseline |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Measures and Endpoints:
1,2,3) Recorded in patient diary daily throughout 12 week study treatment period
4 and 5) Visit 2 (Day 1) and Visit 5 (Day 84)
Safety Measures and Endpoints
This will be monitored throughout the 12 week treatment period through the patient diary and at all visits (visits 2 to visit 5)
Subset Endpoints
1,2,3) Visit 2 (Day1- baseline), Visit 3, (Day 28) Visit 4 (Day 56), Visit 5 (Day 84) - please refer to protocol Study Procedures and Assessments for more information on timings of spirometry at each visit. |
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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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 107 |
| 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 |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Austria |
| Netherlands |
| Poland |
| Russian Federation |
| Czech Republic |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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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