| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 | 19.0 |
| 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 |
|
| 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 compare serious asthma outcomes (a composite endpoint defined as asthmarelated:
hospitalizations, intubations, and deaths) in subjects treated with MF/F MDI BID versus subjects treated with MF MDI BID. |
|
| E.2.2 | Secondary objectives of the trial |
To compare asthma exacerbations (defined as deteriorations of asthma requiring the use of systemic corticosteroids [tablets, suspension, or injection] for at least 3 consecutive days
OR an in-patient hospitalization OR emergency department visit less than 24 hours that required systemic corticosteroids) in subjects treated with MF/F MDI BID versus subjects treated with MF MDI BID. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Diagnosis and Criteria for Inclusion: Adult and adolescent subjects, of either sex and any race, at least 12 years of age, with a diagnosis of persistent asthma for at least 1 year will be selected to participate in the
study. Subjects must meet all of the inclusion criteria and none of the exclusion criteria to receive treatment assignment.
Key Inclusion Criteria Include:
1. A subject must report using one of the following asthma therapies and meet the associated requirements defined below:
ICS or ICS with one or more adjunctive therapies (LABA, LTRA or theophylline) at a stable dose for at least 4 weeks prior to randomization. Note: Any subject maintained on a stable high dose ICS with or without one or more adjunctive therapies (LABA, LTRA or theophylline) must have an ACQ-6 Total Score < 1.5 (controlled) at the Screening Visit.
Leukotriene receptor antagonist (i.e. LTRAs such as montelukast, zafirlukast, or pranlukast) OR xanthines (e.g. theophylline) as monotherapy at a stable dose for at least 4 weeks prior to randomization.
Note: Subjects on LTRAs, or xanthines, are eligible only if they record an ACQ-6 Total Score of not greater than 1.5
(not well controlled) and in the investigator’s clinical judgment, the subject’s asthma severity could
justify treatment with ICS ±LABA.
Daily albuterol/salbutamol (used on most days) without any other asthma controller, in the 4 weeks prior to randomization, but not more than 8 inhalations a day on 2 consecutive days, or not greater than 25
inhalations in one day, in the 7 days prior to Visit 1.
Note: Subjects on daily albuterol/salbutamol are eligible only if they record an ACQ-6 Total Score of not greater than 1.5 and in the investigator’s clinical judgment, the subject’s asthma severity could justify treatment with ICS ± LABA |
|
| E.4 | Principal exclusion criteria |
Key Exclusion Criteria Include:
1. A subject with unstable asthma. Subjects who meet any of the following criteria (based on the 7 days prior to randomization), despite adequate dosing technique, adherence to prescribed asthma medication, and appropriate use of rescue medication, are deemed unstable:
Asthma symptoms that persists throughout the day on 2 consecutive days
Nighttime awakening due to asthma ≥3 nights in a week
Albuterol/salbutamol rescue use (not for prevention of EIB) ≥ 8 puffs/day for 2 consecutive days
or ≥ 25 puffs in one day. (Note: Prophylactic use of albuterol/salbutamol is permitted, at the udgment of the investigator, when previously prescribed for EIB. However, SABA should not be
otherwise taken in anticipation of asthma symptoms.)
Asthma symptoms so severe that the subject was limited in their ability to perform normal daily activities
Note: Subjects meeting any of these unstable asthma criteria are ineligible to be randomized. At the judgment of the investigator, subjects may be rescreened once per calendar year (approximately every
52-weeks), after waiting at least 4-weeks from the initial date of screening.
2. A subject with COPD, cystic fibrosis (CF), or other significant, non-asthmatic, lung disease.
3. A subject with a clinically significant abnormality, illness or disorder of any body or organ system, which in the judgment of the investigator, could interfere with the study or the subject’s ability to participate in the full duration of the trial, or could require prohibited medications or other treatment which could interfere with the trial.
Note: The investigator is advised to review the subject's medical history in the context of the most current investigational brochure and prescribing information.
4. A subject with a cumulative history of smoking greater than 10-pack years.
5. A subject with a significant underlying cardiovascular condition, including cardiac ischemia, arrhythmia, prolonged QTc interval, hypertrophic obstructive cardiomyopathy (idiopathic subvalvular aortic stenosis), which in the judgment of the investigator may contraindicate use of a beta-agonist.
6. A subject who had an asthma exacerbation within 4 weeks of randomization. An asthma exacerbation is
considered a clinical deterioration of asthma that includes at least one of the following:
Use of systemic corticosteroids (tablets, suspension, or injection)
An in-patient hospitalization (defined as a >24 hour stay in hospital or equivalent facility, depending on the country and healthcare system.
7. A subject who reports more than 4 separate asthma exacerbations (as defined above) within 52 weeks prior to the Baseline Visit. Each exacerbation must be separated by > 7 days to be considered a separate event. Note: Investigators should use clinical judgment, considering the subject's history of exacerbation,
including the severity and interval since the last exacerbation per current clinical guidelines, in determining whether a subject with multiple exacerbations in the prior year should be enrolled in the study.
8. A subject who reports more than 2 separate hospitalizations (as defined above) within 52 weeks of the
randomization visit. Each hospitalization must be separated by > 7 days to be considered a separate event.
9. A subject with a known or suspected hypersensitivity or intolerance to corticosteroids, β-2 agonists, or any
of the (inactive ingredients) excipients present in the medications used in this study.
10. A subject who requires the use of chronic systemic corticosteroids, omalizumab (Xolair®) or other
monoclonal or polyclonal antibodies.
11. A subject who requires the use of beta-blockers, including eye drops.
12. A subject with a history of life-threatening asthma, including an asthma episode that required intubation and/or was associated with hypercapnia requiring non-invasive ventilatory support.
13. A subject who is currently participating in any other investigational trial or who plans to participate in any other investigational trial during the next 26 weeks.
14. A subject who has been randomized and has taken at least one dose of study medication in this trial or in one of the other LABA Sponsor studies assessing the safety of LABAs as a class added to ICS, compared with ICS alone.
15. A female subject who is lactating, pregnant, or plans to become pregnant during the course of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary safety endpoint for the trial is the time-to-first serious asthma outcome(composite endpoint of asthma-related: hospitalizations, intubations, and deaths). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The key secondary efficacy endpoint is the time-to-first asthma exacerbation, ( as defined above). The key secondary efficacy hypothesis will be evaluated using the Cox proportional-hazard model with covariates, the same as those described for the primary safety analysis.
Kaplan-Meier curves will also be plotted to display treatment responses. Superiority of MF/F MDI BID is determined if the HR of MF/F MDI BID to MF MDI BID is less than 1 and achieves statistical significance (onesided
p-value < 0.025). Further details are provided in the efficacy analysis section. Superiority of MF/F MDI BID is determined if the incidence is lower than that of MF MDI BID and achieves statistical significance (onesided p-value <0.05). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 119 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| China |
| Colombia |
| Croatia |
| Czech Republic |
| Estonia |
| France |
| Germany |
| Hungary |
| India |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Latvia |
| Malaysia |
| Mexico |
| Peru |
| Poland |
| Puerto Rico |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last visit of last patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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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