| 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 |
|
| 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 |
|
| 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 evaluate whether the addition of LABA to ICS therapy (FSC) is non-inferior to ICS therapy alone (FP) in terms of the risk of serious asthma related events (asthma-related hospitalization, endotracheal intubation, and death). |
|
| E.2.2 | Secondary objectives of the trial |
| A secondary objective of the study is to evaluate whether the addition of LABA to ICS therapy (FSC) is superior to ICS therapy alone (FP) in terms of measures of efficacy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
French subjects: In France, a subject will be eligible for inclusion in this study only if
either affiliated to or a beneficiary of a social security category.
1. Informed Consent:
• The subject and/or the subject’s legal guardian (if applicable) must provide
written informed assent/consent to take part in the study.
• Subjects and/or their legal guardians (if applicable) understand that they must
comply with study treatment and study assessments including recording of daily
information regarding their asthma status and attend scheduled study visits, and
be accessible by telephone.
2. Subject: 12 years of age and older.
3. Gender: Male or female.
4. Asthma Diagnosis: Persistent asthma, defined by national and international asthma
guidelines [GINA, 2009; NIH, 2007; etc.] for at least 1 year prior to study enrolment.
If the subject is naïve to the study site, the diagnosis of asthma must be confirmed by subject history.
5. PEF: A clinic PEF≥50% of predicted normal value. Percent predicted PEF values
must be calculated using NHANES III with relevant equations that adjust for race
and national origin. [Hankinson, 1999; Hankinson, 2010].
6. Current Asthma Therapy: Subjects must be appropriately using one of the
following for the treatment of asthma and meet the criteria outlined below:
• ICS or ICS with one or more adjunctive therapies (LABA, LTRA or
theophylline) for at least 4 weeks prior to randomization (see Table 1: for ICS
dose equivalents). Any subject maintained on a stable high dose ICS or stable
high dose ICS with one or more adjunctive therapies (LABA, LTRA or
theophylline) must have an ACQ-6 < 1.5 (i.e., controlled) at Visit 1.
• Leukotriene receptor antagonist (i.e. LTRAs such as montelukast, zafirlukast, or
pranlukast) OR theophylline as monotherapy at a stable dose for at least 4 weeks
prior to randomization. Subjects on LTRAs or theophylline are eligible only if
they record an ACQ-6 score of ≥ 1.5 (i.e. not well controlled) and in the
Investigator’s clinical judgement, the subject’s asthma severity could justify
treatment with ICS or ICS + LABA.
• Daily rescue medication (e.g., albuterol/salbutamol or other inhaled short-acting
beta-agonist used to treat acute asthma) in the 4 weeks prior to randomization
Subjects on daily rescue medication are eligible only if they record an ACQ-6
score of ≥ 1.5 and in the investigator’s clinical judgement, the subject’s asthma
severity could justify treatment with ICS or ICS + LABA.
7. Exacerbation History: Subject must have a history of one of the following:
• at least one asthma exacerbation requiring treatment with a systemic
corticosteroid (tablets, suspension, or injection) between 30 days and 12 months
prior to randomization OR
• an asthma-related hospitalization (defined as an inpatient stay or a 24-hour stay
in an observation area in an emergency room or other equivalent facility)
between 30 days and 12 months prior to randomization
8. Questionnaire: Ability to answer questions regarding asthma status and quality of
life and ability to use a daily electronic data capture system.
9. Inhaler Usage: Ability to demonstrate proper use of a metered-dose inhaler and dry powder inhaler (DPI) device. |
|
| E.4 | Principal exclusion criteria |
1. History of Life-Threatening Asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea requiring non-invasive ventilatory support.
2. Concurrent Respiratory Disease: Subjects with current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other respiratory abnormalities other than asthma.
3. Chronic Obstructive Pulmonary Disease: chronic bronchitis, emphysema, or chronic obstructive pulmonary disease.
4. Tobacco Use.
5. Exercise-induced Asthma: Subjects with exercise induced asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine.
6. 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 at randomization.
7. Unstable Asthma Status: Subjects must not meet the following unstable asthma severity criteria within 7-days prior to randomization:
• Asthma symptoms that persisted throughout the day on 2 consecutive days
• Nighttime awakening due to asthma ≥3 times
• Albuterol/salbutamol (or equivalent) use for the acute worsening of asthma
symptoms >8 puffs a day over 2 consecutive days or ≥25 puffs in one day
• Asthma symptoms so severe that the subject was limited in their ability to perform normal daily activity on any 1 day
8. Asthma Exacerbation: An asthma exacerbation requiring systemic (tablets, suspension or injection) corticosteroids within 4 weeks of randomization or more than 4 separate exacerbations in the 12 months preceding randomization. For exacerbations to be considered separate events there must be at least 7 days from the resolution of one exacerbation to the start of the second exacerbation.
9. Asthma Hospitalizations: More than 2 hospitalizations for greater than 24 hours duration for treatment of asthma in the 12 months preceding randomization. Each hospitalization must be separated by >7 days to be considered
an individual event.
10. Pregnancy and Lactation: Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. All females of childbearing potential must have a
negative urine pregnancy test result prior to randomization to continue in the study.
11. Concurrent Diseases/Abnormalities: A subject with any known, pre-existing,
clinically significant condition, disorder or disease of any body or organ system that is uncontrolled with standard treatment and that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the results if the condition, disorder or disease exacerbated during the study.
12. Investigational Medications: A subject who has participated in an interventional study, or used any investigational drug for any disease state, within 30 days prior to randomization.
13. Participation in a Concurrent LABA Safety Study: A subject who has taken at least one dose of study medication in one of the other sponsored studies, being conducted concurrently, to investigate the safety of the addition of LABA to ICS.
14. Drug Allergy: Any adverse reaction including immediate or delayed
hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy or any component of these combination medications including severe milk protein hypersensitivity.
15. Monoclonal Antibody Use: Anti-IgE, or any other monoclonal antibody, for any reason in the 6-months prior to randomization.
16. Concomitant Medications: Use of β-blockers within 1 day prior to first dose of study medication. Use of ICS, LABA, ICS+LABA, LTRAs, leukotriene modifiers, anticholinergics, or theophylline must be discontinued prior to the first dose of study
medication. 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 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and study Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
17. Potent Cytochrome P450 3A4 (CYP3A4) inhibitors: A subject who has received potent CYP34A inhibitor within 4 weeks of randomization.
18. Risk of Non-Compliance: Subjects who are unable to follow study instructions such
as dosing directions or use of the DISKUS/ACCUHALER or metered dose inhaler.
A subject who has any neurological or psychiatric disease or history of drug or alcohol use which in the opinion of the Investigator could interfere with the subject’s proper completion of the protocol requirements.
19. Child in Care.
20. Affiliation with Investigator’s Site. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary safety endpoint is the number of subjects experiencing an event in the
composite endpoint of serious asthma outcomes (i.e., asthma-related hospitalization,
asthma-related endotracheal intubation, or asthma-related death) over the 26-week study
period.
The primary efficacy endpoint is severe asthma exacerbations. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within the 6 months post-randomization |
|
| E.5.2 | Secondary end point(s) |
Secondary safety endpoints include the individual component endpoints of asthmarelated
hospitalization, endotracheal intubation, and death, and withdrawals from the
study treatment due to asthma exacerbation.
The secondary efficacy endpoints is albuterol/salbutamol use. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Entire treatment period (up to 6 months) |
|
| 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) | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 314 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Croatia |
| European Union |
| Hong Kong |
| India |
| Indonesia |
| Japan |
| Malaysia |
| New Zealand |
| Thailand |
| Israel |
| Peru |
| Russian Federation |
| South Africa |
| Taiwan |
| Turkey |
| 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 post-treatment follow up phone contact last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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