| 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 | 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 |
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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 compare the efficacy of ICS/LABA reliever therapy with SABA reliever therapy and with maintenance ICS and SABA reliever therapy in adult patients using SABA monotherapy (i.e. without any other asthma medication).
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| E.2.2 | Secondary objectives of the trial |
1. To compare the safety of ICS/LABA reliever therapy with SABA reliever therapy and with maintenance ICS and SABA reliever therapy in adult patients using SABA monotherapy (i.e. without any other asthma medication).
2. To determine whether baseline clinical characteristics such as reported beta agonist use, Th2 profile, smoking status or history of severe exacerbations predict preferential response to randomised treatments.
3. To examine patterns of inhaler use with the randomised regimens.
4. To examine patient attitudes to and experience with the treatment regimens.
5. To examine the cost effectiveness of each treatment regimen. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adults aged 18 to 75 years.
2. Self-report of a doctor’s diagnosis of asthma with:
a. Self-reported use of a SABA on ≥2 occasions in the previous 4 weeks but on average ≤2 occasions per day in the previous 4 weeks, if there have been no severe exacerbations in the last 12 months, or
b. Self-reported use of a SABA on average ≤2 occasions per day in the previous 4 weeks, if there has been a history of a severe exacerbation in the last 12 months.
3. Willing and able to give informed consent for participation in the trial.
4. In the Investigator’s opinion, able and willing to comply with all trial requirements.
5. Willing to allow their General Practitioner and/ or consultant, if appropriate, to be notified of participation in the trial.
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| E.4 | Principal exclusion criteria |
1. Self-reported use of ICS, LABA, leukotriene receptor antagonist, theophylline, anticholinergic agent or cromone as regular maintenance therapy in the 3 months before potential study entry. Note nasal corticosteroid therapy is permitted.
2. Self-reported past admission to the Intensive Care Unit (ICU) with life-threatening asthma (patients at highest risk of adverse asthma outcomes).
3. Self-reported hospital admission for asthma in the 12 months before potential study entry (patients at highest risk of adverse asthma outcomes).
4. Self-reported treatment with oral prednisone in the six weeks before potential study entry, representing recent unstable asthma.
5. A home supply of prednisone for use in worsening asthma.
6. Self-reported diagnosis of COPD, bronchiectasis or interstitial lung disease.
7. Self-reported greater than 20 pack year smoking history, or onset of respiratory symptoms after the age of 40 years in current or ex-smokers with ≥10 pack year history.
8. Self-reported current pregnancy or breast feeding at the time of enrolment or planned pregnancy within the study period.
9. Self-reported congestive heart failure, unstable coronary artery disease, atrial fibrillation or other clinically significant cardiac disease.
10. Unwilling or unable to switch from current asthma treatment regimen.
11. Other illness(es) likely to compromise participant safety or impact on the feasibility of results, at the discretion of the investigator.
12. Self-report of participation in another research trial involving an investigational product, in the past 12 weeks.
13. An on treatment FEV1 ≤50% of predicted at Visit 1 (predicted values must be calculated using the Global Lung Function Initiative equations).
14. Any known or suspected contraindications to the Investigational Medicinal Products or excipients.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Asthma exacerbation rate expressed as number of exacerbations per patient per year. An asthma exacerbation is defined as:
- Worsening asthma resulting in urgent medical review (primary care visit, ED visit or hospital admission) and/or
- Worsening asthma resulting in use of systemic corticosteroids, such as a course of prednisone for any duration and/or
- Worsening asthma resulting in a high beta agonist use episode, defined as >16 actuations of salbutamol or >8 actuations of budesonide/formoterol per 24 hour period.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Clinical outcomes
- The proportion of exacerbations
- The proportion of participants with at least one exacerbation
- Time to first exacerbation of asthma
- Proportion of participants withdrawn due to “treatment failure”:
- The proportion of “treatment failures”
- Rate of severe exacerbations defined by the ATS/ERS criteria
- Time to withdrawal due to severe exacerbation
- The proportion of severe exacerbations defined by each of the above criteria
- Asthma Control Questionnaire (ACQ-5 score)
- GINA question category (well, partly or un-controlled)
- On-treatment FEV1, i.e. without withholding of bronchodilator medication
- On-treatment FEV1 percentage predicted, i.e. without withholding of bronchodilator medication
- FeNO (a measure of airways inflammation)
2. Medication use
- Mean ICS dose per day (budesonide µg/day);
- Periods without ICS use
- Total corticosteroid use:
- High beta agonist use:
- Marked beta agonist overuse, defined as >24 actuations of salbutamol or >12 actuations of budesonide/formoterol per 24 hour period, as previously defined.
- Maximum number of beta agonist actuations in a 24 hour period.
- Use of study medications in the 14 days prior to severe exacerbations, as previously defined, with graphical presentation of the median (interquartile range) daily medication use for the randomised groups, and the medication use for the individual participants within each randomised group.
- Inhaler use for exercise induced asthma
- Proportion of participants who self report use of reliever inhaler before exercise to prevent exercise induced asthma in the past 2 weeks
- If yes, number of times in the past 2 weeks.
3. Adverse events
- Adverse events.
- Serious adverse events.
4. Cost-effectiveness
- The medical costs (medications, emergency medical and ED visits, hospital admissions), and non-medical costs (days off work). The cost-effectiveness data collected will allow extrapolation to future pricing models.
5. Patient attitudes
- ASK-12 questionnaire.
- Qualitative interview results.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | Yes |
| 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 | 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 | 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 | 5 |
| 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 |
| Australia |
| Italy |
| New Zealand |
| United Kingdom |
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| 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
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Database lock, subsequent to LVLS. To allow adequate time for collection and cleaning of all data for the final analysis, the end of the study will be at database lock.
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 30 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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