| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild to moderate atopic asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mild to moderate allergic asthma |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001705 |
| E.1.2 | Term | Allergic asthma |
| E.1.2 | System Organ Class | 100000004855 |
|
| 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 determine whether in asthma it is more efficacious to take inhaled corticosteroid in the morning, in the afternoon or in divided doses both in the morning and afternoon.
Efficacy will be assessed through the measurement of airway narrowing and airway inflammation |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine why the efficacy of inhaled corticosteroids varies by time of day in asthma.
2. To determine if it is possible to ‘phenotype’ subjects with asthma based on circadian profiles.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female adults aged 18 to 65 years at the time of screening and with written informed consent obtained prior to any study-related procedure.
2. Subjects with a physician diagnosis of mild to moderate allergic asthma and with symptoms compatible with asthma for at least 1 year prior to screening.
3. Clinically stable asthma in the 3 months prior to screening and prior to randomisation.
4. Treatment with low to medium doses of inhaled corticosteroids (doses as per Appendix 2) with or without long acting beta agonists.
5. Asthma Control Questionnaire (ATS, 2016) score of < 1.5 score at Screening.
6. Body mass index (BMI) in the range of 18.0 to 33.0 kg/m2 at screening.
7. Non-smokers or ex-smokers being defined as someone who completely stopped smoking cigarettes (including e-cigarettes) for at least 12 months prior to screening and with a smoking history of less than 5-pack years.
8. Oxygen saturation above ≥92% on room air at screening.
9. Pre-bronchodilator spirometry FEV1 ≥65% to ≤90% of predicted and FEV1> 1.0 litre at screening, Day -4, Baseline Period (Visit 2) and predose on Day 1, Treatment Period 1 (Visit 4).
10. Bronchial hyperresponsiveness assessed as documented evidence of variable expiratory airflow limitation at Screening or in the past 2 years prior to Screening, defined as one of the following:
• ≥12% or ≥200 mL improvement in FEV1 in a bronchodilator reversibility test,
• Provocative dose or concentration of methacholine resulting in a ≥20% drop in FEV1 (PD20 or PC20, respectively) of ≤ 1mg or ≤ 16 mg/mL, respectively.
11. Able to generate an adequate sputum sample for processing (as per study reference manual) following induction with inhaled, nebulized hypertonic saline at screening.
12. Subject is willing and, in the opinion of the Investigator, able to change current asthma therapy (i.e. withdraw form inhaled steroids and long acting bronchodilators; if applicable) as required by the protocol.
13. Documented allergy to at least one common allergen (i.e. cat dander, house dust mite or grass pollen) as confirmed by the skin prick test wheal ≥ 3mm over the negative control in diameter. Historical data up to one year can be used.
14. Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method (see Appendix 3).
|
|
| E.4 | Principal exclusion criteria |
1. Inability to comply with study procedures, required restrictions, study treatment intake or any other reason that the Investigator considers makes the subject unsuitable to participate.
2. Asthma exacerbation or chest infection requiring oral steroids and/or antibiotics, in the 3 months prior to screening or prior to randomisation.
3. History of near fatal asthma or of past hospitalisation for asthma in an Intensive Care unit
4. Inability to perform technically acceptable spirometry measurements at screening
5. Pregnant (or planning a pregnancy during the study) or lactating at screening or prior to randomisation.
6. Positive urine pregnancy test at screening or prior to randomisation.
7. Requires oxygen therapy, even on an occasional basis.
8. Known respiratory disorders other than asthma according to investigator’s judgement. This can include but is not limited to known alpha-1 antitrypsin deficiency, active tuberculosis, lung cancer and bronchial carcinoma, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease.
9. Concomitant disease or condition that could interfere with, or for which the treatment of might interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
10. An abnormal and clinically significant 12-lead ECG which may impact the safety of the subject according to investigator’s judgement. N.B: Subject whose electrocardiogram (ECG) (12 lead) shows QTcF>450 males or QTcF> 470 ms for females at screening are not eligible.
11. History of hypersensitivity to β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator’s judgement.
12. Clinically significant laboratory abnormalities at screening indicating a significant or unstable concomitant disease which may impact the efficacy of the study drug or the safety of the, according to investigator’s judgement.
13. Subjects with a history of chronic uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, haematological, urological, immunological, or ophthalmic diseases that the Investigator believes are clinically significant.
14. Uncontrolled cardiovascular disease: arrhythmias, angina, recent or suspected myocardial infarction, congestive heart failure, a history of unstable, or uncontrolled hypertension, or has been diagnosed with hypertension in the 3 months prior to screening or prior to randomisation.
15. History of alcohol abuse and/or substance/drug abuse within 2 years prior to screening visit.
16. Has had major surgery, (requiring general anaesthesia) in the 8 weeks prior to screening or prior to randomisation or has planned surgery through the end of the study.
17. Previous lung resection or lung reduction surgery.
18. Participation in another clinical trial and received investigational drug within 30 days (or 5 half-lives whichever is longer) prior to screening. N.B.: For biologic products with slow elimination a washout of at least 6 months needs to be met prior to screening.
19. Occupations or activities involving night shift work (i.e. subjects who do not sleep at night), jetlag or sleep disruption in the 8 weeks prior to screening or likely to do so at anytime throughout the duration of the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy variables
• 6 hourly Forced Expired Volume in 1 second (FEV1), L
• Twice daily Peak Expiratory Flow, L/minute
• 6 hourly Fractional expired nitric oxide (FeNO) ppb
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
FEV1- Performed On: Day -4 at 4pm and 10pm, Day -3 at 4am and 10am, Day 1 pre Dose, Day 25 at 4pm and 10pm, Day 26 at 4am, 10am.
Peak Flow- Performed between 7am & 9am, and between 7pm and 9pm daily
FeNO- Performed on: Day -4 at 4pm and 10pm, Day -3 at 4am and 10am,Day 25 at 4pm and 10pm, Day 26 at 4am, 10am. |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy variables
• 6 hourly Blood Eosinophils
• Morning and evening Sputum Eosinophils (% of total)
• 6 hourly Serum cortisol
• Asthma Control Test Score/ Asthma Questionnaire (ACQ-7)
• Forced Vital Capacity (FVC), L
• Compliance (i.e. adherence) with study medication
• 6 hourly rhythm in exhaled breath volatile organic compounds (VOCs)
• Mechanistic variables-include 6 hourly serum for downstream lipidomic and proteomic analyses, 3 hourly analysis of gene expression in whole blood.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood eosinophils, Serum Cortisol and VOC Performed on: Day -4 at 4pm and 10pm, Day -3 at 4am and 10am, Day 25 at 4pm and 10pm, Day 26 at 4am, 10am.
Sputum eosinophils- Performed on: Day -3 at 4am, Day -1 at 4pm, Day 26 at 4am, Day 28 at 4pm
ACT/ ACQ- Performed on: Day -4 at 4pm and on Day 25 at 4pm.
FVC- Performed on: Day -4 at 4pm and 10pm, Day -3 at 4am and 10am, Day 1 pre Dose and Day 25 at 4pm and 10pm, Day 26 at 4am, 10am.
Compliance: at each scheduled visit
Mechanistic variables serum: Day -4 at 4pm and 10pm, Day -3 at 4am and 10am, Day 25 at 4pm and 10pm, Day 26 at 4am, 10am.
Mechanistic variables gene expression: Performed on Day -4 at 4pm, 7pm, 10pm, on Day -3 at 1am, 4am, 7am, 10am and 1pm, Day 25 at 4pm, 7pm, 10pm, and on Day 26 at 1am, 4am, 7am, 10am and 1pm |
|
| 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 | No |
| 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 | 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 |
|
| 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) | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| No comparator- the IMP will used in 3 different dosing regimens |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The end of the trial is defined as the last scheduled follow up telephone call or last visit to the unit, of the last subject in the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
Print
