| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
This study will be performed in men and non-pregnant, non-lactating women, all between 12 and 95 years of age with asthma symptomatic on ICS and fulfilling the reversibility criterion (improvement of FEV1≥12% and 200 mL after administration of salbutamol/albuterol) at Visit 2.
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| E.1.1.1 | Medical condition in easily understood language |
| Asthma (an illness that causes breathing difficulty) that is not fully controlled, so that episodes of breathing difficulty are still occurring despite the use of other available treatments. |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003560 |
| E.1.2 | Term | Asthma NOS |
| E.1.2 | System Organ Class | 100000004855 |
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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 is to investigate the efficacy of abediterol once daily after 4 weeks of treatment as measured by change from baseline in trough FEV1 on Day 29 |
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| E.2.2 | Secondary objectives of the trial |
- To investigate the efficacy of abediterol as measured by changes in other spirometry parameters after 4 weeks of treatment in patients with asthma
- To investigate the efficacy of abediterol in patient reported outcomes after 4 weeks of treatment in patients with asthma
- To investigate the onset of action of abediterol
- To characterize the dose-response curve
- To investigate PK parameters of abediterol in a subset of patients |
|
| 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 |
A subset of approximately 206 patients will undergo PK
assessments. All patients from Japan and all adolescents will be included in the PK sub-study. |
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| E.3 | Principal inclusion criteria |
1. Patient or patient’s parents/legal guardians who provided written informed consent (assent for underage patients) prior to any study-specific procedures.
2. Men and non-pregnant, non-lactating women between 12 and 95 years of age, inclusive.
3. Non-smoker or former smoker who quit ≥6 months prior to Visit 1 and have a total smoking history of ≤10 pack-years.
4. Patient with documented clinical diagnosis of asthma for ≥6 months before Visit 1 according to GINA guidelines.
5. Patient with normal or controlled blood pressure (defined as systolic blood pressure [SBP] between 90 and 150 mm Hg, and diastolic blood pressure [DBP] between 40 and 90 mm Hg) at Screening, measured after resting in the supine position for 5 min. Patients stable on anti-hypertensive can be included.
6. Patient with no relevant clinical laboratory findings at Screening (Visits 1 or 2) as judged by the Investigator.
7. Patient on stable dose of ICSs or ICS/LABA FDC, for at least 1 month prior to Visit 1, at the doses approved in the country of enrolment.
8. Patient with a compliance with their ICS with inhalation treatment during Run-in Period of at least 75%, as measured with the eDiary.
9. Patient with pre-bronchodilator FEV1at Visit 2 ≥40% and ≤90% of predicted (mean of 2 pre-bronchodilator measurements taken 30 min apart).
10. Patient who fulfils reversibility criteria to salbutamol/albuterol at Visit 2, with reversibility as defined per the 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria, ie, ≥12% and ≥200 mL after administration of 4 puffs of salbutamol/albuterol.
11. Patient with an asthma symptom score >0 as recorded on eDiary on at least 3 out of the last 7 days of Run-in Period.
12. Patient who demonstrates the ability to use the study inhalation device properly.
13. Patient able to perform acceptable pulmonary function testing for FEV1according to ATS/ERS acceptability criteria.
14. Negative pregnancy test (serum pregnancy test at Screening) for female patients.
15. Female patients must be 1 year post-menopausal, surgically sterile, or must be able to adhere to the conditions of contraceptive requirements as described in the protocol. Male patients must be surgically sterile or must be able to adhere to the conditions of contraceptive requirements as described in the protocol.
16. Patients willing not to donate blood during the study and for 3 months following their last dose of IP for patients participating in the PK sub-study and for 8 weeks for other patients.
17. Patient willing and able to follow study directions and restrictions. |
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| E.4 | Principal exclusion criteria |
1. Patient has known or suspected hypersensitivity to the IP or excipients, including lactose (Note: lactose intolerance is not an exclusion criterion).
2. Patient who has used systemic steroid in the 6 weeks before Visit 1.
3. Patient with a history of hospitalisation due to asthma in the 6 months prior to Visit 1 or a history of intubation because of asthma at any time in their lifetime.
4. Patient with any active pulmonary disease other than asthma.
5. Patient non-compliant with study procedures in the Run-in Period – as judged by the Investigator.
6. Patient under treatment with biologicals such as monoclonal antibodies or chimeric biomolecules including omalizumab, mepolizumab, and reslizumab within 6 months or 5 half-lives before Visit 1, whichever is longer.
7. Patient treated with any investigational drug within 30 days (or 5 half-lives, whichever is longer) prior to Visit 1.
8. Patient on treatment with strong cytochrome P450 (CYP)3A4 inhibitors such as ketoconazole or itraconazole or CYP3A4 inducers such as rifampin at Visit 1 or within 14 days prior to administration of IP.
9. Patient with a history, laboratory abnormality, or clinical suspicion of any clinically relevant disease or disorder, including uncontrolled hypertension or uncontrolled diabetes, which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient’s ability to participate in the study, or any other safety concerns in the opinion of the Investigator.
10. Patient with diagnosis of any kind of chronic hepatitis or know human immunodeficiency virus (HIV) infections at the time of enrolment.
11. Patient with any active malignancy or treatment thereof within the five years prior to enrolment.
12. Patient with any clinically important abnormalities in rhythm, conduction, or morphology of the screening 12-lead ECG as judged by the Investigator on the screening ECG.
13. Patient with prolonged QT interval using Fridericia’s correction ≥450 msec on the screening ECG or family history of long QT syndrome.
14. Patient with PR (PQ) interval prolongation (>240 msec), intermittent second or third degree atrio-ventricular (AV) block or AV dissociation on the screening ECG.
15. Patient with heart rate (HR) <45 beat per minute (bpm) or >90 bpm at Screening ECG.
16. Patient with implanted cardiac defibrillator and patients with sustained symptomatic ventricular and/or atrial tachyarrhythmia.
17. Patient with any contraindication against the use of sympathomimetic drugs as judged by the Investigator.
18. Patient with unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society Class II, or a myocardial infarction, or stroke within 6 months before Visit 1.
19. Patient with a history of hospitalisation within 12 months caused by heart failure or a diagnosis of heart failure higher than New York Heart Association (NYHA) Class II.
20. Patient with previous participation or prior screen failure in the current study.
21. Patient with a history of or current alcohol or drug abuse (including marijuana), as judged by the Investigator.
22. Patient with planned in-patient surgery, major dental procedure or hospitalisation during the study.
23. Patient involved in the planning and/or conduct of the study (applies to both AstraZeneca staff, contract research organisation (CRO) staff and/or staff at the study site).
24. Vulnerable person (eg, person kept in detention).
25. Patient with daily rescue medication use of ≥12 puffs for ≥3 consecutive days or an asthma exacerbation or a change in the dose of ICS during the Run-in Period.
26. Patient who intends to use any concomitant medication not permitted by this protocol as indicated in Table 6.
27. Patient who received live attenuated vaccine within 30 days prior to Visit 1 or who received inactivated vaccine within 7 days prior to Visit 1. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Change from baseline (pre-dose, Visit 3) in morning trough FEV1 on Day 29 (Visit 7) (defined as the average of the FEV1 values at 23:15 and 23:45 hours after IP administration on Day 28)
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| FEV1 values at 23:15 and 23:45 hours after IP administration on Day 28 |
|
| E.5.2 | Secondary end point(s) |
• Changes from baseline (pre-dose, Visit 3) in peak FEV1, FEV1 area under the curve from time 0 to 6 hours (AUC(0-6)), FEV1AUC(0-12), FEV1 AUC(0-24), peak forced vital capacity (FVC), trough FVC, FVC AUC(0-6), FVC AUC(0-24) on Day 29
• Change from baseline (pre-dose, Visit 3) in trough FEV1, peak FEV1, FEV1(AUC(0-6)), FEV1 AUC(0-12), FEV1AUC(0-24), peak FVC, FVC AUC(0-6), FVC AUC(0-12), and FVC AUC(0-24), after first dose (on Day 1)
• Change from baseline in trough FEV1, peak FEV1, peak FVC, trough FVC, over the whole treatment period (from Day 8 to Day 29)
• Percentage of patients achieving an increase of 200 mL and 12% in FEV1from baseline at each time point of Day 1 and Day 29
• Percentage of patients achieving an increase from baseline in peak and trough FEV1, of 12% and 200 mL on Day 29
• Change from baseline (last 2 weeks of Run-in Period) in daily symptoms, use of daily rescue medication, morning peak expiratory flow (mPEF), evening peak expiratory flow (ePEF), nocturnal awakenings over the 29-day treatment period
• Change from baseline (last week of Run-in Period) in Asthma Control Questionnaire (ACQ) on Day 29
• Change from baseline (pre-dose, Visit 3) in EuroQoL health-related quality of life, 5 dimensions questionnaire (EQ-5D) on Day 29
• Change from baseline in FEV1at each time point on Day 1 and Day 29
• Time to achieve 200 mL and 12% improvement in FEV1 from baseline on Day 1
• Emax model fit to trough FEV1and peak FEV1
• Day 1: maximum plasma concentration (Cmax), time to reach maximum plasma concentration (tmax), terminal rate constant (λz), terminal half-life (t1/2λz), area under the plasma concentration-curve from time 0 to the time of last quantifiable concentration (AUClast), AUC(0-6), AUC(0-12), AUC(0-24), Cmax/D, AUC(0-6)/D, and AUC(0-24)/D
• Day 29: Cmax, tmax, λz, t1/2λz, AUClast, AUC(0-6), AUC(0-12), AUC(0-24), average plasma concentration during a dosing interval (Cavg), Cmax/D, AUC(0-24)/D, accumulation ratio for Cmax (Rac[Cmax]), accumulation ratio for AUC(0-24)
(Rac[AUC(0-24)]), Rac[AUC(0-6)], and Fluctuation index during a dosing interval (%Fluctuation) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| as specified in Sections 2.2 and 4.2 of the protocol; Most of secondary endpoints will be measured at Day 8, 15, 22 and 29 main ones on Day 29 only |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 7 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Bulgaria |
| Germany |
| Hungary |
| Japan |
| Poland |
| South Africa |
| Ukraine |
| United States |
|
| 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 study is defined as ‘the last visit of the last patient undergoing the study’. For this study, last visit corresponds to the follow-up contact. |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| 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 | 0 |
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