| 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 |
| 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 |
|
| 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 |
|
| 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 investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS |
|
| E.2.2 | Secondary objectives of the trial |
- To describe the (steady state) pharmacokinetics (PK) of AZD7594 in a subset of asthmatics symptomatic on low dose ICS
- To describe the pharmacodynamics of AZD7594 by measuring cortisol suppression in a subset of asthmatics symptomatic on low dose ICS
- To evaluate the safety and tolerability of AZD7594 in relation to placebo in asthmatics symptomatic on low dose ICS |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study-specific procedures
2. Men and women 18 to 85 years of age, inclusive, with body mass index (BMI) ≤35
3. Patients need to be non-smokers or ex-smokers (have quit e-cigarettes or other inhaled tobacco products ≥6 months before Visit 1) with a total smoking history of less than 10 pack-years (not applicable for e-cigarettes)
4. Documented clinical diagnosis of asthma for ≥6 months before Visit 1
5. Patients on stable medium to high dose ICS (equivalent of budesonide >400 μg/day) or low to medium dose ICS/LABA for at least 4 weeks prior to screening (Visit 1).
6. Patients must demonstrate reversibility to inhaled bronchodilators at Visit 2 (a ≥12% and ≥200 mL improvement in FEV1 after administration of a 4 puffs of salbutamol/albuterol)
7. Pre-bronchodilator FEV1 at Visit 3 between 40% and 90% predicted at either −45 or −15 minutes pre-dose
8. At Visit 3, patients need to be symptomatic on low dose ICS as evidenced by combined daily asthma mean symptom score of >1 over the previous 7 days or SABA use on ≥3 of the last 7 days during the Run-in Period
9. Demonstrate the ability to use the study inhalation device properly
10. Patient able to perform acceptable pulmonary function testing for FEV1 according to American Thoracic Society/European Respiratory Society (ATS/ERS) acceptability criteria.
11. Patient is willing and able to follow study procedures and restrictions. Women of child bearing potential (WOCBP) should be stable on their chosen method of highly effective birth control for a minimum of 3 months prior to Visit 1, and willing to use that for the entire duration of the study (from the time they sign the informed consent), and for 1 month after the last dose of IP
12. For optional inclusion in the Gx component of the study, patients must provide separate informed consent for the genomic sampling and analysis |
|
| E.4 | Principal exclusion criteria |
1. Known or suspected hypersensitivity to any of the IPs, including budesonide, or excipients, including lactose
2. Systemic steroid use within the 6 weeks before Visit 1
3. Concomitant chronic respiratory disease (including current sleep apnea)
4. History or clinical suspicion of any clinically relevant or active disease or disorder 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
5. Use of prohibited medications that cannot be stopped during the entire period of the study (starting Visit 1).
6. Patients with <80% eDiary compliance during Run in Period at Visit 3
7. ACQ-5 of ≥3 at Visit 1, Visit 2, or Visit 3
8. Daily rescue use of SABA ≥12 puffs for ≥3 consecutive days at any time during Run-in Period, before randomisation.
9. Any clinically important abnormalities in rhythm, conduction or morphology of the digital ECG at rest and any abnormalities in the digital ECG (at Visit 1 or Visit 3) that, as considered by the Investigator, may interfere with the interpretation of QT interval corrected (QTc) interval changes
10. Prolonged QT interval corrected using Fridericia’s formula (QTcF) ≥450 msec based on ECG at Visit 1 or Visit 3; or family history of long QT syndrome
11. PR (PQ) interval prolongation (>240 msec), intermittent second or third degree atrial-ventricular (AV) block or AV dissociation at Visit 1 or Visit 3
12. Patients with implantable cardiac defibrillator and patients with sustained symptomatic ventricular and/or atrial tachyarrhythmia
13. Patients 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
14. History of hospitalisation within 12 months before Visit 1 caused by heart failure or a diagnosis of heart failure higher than New York Heart Association Class II
15. Patients who are positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) at Visit 1
16. Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1
17. Suspected poor capability to follow instructions of the study, as judged by the Investigator
18. Previous participation or prior screen failure in the current study, or participation in any other research study within 1 month prior to Visit 1
19. 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
20. Patient treated with any investigational drug within 30 days (or 5 half-lives, whichever is longer) prior to Visit 1
21. Positive drug screening result that cannot be justified by patient's medical history and its relevant treatment (over-the-counter product or a valid prescription), or history of or current alcohol or drug abuse (including marijuana and marijuana-containing valid prescriptions) as judged by the Investigator
22. Planned in-patient surgery, major dental procedure or hospitalisation during the study
23. Pregnant woman or lactating woman
24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, contract research organisation staff and/or staff at the study centre)
25. Suspicion of Gilbert’s syndrome
26. Vulnerable persons (eg, persons kept in detention)
Exclusion criteria for the pharmacogenomic part of the study:
• Previous allogeneic bone marrow transplant.
• Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genomic sample collection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
• Change from baseline in trough FEV1 at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| as outlined in section E.5.1 |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
• Change from baseline in trough FEV1 at Weeks 2, 4, 8, and average over the treatment period
• Change from baseline in FENO at Weeks 2, 4, 8, 12, and average over the treatment period
• Change from baseline in peak FEV1 at Weeks 2, 4, 8, 12, and average over the treatment period
• Change from baseline in trough FVC at Week 12 and average over the treatment period
• Change from baseline in ACQ-5 at Week 12 and average over the treatment period
• Change from baseline in average morning PEF over the treatment period
• Change from baseline in average evening PEF over the treatment period
• Change from baseline in average daily use of rescue medication over the treatment period
• Change from baseline in percent night-time awakening days over the treatment period
• Change from baseline in average daily asthma symptom score over the treatment period
• Change from baseline in percent asthma control days over the treatment period
• Change from baseline in percent rescue-free days over the treatment period
• Change from baseline in percent symptom-free days over the treatment period
• Time to first CompEx event, time to recurrent CompEx event, and CompEx event rate
PK endpoint:
• AZD7594 plasma concentration and (steady state) PK parameters (Css,max, Css,min, tss,max, AUClast, AUCτ, Css, avg, Css,max /D, and AUCτ/D and %Fluctuation) will be derived
PD endpoint:
• Area under the plasma cortisol concentration-time curve from zero to 24 hours after dosing (AUEC(0-24)), compared to placebo
Adverse event endpoint:
• Adverse events (AEs)/Serious adverse events (SAEs)/Discontinuation of IP due to AE (DAEs)
Vital signs
Clinical chemistry/haematology parameters
Electrocardiogram (ECG) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints for evaluation of Secondary efficacy endpoints are listed in section E.5.2
• PK timepoints: V5: pre-dose blood sample immediately after spirometry. V7: PK samples start 24h prior to V7 (Day 84) (pre-dose +0.25, 0.5, 1, 2, 4, 8, 12, 16 + 24h post-dose) • PD timepoints: Plasma cortisol measurement before and at end of V3 (Day1) and V7 (Day85): Day -1 (at -24, -22, -20, -18, -16, -14, -12, -8, -4, and -2h), on Day 1 (0h pre-dose) and on Day 84 (at 0 [pre-dose], 2, 4, 6, 8, 10, 12, 16, 20, 22 and 24h relative to IP administration • Timepoints for AEs /SAEs /Discontinuation of IP due to AE: Throughout the study: from V1 to V8 Vital signs: From V1 to ETV Clin. chemistry/haematology parameters - V1, V3, V5, V7 and ETV Electrocardiogram - V 1, 3,4,7 and ETV |
|
| 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 | 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Open label active comparator fluticasone furoate will be used for bench marking |
|
| 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 | 47 |
| 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, the last visit corresponds to the Follow-up Contact (Visit 8) |
|
| 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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