Asthma
Conditions
Interventions
Eligible participants with moderate-to-severe uncontrolled asthma will be
randomised to 1 of 2 separate treatment groups.
In the Lead-in PK cohort and Part 1 of the study, participants will be
rand
a
screening period of up to 28 days, a 2-week treatment period and a 1-week
follow-up.
*Part 1: The overall study period is approximately 19 weeks
a 2-week screening
period (not including Visit 0), a 4-week run-in period, a
12-week treatment period, and a 1-week follow-up.
Sponsors
Astra Zeneca
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Part 1 and Part 2 protocol 5.1.2. General Inclusion Criteria for Part 1 and Part 2 10. Capable of giving signed informed consent 11. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative. 12. Participant is willing and able to follow study procedures and restrictions. 13. Participant must be 18 to 80 years of age inclusive, at the time of signing the ICF. 14. Body weight 50 - 120 kg and body mass index (BMI) 18 -35 kg/m2. 15. Documented physician-diagnosed asthma >= 12 months prior to Visit 1. 16. Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria. 17. Documented evidence of asthma as demonstrated by either: * Post-BD reversibility of FEV1 >= 12% and >= 200 within 5 years prior to Visit 1, or at Visit 1, or * PEF average daily variability > 10% over a 2-week period within 5 years prior to Visit 1, or * Variability of FEV1 > 12% and 200 mL between any two clinical visits within 5 years prior to Visit 1, or * Positive methacholine challenge test within the 5 years prior to Visit 1. A positive result is defined as a PC20 = 40% and = 1 severe asthma exacerbation within 3 years prior to Visit 1. 20. Treated with low dose ICS-LABA or medium-high dose ICS (as per GINA 2021 ICS equivalence table - Appendix C) alone or in combination with LABA at a stable dose for at least 3 months prior to Visit 1. (The ICS can be contained within an ICS-LABA fixed dose combination product). * Treatment with additional asthma controller therapies (eg, LAMA) at a stable dose >= 3 months prior to Visit 1 is allowed. (Treatment with LTRAs or 5-LO inhibitors is not allowed. 21. An ACQ-6 score >= 1.5 at Visit 1 and at Visit 3. 22. Able and willing to comply with the requirements of the protocol including ability to read, write, be fluent in the translated language of all participant facing questionnaires used at site, and use electronic devices, eg, eCOA device and spirometry. 28. At least 80% compliance with usual asthma background medication during run-in period (from Visit 2 to Visit 3) based on the daily asthma ePROs. 29. Minimum 80% compliance with daily eCOA assessments. 24. For female participants, a negative serum pregnancy test. 25. Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. There are no restrictions on male participants or their female partners.
Exclusion criteria
Exclusion criteria: Protocol 5.2.1. 1. A severe asthma exacerbation within 8 weeks of randomisation. 2. A positive nucleic acid test (eg RT-PCR) at Visit 1 or at Visit 3 for SARS-CoV-2, the virus responsible for COVID-19. 3. Participants with a significant COVID-19 illness within 6 months of enrolment: * Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment. * Participants with a diagnosis of COVID-19 requiring hospitalisation and/or oxygen supplementation therapy. 4. Clinically important pulmonary disease other than asthma eg, active lung infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, history or planned lung lobectomy, alpha-1 anti-trypsin deficiency, primary ciliary dyskinesia, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis and hyper-eosinophilic syndrome. 6. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and could: * Affect the safety of the participant throughout the study. * Influence the findings of the study or the interpretation. * Impede the participant's ability to complete the entire duration of study. 7. Any clinically significant cardiac disease: * Acute coronary syndrome (acute myocardial infarction, unstable angina), coronary intervention with percutaneous coronary intervention/coronary artery bypass surgery or stroke within 6 months. * Heart failure NYHA II-IV. * Untreated high degree atrioventricular-block (>= 3:1 conduction rate/Grade III block)/ significant sinus node dysfunction/pause or therapy requiring tachyarrhythmia. * History or family history of long QT-syndrome. * History of QT prolongation associated with other medications that required discontinuation of that medication. * Hypertrophic cardiomyopathy or clinically significant valvular heart disease. * Stroke within 3 months of Visit 1. 8. History of severe renal disease (CKD stage 4 or 5) or history of creatinine clearance < 30 mL/min × m2 calculated using Cockcroft-Gault equation. 9. Severe hepatic impairment (Child-Pugh class C). 10. Previous hepatotoxicity related to zileuton or LTRAs (eg montelukast) 11. Participants with a recent history of, or who have a positive test for, infective hepatitis or unexplained jaundice, or participants who have been treated for hepatitis B, hepatitis C, or HIV. For the hepatitis B testing (HbsAg, anti-HBs, and anti-HBc), any of the following would exclude the participant from the study: * Participants positive for HbsAg. * Participants positive for anti-HBc. 12. Evidence of active or untreated latent TB: * Positive IGRA, or repeated indeterminate IGRAs, no evidence of active TB and untreated for LTBI, unable to be treated for, or declines treatment of LTBI. * Participants newly diagnosed with LTBI at Visit 1 could be considered for rescreening if they complete a full course of treatment for LTBI in accordance with recommended treatment guidelines prior to rescreening. In this situation, repeat IGRA test is not required after completion of treatment for LTBI. * Participants with an indeterminate IGRA should underg
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary endpoint: - time to first CompEx Asthma event | — |
Secondary
| Measure | Time frame |
|---|---|
| Secundary endpoint: - Endpoint and population-level summary measure are the same as for the primary objectives Further endpoints: change from baseline in: - pre-BD FEV1: Baseline, Week 4, and Week 12 - SGRQ: Baseline, Week 4, and Week 12 - ACQ-6: Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period - average morning and average evening PEF: Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period - daily asthma symptom score (total, daytime, and night-time): Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period - time to first severe asthma exacerbation - event status (CompEx Asthma event yes/no) PK endpoints: - AZD5718 plasma concentrations and PK parameters - AZD5718 plasma concentrations: pre-dose samples at Baseline, Week 4, and Week 12 Safety endpoints: - safety and tolerability evaluations using AEs, vital sign measures, clinical laboratory assessments, ECG, and C-SSRS | — |
Countries
Netherlands
Outcome results
None listed