Moderate-to-Severe Uncontrolled Asthma MedDRA version: 20.0 Level: PT Classification code 10003553 Term: Asthma System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Conditions
Interventions
Product Name: Atuliflapon
Product Code: AZD5718
Pharmaceutical Form: Tablet
INN or Proposed INN: Atuliflapon
CAS Number: 2041075-86-7
Current Sponsor code: AZD5718
Concentration unit: mg milligram(s)
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Lead-in PK Cohort – Recruitment Completed 1. Provision of signed informed consent prior to any study-specific procedures. 2. Participant is willing and able to follow study procedures and restrictions. 3. 18 to 55 years of age inclusive at the time of signing the ICF at Screening (Visit 1). 4. Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m2 (inclusive) at Screening (Visit 1). 5. Documented asthma diagnosis = 12 months prior to Screening (Visit 1). 6. Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria. 7. Documented evidence of asthma. 8. Morning pre-BD FEV1 = 40% predicted at Screening (Visit 1) and Visit 2. 9. Treated with low dose ICS-LABA or medium-high dose ICS alone or in combination with LABA at a stable dose for at least 3 months prior to Screening (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 Screening (Visit 1) is allowed. Treatment with LTRAs or 5-LO inhibitors is not allowed (see exclusion criteria). 10. Able and willing to comply with the requirements of the CSP including ability to read, write, be fluent in the translated language of all participants facing questionnaires used at site, and use electronic devices (eg, spirometer). 11. Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2. 12. For female participants, a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test prior to administration of study intervention (Visit 2). 13. 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. Part 1 14. Capable of giving signed informed consent. 15. 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. 16. Participant is willing and able to follow study procedures and restrictions. 17. Participant must be 18 to 80 years of age inclusive, at the time of signing the ICF. 18. Body weight = 40 kg and BMI < 35 kg/m2. 19. Documented physician-diagnosed asthma = 12 months prior to Screening (Visit 1). 20. Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria. 21. Documented evidence of asthma. 22. Morning pre-BD FEV1 between = 40% and = 85% predicted at Screening (Visit 1) and Visit 3. 23. Documented history of = 1 severe asthma exacerbation within 1 year prior to Screening (Visit 1). 24. Treated with low dose ICS-LABA or medium-high dose ICS alone or in combination with LABA at a stable dose for at least 3 months prior to Screening (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 Screening (Visit 1) is allowed. Treatment with LTRAs or 5-LO inhibitors is not allowed. 25. An ACQ-6 score = 1.5 at Screening (Visit 1) and at Visit 3. 26. Able and willing to comply with the requirements of the CSP including ability to read, write, be fluent in the translated language of all participants facing questionnaires used at site, and use electronic device
Exclusion criteria
Exclusion criteria: 1. A severe asthma exacerbation within 8 weeks of Screening (Visit 1) or within 12 weeks of randomisation (Visit 3). 2. A positive test result of an approved antigen test (confirmed by a positive RT-PCR) or a positive RT-PCR test 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. 5. 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. 6. Any clinically significant cardiac disease: - Acute coronary syndrome (acute myocardial infarction, unstable angina) or coronary intervention with percutaneous coronary intervention/coronary artery bypass surgery 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 Screening (Visit 1). 7. History of severe renal disease (CKD stage 4 or 5) or history of creatinine clearance < 30 mL/min × m2 calculated using Cockcroft-Gaultequation. 8. Severe hepatic impairment (Child-Pugh class C). 9. Previous hepatotoxicity related to zileuton or LTRAs (eg, montelukast) 10. 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. 11. Evidence of active or untreated latent TB: - Positive IGRA, or repeated indeterminate IGRAs, untreated LTBI (unable to be treated for, or declines treatment of LTBI). - Participants newly diagnosed with LTBI at Screening (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 undergo a repeat test and if still indeterminate may be enrolled only after being treated for LTBI. 12. Abnormal findings
Design outcomes
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Clinical efficacy endpoints: change from baseline in: 1. pre-BD FEV1: Baseline, Week 4, and Week 12 2. SGRQ: Baseline, Week 4, and Week 12 Clinical efficacy endpoints: change from baseline in: 1. ACQ-6: Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period 2. average morning and average evening PEF: Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period 3. daily asthma symptom score (total, daytime, and night-time): Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period Clinical efficacy endpoints: 1. time to first severe asthma exacerbation 2. event status (CompEx Asthma event yes/no) To evaluate the PK of Atuliflapon: 1. Atuliflapon plasma concentrations and PK parameters 3. Atuliflapon 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 Exploratory Endpoints: - Change from baseline in: 1. Post BD FEV1: Baseline, and Week 12 2. Percent reversibility: Baseline and Week 12 3. Forced expiratory flow 25-75%: Baseline, Week 4, and Week 12 - Change from baseline in FeNO: Baseline, Week 4, and Week 12 - Change from baseline in cough VAS: Baseline, Week 4, and Week 12 and over the treatment period - Change from baseline in: 1. home spirometry assessment: Baseline, Week 4 and Week 12 - Change from baseline in: 1. time to first CompEx Asthma event 2. Pre-BD FEV1: Baseline, Week 4 and Week 12 3. ACQ-6 and SGRQ: Baseline, Week 4, and Week 12 4. FeNO: Baseline to Week 4 and Week 12 - Blood and urine biomarker concentrations including Type 1, Type 2, and Type 17 cytokines and other arachidonic acid metabolites at baseline, Week 4, and Week 12 - Endpoints: 1. Creatinine normalised uLTE4, plasma LTE4 2. Creatinine normalised uLTE4, plasma LTE4, plasma LTB4 (ex-vivo stimulation) at Week 4 3. Blood and urine bioma | — |
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the clinical efficacy of Atuliflapon as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma;Secondary Objective: - To evaluate the clinical efficacy of Atuliflapon as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma For further secondary objectives please refer to the protocol.;Primary end point(s): Time to first CompEx Asthma event;Timepoint(s) of evaluation of this end point: Week 12 | — |
Countries
Argentina, Australia, Bulgaria, Chile, Croatia, Germany, Hungary, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Romania, Serbia, Slovakia, Slovenia, South Africa, Spain, Türkiye, United Kingdom, United States
Contacts
Public ContactClinical Study Information Center
AstraZeneca AB
Outcome results
None listed