A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Assess Efficacy and Safety of Atuliflapon Given Orally Once Daily for Twelve Weeks in Adults with Moderate to Severe Uncontrolled Asthma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

12 Apr 2023 → 7 Jan 2026

Decision date (initial)

2024-08-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca AB

External identifiers

EU CT number

2023-509243-27-00

EudraCT number

2021-003338-35

ClinicalTrials.gov

NCT05251259

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Efficacy, Safety

To evaluate the clinical efficacy of Atuliflapon as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma

Secondary objectives 1

1. 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

Conditions and MedDRA coding

Moderate-to-Severe Uncontrolled Asthma

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 30

1. Lead-in PK Cohort – Recruitment Completed: Provision of signed informed consent prior to any study-specific procedures
2. Part 1: Body weight ≥ 40 kg and BMI < 35 kg/m2
3. Part 1: Documented physician-diagnosed asthma ≥ 12 months prior to Screening (Visit 1)
4. Lead-in PK Cohort – Recruitment Completed: 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)
5. Part 1: Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria
6. Lead-in PK Cohort – Recruitment Completed: Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2
7. Lead-in PK Cohort – Recruitment Completed: 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)
8. Lead-in PK Cohort – Recruitment Completed: 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
9. Part 1 Capable of giving signed informed consent
10. Part 1: 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
11. Lead-in PK Cohort – Recruitment Completed: Participant is willing and able to follow study procedures and restrictions
12. Lead-in PK Cohort – Recruitment Completed: Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m2 (inclusive) at Screening (Visit 1)
13. Lead-in PK Cohort – Recruitment Completed: 18 to 55 years of age inclusive at the time of signing the ICF at Screening (Visit 1)
14. Lead-in PK Cohort – Recruitment Completed: Documented evidence of asthma
15. Part 1: Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at Screening (Visit 1) and Visit 3
16. Part 1: Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Screening (Visit 1)
17. Part 1: 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
18. Part 1: An ACQ-6 score ≥ 1.5 at Screening (Visit 1) and at Visit 3
19. Lead-in PK Cohort – Recruitment Completed: Documented asthma diagnosis ≥ 12 months prior to Screening (Visit 1)
20. Lead-in PK Cohort – Recruitment Completed: Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria
21. Part 1: Documented evidence of asthma
22. Lead-in PK Cohort – Recruitment Completed: Morning pre-BD FEV1 ≥ 40% predicted at Screening (Visit 1) and Visit 2
23. Lead-in PK Cohort – Recruitment Completed: 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)
24. Part 1: Participant is willing and able to follow study procedures and restrictions
25. Part 1: Participant must be 18 to 80 years of age inclusive, at the time of signing the ICF
26. Part 1: 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, eCOA device and spirometry
27. Part 1: 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
28. Part 1: Minimum 80% compliance with daily eCOA assessments. Compliance is defined as completing the daily ePRO questions and PEF measurement at least 80% of the time during the run-in period and during the 14 days preceding Visit 3
29. Part 1: For women of childbearing potential, a negative serum pregnancy test at Screening (Visit 1) and negative urine pregnancy test at Visit 3
30. Part 1: 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. Please refer to the protocol for the full list of inclusion criteria

Exclusion criteria 12

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 test) 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 hospitalization 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-Gault equation
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. Participants who, as judged by the Investigator, have evidence of active TB, either treated or untreated, or latent TB without completion of an appropriate course of treatment or appropriate ongoing prophylactic treatment. Evaluation will be according to the local standard of care as determined by local guidelines and may consist of medical history and physical examinations, chest X-ray, or TB test (eg, purified protein derivative or QuantiFERON® test).
12. Abnormal findings identified on physical examination, ECG, or laboratory testing include, but are not limited to: − ALT or AST ≥ 2 × ULN. − TBL ≥ 1.5 × ULN (unless due to Gilbert's disease). − Evidence of chronic liver disease. − Abnormal vital signs, after 5 minutes of supine or sitting rest (confirmed by one controlled measurement), defined as any of the following: o SBP < 80 mmHg or ≥ 150 mmHg. o DBP < 50 mmHg or ≥ 95 mmHg. o Pulse < 45 or > 100 beats per minute. − Signs of pulmonary oedema or volume overload. − Any clinically significant rhythm, conduction, or morphology abnormalities in the ECG including but not limited to QTcF > 450 ms. Please refer to the protocol for the full list of exclusion criteria

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Time to first CompEx Asthma event

Secondary endpoints 5

1. Clinical efficacy endpoints: Change from baseline in: 1 pre-BD FEV1: Week 4, and Week 12 2 SGRQ: Week 4, and Week 12
2. Clinical efficacy endpoints: Change from Baseline in: 1 ACQ-6: Week 4, 8, 12, and average over the 12-weeks 2 average morning and average evening PEF: Week 4, 8, 12, and average over 12-weeks 3 daily asthma symptom score (total, daytime, and night-time): Week 4, 8, 12, and average over the 12-weeks
3. Clinical efficacy endpoints: 1 time to first severe asthma exacerbation 2 event status (CompEx Asthma event yes/no)
4. To evaluate the PK of Atuliflapon: 1 Atuliflapon plasma concentrations and PK parameters 2 Atuliflapon plasma concentrations: pre-dose samples at Baseline, Week 4, and Week 12
5. Safety Endpoints: Safety and tolerability evaluations using AEs, vital sign measures, clinical laboratory assessments, ECG and C-SSRS. For full information please refer to the protocol

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Centre

Third parties 1

Locations

10 EU/EEA countries · 70 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 168 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications