Efficacy and Safety Evaluation of Atuliflapon in Adults with Moderate-to-Severe Uncontrolled Asthma: A Phase 2a Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2023-509243-27-00
Protocol: D7552C00001
Sponsor: AstraZeneca AB

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Diseases & Conditions

Asthma

Objectives

The primary objective of this study is to evaluate the **clinical efficacy** of Atuliflapon compared to placebo in adult participants with moderate-to-severe uncontrolled asthma. This is clinically relevant as it aims to determine the potential of Atuliflapon to improve asthma control in a population that is not adequately managed by current treatments, thereby addressing a significant unmet medical need.

Secondary objectives include assessing the clinical efficacy of Atuliflapon in comparison to placebo in the same patient population. Further secondary objectives are detailed in the study protocol.

Participants

The clinical trial involves a total of **448 participants** diagnosed with **moderate-to-severe uncontrolled asthma**. The study population includes both male and female subjects, aged between **18 to 80 years**. Participants were selected based on specific criteria, including documented evidence of asthma and a history of at least one severe asthma exacerbation within the year prior to screening. The trial population is required to have been treated with low-dose ICS-LABA or medium-high dose ICS alone or in combination with LABA at a stable dose for at least three months prior to screening. Participants must also demonstrate compliance with asthma background medication and daily assessments. The study includes individuals who are able to perform acceptable lung function testing and are willing to comply with study procedures. The trial does not restrict participation based on gender, and both male and female participants are included. The trial also considers lifestyle factors such as the ability to use electronic devices for assessments and compliance with local contraceptive regulations for female participants. The study population is characterized by a diverse age range and includes a vulnerable population, ensuring a comprehensive evaluation of the clinical efficacy of Atuliflapon compared to placebo.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **Atuliflapon** administered orally once daily over a period of twelve weeks in adults with moderate-to-severe uncontrolled **asthma**. The trial aims to assess the clinical efficacy of Atuliflapon compared to a placebo, with the primary endpoint being the time to the first CompEx Asthma event. Secondary endpoints include changes from baseline in pre-bronchodilator FEV1, SGRQ, ACQ-6 scores, and asthma symptom scores at various intervals throughout the study.

Participants will be involved in the study for a total duration of approximately twelve weeks, with the trial estimated to conclude by January 29, 2026. The study will commence with an inclusion (screening) visit, where eligibility criteria such as age, body weight, and documented evidence of asthma will be assessed. Participants must be between 18 to 80 years of age and have a documented history of at least one severe asthma exacerbation within the year prior to screening. They must also have been treated with stable doses of low-dose ICS-LABA or medium-high dose ICS alone or in combination with LABA for at least three months prior to screening.

Following the screening visit, participants will undergo a series of follow-up visits at weeks 4, 8, and 12 to monitor efficacy and safety outcomes. These visits will include assessments of lung function, asthma control, and symptom scores, as well as safety evaluations through adverse event monitoring, vital signs, laboratory assessments, ECG, and C-SSRS. The end-of-study visit will occur at week 12, marking the completion of the participant's involvement in the trial.

Participants may be subject to early termination from the study if they fail to comply with study procedures, experience significant adverse events, or if the investigator deems it necessary for their safety. The study will ensure that all participants provide informed consent prior to any study-specific procedures, and compliance with the study protocol will be closely monitored throughout the trial duration.

Treatment

The clinical trial involves the administration of **Atuliflapon**, an experimental medication, in the form of a **tablet**. The active substance in Atuliflapon is chemically derived and is administered orally. Participants will receive a daily dose of Atuliflapon for a maximum treatment period of 12 weeks. The dosage is measured in milligrams, although specific dosing details are not provided. The trial aims to evaluate the efficacy and safety of Atuliflapon in adults with moderate to severe uncontrolled asthma.

In addition to Atuliflapon, the study includes a **placebo** group to serve as a control. The placebo is designed to mimic the appearance and administration route of Atuliflapon but does not contain any active pharmaceutical ingredients. The placebo is administered orally once daily, following the same schedule as the experimental medication, to ensure blinding and maintain the integrity of the study.

**Salbutamol** is used as an auxiliary treatment in the trial. It is a bronchodilator and **β2-adrenergic agonist** provided in the form of a pressurised inhalation suspension. The active substance, salbutamol, is chemically derived and administered via inhalation. The device used for administration is the Ventolin 100 Inhaler, which is CFC-free and contains a suspension of salbutamol sulphate and HFA 134a as the propellant gas. Salbutamol is not the primary focus of the study but is included to manage asthma symptoms as needed, ensuring participant safety and comfort throughout the trial.

Efficacy

The efficacy of Atuliflapon in the treatment of moderate-to-severe uncontrolled asthma will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to the first **CompEx Asthma** event. Secondary endpoints include changes from baseline in pre-bronchodilator forced expiratory volume in one second (FEV1) at weeks 4 and 12, and the St. George's Respiratory Questionnaire (SGRQ) scores at the same time points. Additionally, changes from baseline in the Asthma Control Questionnaire (ACQ-6) scores will be evaluated at weeks 4, 8, and 12, as well as the average over the 12-week period. Other secondary endpoints include average morning and evening peak expiratory flow (PEF) at weeks 4, 8, and 12, and the average over 12 weeks, along with daily asthma symptom scores (total, daytime, and nighttime) at the same intervals.

Measurements will be collected at specified time points throughout the study, including baseline, week 4, week 8, and week 12. The tools and instruments used for these assessments include validated scales and spirometry for lung function testing. The analysis will focus on comparing the efficacy of Atuliflapon to placebo in achieving these endpoints, providing insights into its potential benefits for patients with moderate-to-severe uncontrolled asthma.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Lead-in PK Cohort – Recruitment Completed: Provision of signed informed consent prior to any study-specific procedures
Part 1: Body weight ≥ 40 kg and BMI < 35 kg/m2
Part 1: Documented physician-diagnosed asthma ≥ 12 months prior to Screening (Visit 1)
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)
Part 1: Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria
Lead-in PK Cohort – Recruitment Completed: Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2
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)
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
Part 1 Capable of giving signed informed consent
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
Lead-in PK Cohort – Recruitment Completed: Participant is willing and able to follow study procedures and restrictions
Lead-in PK Cohort – Recruitment Completed: Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m2 (inclusive) at Screening (Visit 1)
Lead-in PK Cohort – Recruitment Completed: 18 to 55 years of age inclusive at the time of signing the ICF at Screening (Visit 1)
Lead-in PK Cohort – Recruitment Completed: Documented evidence of asthma
Part 1: Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at Screening (Visit 1) and Visit 3
Part 1: Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Screening (Visit 1)
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
Part 1: An ACQ-6 score ≥ 1.5 at Screening (Visit 1) and at Visit 3
Lead-in PK Cohort – Recruitment Completed: Documented asthma diagnosis ≥ 12 months prior to Screening (Visit 1)
Lead-in PK Cohort – Recruitment Completed: Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria
Part 1: Documented evidence of asthma
Lead-in PK Cohort – Recruitment Completed: Morning pre-BD FEV1 ≥ 40% predicted at Screening (Visit 1) and Visit 2
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)
Part 1: Participant is willing and able to follow study procedures and restrictions
Part 1: Participant must be 18 to 80 years of age inclusive, at the time of signing the ICF
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
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
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
Part 1: For women of childbearing potential, a negative serum pregnancy test at Screening (Visit 1) and negative urine pregnancy test at Visit 3
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

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Exclusion Criteria

A severe asthma exacerbation within 8 weeks of Screening (Visit 1) or within 12 weeks of randomisation (Visit 3)
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
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
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
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
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)
History of severe renal disease (CKD stage 4 or 5) or history of creatinine clearance < 30 mL/min × m2 calculated using Cockcroft-Gault equation
Severe hepatic impairment (Child-Pugh class C)
Previous hepatotoxicity related to zileuton or LTRAs (eg, montelukast)
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
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).
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

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	20 Apr 2023	43
Croatia	Not Recruiting	20 Apr 2023	25
Germany	Not Recruiting	20 Apr 2023	60
Hungary	Not Recruiting	20 Apr 2023	27
The Netherlands	Not Recruiting	20 Apr 2023	—
Poland	Not Recruiting	20 Apr 2023	103
Romania	Not Recruiting	20 Apr 2023	79
Slovakia	Not Recruiting	20 Apr 2023	17
Slovenia	Not Recruiting	20 Apr 2023	25
Spain	Not Recruiting	20 Apr 2023	39