Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma

Study Overview
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Brief Summary
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This is a randomised, placebo-controlled, double-blind study to assess the efficacy and safety of Atuliflapon administered at multiple dose levels over a 12-week treatment period to adult participants with moderate to severe uncontrolled asthma.

Detailed Description
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The study will enroll participants with moderate to severe uncontrolled asthma who are on low-dose inhaled corticosteroid (ICS) - a long-acting beta-agonist (LABA) or medium-to-high-dose ICS with or without LABA background treatment. The study will be performed as a 2-part study Part 1 and Part 2 with a Lead-in pharmacokinetics (PK) cohort. In the Lead-in PK cohort, participants will be randomised to Atuliflapon or placebo. In Part 1 of the study, participants will be stratified based on high or low levels of biomarker at screening (Visit 1) and randomised 1:1 to Atuliflapon or placebo. Interim analysis 1 (IA-1) will be an event driven analysis and will be performed once 30 participants with at least 1 CompEx (Composite endpoint for Exacerbations) event are observed in the group having high levels of biomarker. After all participants in Part 1 have completed 12 weeks of treatment, interim analysis-2 (IA-2) will be performed to assess a selected biomarker threshold level. In Part 2 of the study, participants with a biomarker level above the selected threshold (established at IA-2) at Screening (Visit 1) will be selected and randomised to 1 of 4 treatment groups (Atuliflapon: Dose A, B, C, or placebo).

Official Title
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A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Assess Efficacy and Safety of Multiple Dose Levels of Atuliflapon Given Orally Once Daily for Twelve Weeks in Adults With Moderate to Severe Uncontrolled Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Atuliflapon
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Lead-in PK Cohort: 18 to 55 years of age inclusive at the time of signing the informed consent at screening Visit 1. Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m^2 (inclusive) at screening Visit 1. Documented asthma diagnosis ≥12 months prior to screening Visit 1. Able to perform acceptable lung function testing for FEV1 according to American Thoracic Society / European Respiratory Society (ATS/ERS) 2019 acceptability criteria. Morning pre- bronchodilator (BD) forced expiratory volume (FEV)1 ≥ 40% predicted at screening Visit 1 and Visit 2. Treated with low dose inhaled corticosteroid plus long-acting β2-agonist (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. Also, treatment with additional asthma controller therapies (eg, LAMA) at a stable dose ≥ 3 months prior to screening Visit 1 is allowed. Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2. General Inclusion Criteria for Part 1 and Part 2: Body weight ≥ 40 kg and body mass index (BMI) < 35 kg/m^2. Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to screening Visit 1. Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria. Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at screening Visit 1 and Visit 3. An Asthma Control Questionnaire (ACQ)-6 score ≥ 1.5 at screening Visit 1 and at Visit 3. Exclusion Criteria A severe asthma exacerbation within 8 weeks of screening visit 1. 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, at screening Visit 1 or at Visit 2 for the PK Lead-in cohort. For Part 1 and Part 2 the testing will be done at Visit 3. Results from the mandatory tests at Visit 2 (PK Lead-in cohort) and Visit 3 (Part 1, Part 2) must not be older than 48 hours and must be available before randomisation. Participants with a significant COVID-19 illness within 6 months of enrolment. Clinically important pulmonary disease other than asthma. 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. Any clinically significant cardiac disease. History of severe renal disease 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 leukotriene receptor antagonist (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 human immunodeficiency virus (HIV). Evidence of active or untreated latent tuberculosis (TB). Current or history of alcohol or drug abuse (including marijuana). Current diagnosis of cancer, not including in-situ or non-melanoma skin cancer or other previous malignancies where curative therapy was completed at least 5 years prior to screening Visit 1. Clinically important ongoing or previous psychiatric disease, especially suicidal behaviour, that in the opinion of the investigator might compromise the safety of the participant in the study. Treatment with any serum creatinine-altering drugs within 1 month prior to screening Visit 1 including but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins. Treatment with systemic corticosteroid use within 8 weeks (oral) or 12 weeks (intramuscular) before screening Visit 1. Treatment with marketed biologics including benralizumab, mepolizumab, reslizumab, omalizumab, and dupilumab within 6 months of screening Visit 1 or 5 half-lives whichever is longer. Treatment with 5-lipoxygenase inhibitors (eg zileuton or other 5-LO inhibiting supplements) within 6 weeks prior to Visit 0 and within 8 weeks prior to Visit 1).Treatment with LTRAs (eg, montelukast) within 2 weeks prior to Visit 0 and within 4 weeks prior to screening Visit 1. Inhaled corticosteroid + fast-acting β2 agonist as a reliever (eg Symbicort or Fostair Maintenance and Reliever Treatment) is not allowed 15 days prior to screening Visit 1, during screening (Visit 1)/run-in and the treatment period and preferably 1 week after the last dose of study intervention. Live or attenuated vaccines within 4 weeks of screening Visit 1. Immunoglobulin or blood products within 4 weeks of screening Visit 1. Treatment with Gemfibrozil within 4 weeks of screening Visit 1. Any immunotherapy within 6 months of screening Visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to screening Visit 1 and expected to continue through to the end of the follow-up period. Potent inducers/inhibitors of cytochrome P450 3A4 within 4 weeks of screening Visit 1. Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to screening Visit 1. Treatment with sensitive cytochrome 3A substrates with narrow therapeutic window should be avoided from randomization to study drug. For female participants on ethinyl oestradiol containing combined oral contraceptives. Concurrent enrolment in another clinical study. Previous participation in the current clinical study. Participant treated with any investigational drug within 4 months prior to screening Visit 1. Known history of allergy or reaction to any component of the study intervention formulation. For female participants only: Currently pregnant or breast-feeding. Smokers with smoking history of < 10 pack-years or users of vaping or e-cigarettes, must have stopped at least 6 months prior to screening Visit 1. Involvement in the planning and/or conduct of the study. Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before screening Visit 1. Major surgery within 8 weeks prior to screening Visit 1, or planned inpatient surgery, major dental procedure or hospitalisation during the screening (Visit 1), treatment or follow-up periods.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lead-in PK Cohort (Atuliflapon Dose A)<br>Randomised participants will receive Atuliflapon dose A | Drug: Atuliflapon<br>* Randomised participants will receive Atuliflapon<br>* Other names: AZD5718;|
| Experimental: Part 1: Atuliflapon Dose A<br>Randomised participants will receive Atuliflapon Dose A | Drug: Atuliflapon<br>* Randomised participants will receive Atuliflapon<br>* Other names: AZD5718;|
| Experimental: Part 2: Atuliflapon Dose A<br>Randomised participants will receive Atuliflapon Dose A | Drug: Atuliflapon<br>* Randomised participants will receive Atuliflapon<br>* Other names: AZD5718;|
| Experimental: Part 2: Atuliflapon Dose B<br>Randomised participants will receive Atuliflapon Dose B | Drug: Atuliflapon<br>* Randomised participants will receive Atuliflapon<br>* Other names: AZD5718;|
| Experimental: Part 2: Atuliflapon Dose C<br>Randomised participants will receive Atuliflapon Dose C | Drug: Atuliflapon<br>* Randomised participants will receive Atuliflapon<br>* Other names: AZD5718;|
| Placebo Comparator: Lead-in PK, Part 1 and Part 2 Placebo<br>Randomised participants will receive placebo | Drug: Placebo<br>* Randomised participants will receive placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first CompEx Asthma event | The clinical efficacy of Atuliflapon Dose A will be assessed by calculating a Hazard Ratio between the treatment arms, Atuliflapon Dose A vs. placebo, in a selected population (based on biomarker level). CompEx Asthma, a novel composite endpoint for exacerbations, captures asthma-worsening episodes based on a combination of diary events (worsening in daily peak expiratory flow (PEF), asthma symptoms and reliever medication use) plus severe asthma exacerbation events. | Baseline up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first CompEx Asthma event (Composite endpoint for Exacerbations) | The clinical efficacy of Atuliflapon Dose A will be identified by determining a selected biomarker threshold using the Hazard Ratio of Atuliflapon Dose A vs. placebo, in all participants (with both high and low levels of biomarker) randomised to either placebo or Atuliflapon arms. | Baseline up to Week 12 | 
| Time to first CompEx Asthma event (Composite endpoint for Exacerbations) | The clinical efficacy of Atuliflapon at different dose levels compared to placebo will be assessed by calculating a Hazard Ratio between the following treatment arms: a) Atuliflapon Dose A compared to placebo; b) Atuliflapon Dose B compared to placebo; c) Atuliflapon Dose C compared to placebo | Baseline up to Week 12 | 
| Time to first CompEx Asthma event (Composite endpoint for Exacerbations) | The clinical efficacy of Atuliflapon Dose A will be assessed by calculating the Hazard Ratio of Atuliflapon Dose A vs. placebo, in all participants (with both high and low levels of biomarker) randomised to either placebo or Atuliflapon arms. | Baseline up to Week 12 | 
| Change from baseline in Pre-bronchodilator forced expiratory volume in 1 second | The clinical efficacy of Atuliflapon will be evaluated in comparison to placebo in a selected population (based on biomarker) of adult participants with moderate-to-severe uncontrolled asthma | Baseline, Week 4 and Week 12 | 
| Change from baseline in St. George's Respiratory Questionnaire | The clinical efficacy of Atuliflapon will be evaluated in comparison to placebo in adult participants with moderate-to-severe uncontrolled asthma. The St. George's Respiratory Questionnaire (SGRQ) is a 50-item PRO (Patient Reported Outcomes) instrument to measure the health status of participants with airway obstruction diseases. The questionnaire is divided into two parts: part one consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The SGRQ yields a total score and three domain scores (symptoms, activity, and impacts). The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. | Baseline, Week 4 and Week 12 | 
| Change from baseline in Asthma Control Questionnaire 6 | The clinical efficacy of Atuliflapon will be evaluated in comparison to placebo in adult participants with moderate-to-severe uncontrolled asthma. The Asthma Control Questionnaire 6 (ACQ-6) has 6 questions (the top scoring 5 symptoms and daily rescue bronchodilator use). The symptom and bronchodilator use questions on a 7-point scale (0 = no impairment, 6 = maximum impairment). Score 0 means totally controlled and 6 reflects severely uncontrolled. | Baseline Week 4, Week 8, Week 12 | 
| Change from baseline in average morning and evening Peak Expiratory Flow Measurement | The clinical efficacy of Atuliflapon will be evaluated in comparison to placebo in adult participants with moderate-to-severe uncontrolled asthma. | Baseline Week 4, Week 8, Week 12 | 
| Change from baseline in Daily asthma symptom score (total, daytime, and night-time) | The clinical efficacy of Atuliflapon will be evaluated in comparison to placebo in adult participants with moderate-to-severe uncontrolled asthma. Asthma symptom scores during night-time and day-time will be assessed by the participant each morning and evening according to the following scoring system: (0) You have no asthma symptoms; (1): You are aware of your asthma symptoms, but you can easily tolerate the symptoms; (2): Your asthma is causing you enough discomfort to cause problems with normal activities (or with sleep); (3): You are unable to do your normal activities (or to sleep) because of your asthma. Here, low score reflects no asthma symptoms and high score suggests severe or frequent symptoms. | Baseline Week 4, Week 8, Week 12 | 
| Time to first severe asthma exacerbation | The clinical efficacy of Atuliflapon will be evaluated in comparison to placebo in adult participants with moderate-to-severe uncontrolled asthma. | Baseline up to Week 12 | 
| Event status (CompEx Asthma event yes/no) | The clinical efficacy of Atuliflapon will be evaluated in comparison to placebo in adult participants with moderate-to-severe uncontrolled asthma. | Baseline up to Week 12 | 
| Lead-in PK: Area under the curve (AUC) | PK parameter of Atuliflapon will be assessed. Participants will be randomised to Atuliflapon Dose A in the Lead-in PK Cohort. | Day 1 and Day 15 | 
| Lead-in PK: Maximum (or peak) serum concentration (Cmax) | PK parameter of Atuliflapon will be assessed. Participants will be randomised to Atuliflapon Dose A in the Lead-in PK Cohort. | Day 1 and Day 15 | 
| Lead-in PK cohort: Pre-dose trough concentration (Ctrough) | PK parameter of Atuliflapon will be assessed. Participants will be randomised to Atuliflapon Dose A in the Lead-in PK Cohort. | Day 15 | 
| Atuliflapon plasma concentrations in a subset of participants, post-dose samples | The post-dose plasma concentrations of Atuliflapon will be summarised. | Week 4 | 
| Atuliflapon plasma concentrations in all participants, pre-dose samples | To pre-dose plasma concentrations of Atuliflapon will be summarised. | Baseline, Week 4 and Week 12 | 
| Number of participants with adverse events (AEs) | The safety and tolerability of Atuliflapon will be assessed in adult participants with moderate-to-severe uncontrolled asthma. | Baseline up to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Efficacy, Safety, Multiple Dose Levels, Adults