NCT05251259已完成2 期
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
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 670
- 试验地点
- 234
- 主要终点
- Time to first CompEx Asthma event
研究概览
简要总结
This is a randomised, placebo-controlled, double-blind study to assess the efficacy and safety of Atuliflapon administered once daily over a 12-week treatment period to adult participants with moderate to severe uncontrolled asthma.
详细描述
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 initiated by Lead-in pharmacokinetics (PK) cohort in asthma participants. Participant will be randomised globally, including participants in Lead-in PK cohort (2 arms) and in Part 1 of the study (2 arms).
In the Lead-in PK cohort, participants will be randomised to Atuliflapon or placebo (recruitment completed).
In Part 1 of the study, participants will be stratified by geographical region, and grouped based on high or low levels of biomarker at screening (Visit 1).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Lead-in PK Cohort:
- •18 to 55 years of age inclusive at the time of signing the informed consent at screening Visit
- •Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m^2 (inclusive) at screening Visit
- •Documented asthma diagnosis ≥12 months prior to screening Visit
- •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
- •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
- •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
- •General Inclusion Criteria for Part 1:
- •Body weight ≥ 40 kg and body mass index (BMI) < 35 kg/m^
- •Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to screening Visit
- •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
- •An Asthma Control Questionnaire (ACQ)-6 score ≥ 1.5 at screening Visit 1 and at Visit 3.
排除标准
- •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, at screening Visit 1 or at Visit 2 for the PK Lead-in cohort. For Part 1 the testing will be done at Visit
- •Results from the mandatory tests at Visit 2 (PK Lead-in cohort) and Visit 3 (Part 1) 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 tuberculosis (TB), either treated or untreated or latent 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
- •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) or 12 weeks (oral) or 16 weeks (IM) before randomization (Visit 3).
- •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
- •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
- •Immunoglobulin or blood products within 4 weeks of screening Visit
- •Treatment with Gemfibrozil within 4 weeks of screening Visit
- •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
- •Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to screening Visit
- •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, the ethinyl oestradiol doses exceeding 20 mcg per day.
- •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
- •Known history of allergy or reaction to any component of the study intervention formulation.
- •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
- •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
- •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.
研究组 & 干预措施
Lead-in PK cohort (Atuliflapon)
Experimental
Randomised participants will receive Atuliflapon in Lead-in PK period of the study.
干预措施: Atuliflapon (Drug)
Lead-in PK cohort (Placebo)
Placebo Comparator
Randomised participants will receive matching placebo to Atuliflapon in Lead-in PK cohort of the study.
干预措施: Placebo (Drug)
Part 1 (Atuliflapon)
Experimental
Randomised participants will receive Atuliflapon in Part 1 of the study.
干预措施: Atuliflapon (Drug)
Part 1 (Placebo)
Placebo Comparator
Randomised participants will receive matching placebo to Atuliflapon in Part 1 of the study.
干预措施: Placebo (Drug)
结局指标
主要结局
Time to first CompEx Asthma event
时间窗: Baseline up to Week 12
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.
次要结局
- Change from baseline in Pre-bronchodilator in forced expiratory volume in 1 second (FEV1)(From Baseline up to Week 2, Week 4 and Week 12)
- Change from baseline in St. George's Respiratory Questionnaire(From Baseline up to Week 4 and Week 12)
- Change from baseline in Asthma Control Questionnaire 6(From Baseline up to Week 4, Week 8, Week 12)
- Change from baseline in average morning and evening Peak Expiratory Flow Measurement(From Baseline up to Week 4, Week 8, Week 12)
- Change from baseline in Daily asthma symptom score (total, daytime, and night-time)(From Baseline up to Week 4, Week 8, Week 12)
- Time to first severe asthma exacerbation(From Baseline up to Week 12)
- Event status (CompEx Asthma event yes/no)(From Baseline up to Week 12)
- Lead-in PK: Area under the curve (AUC)(Day 1 and Day 15)
- Lead-in PK: Maximum (or peak) serum concentration (Cmax)(Day 1 and Day 15)
- Lead-in PK cohort: Pre-dose trough concentration (Ctrough)(Day 15)
- Part 1 Cohort: Atuliflapon plasma concentrations in all participants, pre-dose samples(Baseline, Week 4 and Week 12)
- Number of participants with adverse events (AEs)(Baseline up to Week 12)
- Time to first CompEx Asthma event (Composite endpoint for Exacerbations)(From Baseline up to Week 12)
研究者
研究点 (234)
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