CTRI/2024/04/065120已完成2 期
A Phase 2a Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AZD4604 Twice Daily for Twelve Weeks in Adult Patients with Moderate-to-Severe Asthma Uncontrolled on Medium-High Dose ICS-LABA
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 320
- 试验地点
- 7
- 主要终点
- To evaluate the clinical efficacy of AZD4604 1.4 mg BID as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma
研究概览
简要总结
This is a Phase 2a, multicentre, randomised, placebo-controlled, double-blind, parallel-group study designed to evaluate the efficacy, safety and PK of AZD4604 administered BID using the SD3FL dry-powder inhaler at one dose level over a 12-week Treatment period in adult participants with uncontrolled moderate-to-severe asthma. This study will include around 150 study sites globally.
Approximately 320 participants, with uncontrolled asthma despite receiving treatment with medium or high dose ICS-LABA at screening and at Visit 3 (Asthma Control Questionnaire-6 score ≥ 1.5) will be randomly assigned in a 1:1 ratio to 1 of the 2 treatment arms (AZD4604 BID or placebo). To ensure balance between the treatment arms, randomisation will be stratified based on participant’s ICS dose level at Visit 1 (medium, high) and region. AZD4604 1.4 mg and placebo will be administered BID using the SD3FL inhaler, also known and marketed as Genuair® in the Europe and Pressair® in the United States
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Participant and Investigator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 80.00 Year(s)（—）
- 性别
- All
入选标准
- •Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
- •Type of Participant and Disease Characteristics
- •Participants treated with medium-high dose ICS (as per GINA 2022 ICS dose level table in Appendix F) in combination with LABA at a stable dose for at least 3 months prior to Visit 1 (the ICS can be contained within an ICS-LABA fixed dose combination product).
- •Treatment with additional asthma controller therapies (eg, LAMA, LTRA) at a stable dose ≥ 3 months prior to Visit 1 is allowed.
- •Treatment with maintenance systemic corticosteroids (oral or injectable) is not allowed (see Section 5.2, Exclusion Criterion 12).
- •A documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Visit
- •A severe asthma exacerbation is defined as a worsening of asthma that leads to any of the following: Use of systemic corticosteroids for at least 3 consecutive days to treat symptoms of asthma worsening (a single depo-injectable dose of corticosteroids will be considered equivalent to a 3-day bolus/burst of systemic corticosteroids).
- •An emergency room visit (defined as evaluation and treatment for < 24 hours in an emergency department) due to asthma that required systemic corticosteroids (as per the above).
- •An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma.
- •Acceptable documentation of a severe asthma exacerbation in this protocol is: Documented prescription of systemic corticosteroids for at least 3 days to treat asthma worsening (a single depo-injectable dose of corticosteroids will be considered equivalent to 3-day bolus/burst of systemic corticosteroids).
- •In participants with an established self-management plan, documented filling of a prescription will be considered adequate.
- •Clinic visit or consultation (primary or specialized HCP) notes providing evidence of ≥1 exacerbation in the previous 12 months prior to enrolment.
- •Emergency room/hospital records that the participant attended an emergency room visit (defined as evaluation and treatment for < 24 hours in an emergency department) due to asthma that required systemic corticosteroids (as per the above).
- •Discharge summaries from hospital, emergency room or urgent care facility indicating that a participant was hospitalised (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for 24 hours) due to asthma
- •Morning pre-BD FEV1 between ≥ 40% and ≤ 90% predicted at Visit 1 and Visit 3 (pre-randomisation).
- •Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria.
- •Documented evidence of asthma as demonstrated by any of the following in the 10 years up to or including Visit 1: Post-BD reversibility of FEV1 ≥ 12% and ≥ 200 mL, or Average daily variability of PEF > 10% over a 2-week period, or Variability of FEV1 > 12% and 200 mL between any 2 clinical visits, or Positive bronchial challenge test (a positive test is defined as a fall in FEV1 from pre-challenge of ≥ 20% with standard doses of methacholine or histamine, or ≥ 15% with standardised hyperventilation, hypertonic saline, or mannitol challenge), or Positive exercise challenge test (a positive test is defined as a fall in FEV1 of > 10% and > 200 mL from pre-challenge), or A FeNO test with a value of ≥ 40 ppb despite confirmed ICS maintenance therapy.
- •If documentation is not available to support any of these diagnostic criteria, and if in the opinion of the investigator the clinical diagnosis of asthma is still considered likely, the investigation and confirmation of an average daily variability of PEF > 10% over a 2-week period can also be considered as confirmatory of the diagnosis of asthma if undertaken during the period of screening and run-in
- •An ACQ-6 score ≥ 1.5 at Visit 1 and at Visit 3 (pre-randomization).
- •Body weight of ≥ 40 kg and body mass index of < 35 kg/m
- •Sex and Contraceptive/Barrier Requirements
- •Male and/or female Contraceptive use by females 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.
- •Females not of childbearing potential are defined as females who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal.
- •The following age-specific requirements apply: Females < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone levels in the postmenopausal range.
- •Females ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment.
- •All FOCBP who are sexually active with a non-sterilised male partner must agree to use one highly effective method of birth control, as defined below, for a minimum of 3 months prior to Visit 1 and throughout entire duration of the study, and for 1 month after the last dose of IMP.
- •Cessation of contraception after this point should be discussed with a responsible physician.
- •A highly effective method of contraception is defined as one that can achieve a failure rate of < 1% per year when used consistently and correctly.
- •The following are not acceptable methods of contraception: Periodic abstinence (calendar, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea.
- •Female condom and male condom should not be used together.
- •All FOCBP must have a negative serum pregnancy test result at Visit 1 Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the IMP), a vasectomised partner, Implanon, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo-Provera injections, oral contraceptive, and Evra Patch, Xulane, or NuvaRing Informed Consent
- •Capable of giving signed informed consent prior to any study-specific procedures as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
- •Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative Randomisation Inclusion Criteria At the end of the Run-in period (Visit 3), participants must fulfil the following additional criteria in order to be randomised into the study and enter the Treatment period:
- •Pre-BD FEV1 between ≥ 40% and ≤ 90% predicted (pre-randomisation).
- •A pre-BD/pre-IMP dose FEV1 at Visit 3 that has not increased or decreased by 20% or more from the pre-BD FEV1 recorded at Visit 1 and at Visit
- •An ACQ-6 score of ≥ 1.5 (pre-randomisation)
- •Compliance is defined as completing the daily ePRO questions and PEF measurement (morning and evening) at least 80% of the time during the Run-in period and during the 14 days preceding Visit
- •For female participants, a negative urine pregnancy test prior to administration of IMP.
排除标准
- •Medical Conditions
- •A severe asthma exacerbation within 8 weeks of prior to randomisation.
- •(For definition of severe exacerbation see Section 5.1, Inclusion Criterion 3).
- •History of herpes zoster reactivation eg, shingles 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.
- •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, or impede the participant s ability to complete the entire duration of study.
- •Any clinically significant cardiac or cerebrovascular disease: Unstable angina, acute coronary syndrome (acute myocardial infarction, unstable angina), coronary intervention with percutaneous coronary intervention/coronary artery bypass surgery or stroke within 6 months of Visit
- •Heart failure, New York Heart Association, Classes II to IV.
- •Systemic hypertension, except if well-controlled using 2 or fewer medications and stable for at least 6 months.
- •Untreated high degree atrioventricular block (second – third degree atrioventricular block)/significant sinus node dysfunction/pause or therapy requiring tachyarrhythmia.
- •Participants with atrial fibrillation or flutter and optimally controlled ventricular rate at resting < 100 bpm might be included as judged by the investigator.
- •History or family history of long QT-syndrome or sudden cardiac death with age < 40 years old.
- •History of QT prolongation associated with other medications that required discontinuation of that medication.
- •Hypertrophic cardiomyopathy or clinically significant valvular heart disease.
- •History of venous thromboembolism.
- •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 history and physical examinations, chest X-ray, or TB test (eg, purified protein derivative or QuantiFERON test).
- •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.
- •Any of the following would exclude the participant from the study: Participants positive for hepatitis C antibody.
- •Participants positive for hepatitis B virus surface antigen.
- •Note: Participants with a history of hepatitis B vaccination without a history of hepatitis B are permitted.
- •If vaccinated participants test positive for hepatitis B antibody, a confirmatory PCR test will be performed.
- •Current or prior history of alcohol or drug abuse (including marijuana), as judged by the investigator.
- •Positive drug screening result that cannot be justified by participant s medical history and its relevant treatment (over-the-counter product or a valid prescription), or history of or current alcohol or drug abuse (including marijuana and marijuana-containing valid prescriptions), as judged by the investigator.
- •History of malignancy other than superficial basal cell carcinoma.
- •Prior/Concomitant Therapy
- •Treatment with systemic corticosteroid (short-term or maintenance) use within 4 weeks (oral) or 8 weeks (intramuscular) before Visit
- •Any immunosuppressive therapy (including hydroxychloroquine, methotrexate, cyclosporine and tacrolimus) within 12 weeks prior to Visit
- •Treatment with marketed biologics including benralizumab, mepolizumab, reslizumab, omalizumab, dupilumab and tezepelumab within 6 months of Visit 1 or 5 half-lives, whichever is longer.
- •Inhaled corticosteroid plus fast-acting β2 agonist as a reliever (eg, Symbicort, Fostair, or Airsupra Maintenance and Reliever Treatment) is not allowed 15 days prior to Visit 1, during Screening/Run-in and throughout the Treatment period and preferably 1 week after the last dose of IMP.
- •Live, attenuated, or mRNA vaccines within 4 weeks of Visit
- •Any immunotherapy within 6 months of Visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to Visit 1 and expected to continue through to the end of the Follow-up period.
- •Prior/Concurrent Clinical Study Experience
- •Concurrent enrolment in another clinical study.
- •Participant treated with any investigational drug within 4 months (or 5 half-lives, whichever is longer) prior to Visit
- •Participants with a known hypersensitivity to AZD4604 or any of the excipients of the product.
- •Diagnostic Assessments
- •Abnormal findings identified on physical examination, ECG, or laboratory testing include, but are not limited to: ALT or AST ≥ 1.5 × ULN.
- •TBL ≥ ULN (unless due to known Gilbert s disease).
结局指标
主要结局
To evaluate the clinical efficacy of AZD4604 1.4 mg BID as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma
时间窗: Endpoint: Time to first CompEx event | Strategy of intercurrent eventsa: Intercurrent events are events occurring after treatment initiation that affect either the measurement or interpretation of the summary measure associated with the clinical question of interest. | Primary estimand: While on treatment – if an intercurrent event occurs before first CompEx event, the participant will be censored at the time of intercurrent event.
次要结局
- To evaluate the clinical efficacy of AZD4604 mg BID as(compared to placebo in adult participants with moderate-to-severe uncontrolled asthma)
- To evaluate the effect of AZD4604 on airway inflammation as(measured by FeNO)
- To evaluate the effect of AZD4604 BID on cough as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma(Population: Analysis will include participants randomised to either placebo or)
- To evaluate the PK of AZD4604 in all participants after 4 weeks and(12 weeks dosing)
- To assess the safety and tolerability of AZD4604 BID in adult participants with moderate-to-severe uncontrolled asthma(Population: Analysis will include all participants randomised to either placebo)
- To assess the safety and tolerabilityof AZD4604 BID in adult participants with moderate to severe uncontrolled asthma uncontrolled asthma(Strategy for intercurrent eventsa:)
- Exploratory: To further evaluate the clinical efficacy of AZD4604 BID as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma
- Exploratory: To further evaluate the clinical efficacy of AZD4604 BID as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma(Population: Analysis will include participants randomised to either placebo or AZD4604 BID arms)
- To assess the association between AZD4604 response and participant(baseline characteristics including, FeNO, blood eosinophils level, and)
- To assess participant self-reported impression of change in asthma symptoms after starting treatment
- To evaluate responder definition/analysis of change in CAAT scores(Population: Analysis will include participants randomised to either placebo or AZD4604 BID arms)
- To assess the effects of AZD4604 as compared to placebo on(spirometry endpoints measured face-to-face and virtually in)
- To evaluate the impact of AZD4604 on exploratory biomarkers and(gene expression in blood, nasal lining fluid, nasal cells and urine)
- To evaluate the impact of AZD4604 on exploratory biomarkers and gene expression in blood, nasal lining fluid, nasal cells and urine(To evaluate the impact of AZD4604 on exploratory biomarkers and gene expression in blood, nasal lining fluid, nasal cells and urine)
研究者
Dr Santosh Kadam
AstraZeneca Pharma India Ltd,
研究点 (7)
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