A Randomized, Double Blind, Placebo-controlled, Parallel Group, Multicentre, Phase 2a Study to Assess Target Engagement, Safety and Tolerability of AZD4831 in Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- AstraZeneca
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- Change From Baseline in MPO Specific Activity
研究概览
简要总结
A randomized, double-blind, placebo-controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF). The study will be conducted at approximately 15 sites in 5 countries. Approximately 96 patients will be randomized to AZD4831 or placebo (treatment duration 90 days).
详细描述
This is a randomized, double-blind, placebo controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF) and mid-range Ejection Fraction (HRmrEF). The study will be conducted at approximately 15 sites in 5 countries (USA, Sweden, Denmark, Finland, Netherlands). Patients suitable for the study will be checked for eligibility, signing the informed consent and enrolled to the study at visit 1. The study will be divided into two parts, Part A and Part B. In part A 37 patients will be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo for approximately 90 days. After approximately 30 days of treatment, an interim analysis will be done to analyse the safety, tolerability and target engagement. After the evaluation, the randomization to Part B may proceed. In Part B the approximate 59 remaining patients will be randomized and treated for approximately 90 days.
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 45 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed consent
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this CSP
- •Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses
- •Patient must be 45 to 85 years of age inclusive, at the time of signing the informed consent form
- •Type of patient and disease characteristics
- •Signs and symptoms of HF in judgement of Investigator AND
- •Stable NYHA II-IV and
- •Ejection fraction (EF) ≥ 40 % and
- •Elevated NT-proBNP or BNP in the last 1 year defined as:
- •o Measured as out-patient: NT-proBNP ≥125 ng/L or BNP≥35 ng/L with sinus rhythm, NT-proBNP ≥750 ng/L or BNP ≥200 ng/L with atrial fibrillation (AF),
- •o Measured when hospitalized acutely: NT-proBNP ≥500 (ng/L) or BNP ≥125 ng/L with sinus rhythm, NT-proBNP ≥1250 (ng/L) or BNP ≥350 ng/L with AF
- •And at least one of the following:
- •Hospitalization with HF as primary cause in last 12 months
- •Structural heart disease on echo according to ESC guidelines i.e. either enlarged Left atrial volume index (LAVI > 34 ml/m2) or increased LVM (LVM index > 95 g/m2 in women and > 115 g/m2 in men)
- •Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg or >25 mmHg at exercise
- •Spectral tissue Doppler echocardiography - E/e' ratio ≥13 at rest
- •Body Mass Index (BMI) range 18-40kg/m2
- •Male or female of nonchildbearing potential
- •Reproduction
- •Female patients must be 1 year post-menopausal or surgically sterile
- •Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of AZD4831/matching placebo to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period
- •Genetic sampling
- •For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described above and provide informed consent for the genetic sampling and analysis
排除标准
- •Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR <30 ml/min/1.73m2 or dialysis
- •Life expectancy < 3 years due to other reasons than cardiovascular disease
- •Any ongoing skin disorder, history of or ongoing clinically significant allergy/hypersensitivity.
- •Current decompensated HF
- •Primary cardiomyopathy (e.g. constrictive, restrictive, infiltrative, toxic, hypertrophic, congenital or any primary cardiomyopathy) in judgment of investigator
- •Current hemodynamically significant valve disease in opinion of investigator
- •EF ever documented < 40%
- •Any current life-threatening dysrhythmia
- •Probable alternative primary reason for patient's symptoms in judgment of investigator, including but not limited to:
- •Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the absence of left-sided HF
- •Anaemia: Hb <100 mg/L (10g/dL)
- •Severe chronic obstructive pulmonary disease (COPD) or lung disease (chronic O2, nebulizer or oral steroid therapy)
- •Cardiac surgery, acute coronary syndrome (ACS), or non-elective percutaneous coronary intervention (PCI) < 3 months
- •Known or clinically judged significant macrovascular coronary artery disease (CAD) that has not been revascularized
- •Heart transplantation or left ventricular assist device ever
- •Patients with uncontrolled or clinically significant thyroid disease as judged by the investigator.
- •Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥2 x upper limit of normal (ULN). Resampling will not be allowed during the same screening period if detected abnormal values do not have reasonable explanation and are not expected to return to normal level within few days.
- •Known positive HIV, hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at screening
研究组 & 干预措施
AZD4831
AZD4831 tablets taken orally for for 90 days.
干预措施: AZD4831 (Drug)
Placebo
Placebo tablets taken orally for 90 days.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline in MPO Specific Activity
时间窗: Measurements on day 0, 10, 30 and 90. Change reported from day 0 to day 90.
To compare the effect of AZD4831 to placebo on Target engagement, defined as ex vivo zymozan stimulated Myeloperoxidase (MPO) specific activity
次要结局
- Change From Baseline in CFVR Measured in the Mid-distal Segment of the Left Anterior Descending (LAD) Coronary Artery Under Adenosine Infusion Measured by Transthoracic Doppler Echocardiography (TDE).(Measurement on day 0 and 90.)
- Change From Baseline in Walking Distance(Measurement on day 0, 30 and 90. Change reported from day 0 to day 90.)