A Multicenter, International, Randomized, Active Comparator-controlled, Double-blind, Double-dummy, Parallel-group, 2-arm, Phase 3 Study to Compare the Efficacy and Safety of the Oral FXIa Inhibitor Asundexian (BAY 2433334) With Apixaban for the Prevention of Stroke or Systemic Embolism in Male and Female Participants Aged 18 Years and Older With Atrial Fibrillation at Risk for Stroke
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- Bayer
- 入组人数
- 14,830
- 试验地点
- 1,069
- 主要终点
- Number of Participants With Composite of Stroke, Systemic Embolism, or ISTH Major Bleeding
研究概览
简要总结
Researchers are looking for a better way to treat people with atrial fibrillation (AF) and prevent stroke or systemic embolism (blood clots travelling through the blood stream to plug another vessel).
Atrial fibrillation is a condition of having irregular and often rapid heartbeat. It can lead to the formation of blood clots in the heart which can travel through the blood stream to plug another vessel, and like this lead to serious and life-threatening conditions, such as a stroke. A stroke occurs because the brain tissue beyond the blockage no longer receives nutrients and oxygen so that brain cells die. As strokes arising from atrial fibrillation can involve extensive areas of the brain, it is important to prevent them.
Blood clots are formed in a process known as coagulation. Medications are already available to prevent the formation of blood clots. When taken by mouth (orally), they are known as oral anticoagulants (OACs) including apixaban. OACs decrease the risk of the above-mentioned serious and life-threatening conditions. The main side effect of OACs is an increase of the risk of bleeding.
The study treatment asundexian is a new type of anticoagulant currently under development to provide further treatment options. Asundexian aims to further improve the standard of care with regard to the risk of bleeding.
The main purpose of this study is to collect more data about how well asundexian works to prevent stroke and systemic embolism and how safe it is compared to apixaban in people with atrial fibrillation and at high risk for stroke.
To see how well the study treatment asundexian works researchers compare:
- how long asundexian works well and
- how long apixaban works well after the start of the treatment. Working well means that the treatments can prevent the following from happening:
- stroke and/or
- systemic embolism. The study will keep collecting data until a certain number of strokes or embolisms happen in the study.
To see how safe asundexian is, the researchers will compare how often major bleedings occur after taking the study treatments asundexian and apixaban, respectively. Major bleedings are bleedings that have a serious or even life-threatening impact on a person's health.
The study participants will be randomly (by chance) assigned to 1 of 2 treatment groups, A and B. Dependent on the treatment group, the participants will either take the study treatment asundexian by mouth once a day or apixaban by mouth twice a day for approximately 9 - 33 months.
Each participant will be in the study for approximately 9 - 34 months. There will be visits to the study site every 3 to 6 months and up to 7 phone calls. Those participants who do not want or are unable to have visits to the study site may join the study remotely in selected locations. The location name contains the abbreviation - DCT in such cases.
During the study, the study team will:
- take blood samples
- do physical examinations
- examine heart health using an electrocardiogram (ECG)
- check vital signs such as blood pressure and heart rate
- do pregnancy tests
- ask the participants questions about their quality of life
- ask the participants questions about how they are feeling and what adverse events they are having.
An adverse event is any medical problem that a participant has during a study. Doctors keep track of all adverse events that happen in studies, even if they do not think the adverse events might be related to the study treatments.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18 years of age or older
- •The patient willing and able to understand the Patient information Sheet and provide written informed consent
- •Atrial fibrillation with an indication for indefinite treatment with an oral anticoagulant
- •CHA2DS2-VASc score ≥ 3 if male or ≥ 4 if female, OR CHA2DS2-VASc score of 2 if male or 3 if female and at least one of the following enrichment criteria:
- •previous stroke, transient ischemic attack, or systemic embolism
- •renal dysfunction with eGFR < 50 ml/min within 14 days prior to randomization
- •prior episode of non-traumatic major bleeding
- •current single agent antiplatelet therapy planned to continue for at least 6 months after randomization
- •≤ 6 consecutive weeks of treatment with oral anticoagulant prior to randomization.
排除标准
- •Mechanical heart valve prosthesis
- •Moderate-to-severe mitral stenosis at the time of study inclusion.
- •Atrial fibrillation only due to reversible cause.
- •Participants after successful ablation therapy without documented recurrent AF or participants after left atrial appendage occlusion / exclusion or plan for ablation or Left atrial appendage (LAA) occlusion / exclusion within the next 6 months.
- •Recent ischemic stroke (within 7 days prior to randomization).
- •Active non-trivial bleeding; known chronic bleeding disorder ; history of non-traumatic intracranial hemorrhage.
- •Known significant liver disease or known hepatic insufficiency classified as Child-Pugh B or C at randomization.
- •Estimated glomerular filtration rate (eGFR) < 25 mL/min/1.73 m2 within 14 days prior to randomization or on dialysis or expected to be started on dialysis within the next 12 months starting from randomization.
- •Major surgery during the last 30 days prior to randomization.
- •Known allergy, intolerance or hypersensitivity to either of the study interventions.
- •Any contraindication for the use of an anticoagulant or listed in the local labelling for apixaban.
- •Requirement for chronic anticoagulation for a different indication than AF, e.g. mechanical heart valve or left ventricular cardiac thrombus (atrial thrombus is allowed), or dual antiplatelet therapy (single agent therapy is allowed).
- •Treatment with Vitamin K antagonist (VKA) in the 10 days prior to randomization.
- •Concomitant use of or anticipated need for:
- •daily or near daily (> 5 days per week) therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) for more than 4 weeks during the study
- •herbal or traditional medicine, and / or supplements with known anticoagulant and / or antiplatelet effect
- •combined P-glycoprotein (P-gp) and strong cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors
- •combined P-gp and strong / moderate CYP3A4 inducers Respective substances (apart from NSAIDs) must be stopped - in case of combined inhibitors / inducers of CYP3A4 and P-gp for at least 14 days before randomization.
- •Previous (within 30 days or 5 half-lives of the investigational drug, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s) or device(s). Registries and observational studies are allowed.
- •Known current alcohol and / or illicit drug abuse.
- •Close affiliation with the investigational site.
- •Any other history, condition or therapy, or uncontrolled intercurrent illness which would make the participant unsuitable for the study vulnerable or life expectancy < 12 months.
研究组 & 干预措施
Asundexian
Participants will receive asundexian and apixaban matching placebo.
干预措施: Asundexian (BAY2433334) (Drug)
Asundexian
Participants will receive asundexian and apixaban matching placebo.
干预措施: Apixaban matching placebo (Drug)
Apixaban
Participants will receive apixaban and asundexian matching placebo.
干预措施: Apixaban (Drug)
Apixaban
Participants will receive apixaban and asundexian matching placebo.
干预措施: Asundexian matching placebo (Drug)
结局指标
主要结局
Number of Participants With Composite of Stroke, Systemic Embolism, or ISTH Major Bleeding
时间窗: Approximately 12 months
The assessment was based on the cause-specific hazard ratio (csHR), comparing asundexian with apixaban which is based on time to first event.
Number of Participants With Composite of Stroke or Systemic Embolism
时间窗: Approximately 12 months
The assessment was based on the cause-specific hazard ratio (csHR), comparing asundexian with apixaban which is based on time to first event. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. Systemic embolism is defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (this does not include myocardial infarction, thromboembolism of the pulmonary vasculature or venous thrombosis, e.g. pulmonary embolism or deep venous thrombosis).
Number of Participants With International Society on Thrombosis and Hemostasis (ISTH) Major Bleeding
时间窗: Approximately 12 months
Assessment based on the (csHR), comparing asundexian with apixaban which is based on time to first event. ISTH Major Bleeding was defined as an event that meets at least one of the below criteria, based on the definition given by the ISTH (Schulman and Kearon 2005): * Fatal bleeding, and/or * Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular with compromised vision, pericardial, retroperitoneal, intra-articular, or intramuscular with compartment syndrome), and/or * Clinically overt\* bleeding associated with a recent (within 48 hours) decrease in the hemoglobin level of ≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared with the most recent hemoglobin value available before the event, and/or * Clinically overt\* bleeding leading to transfusion of 2 or more units of packed red blood cells or whole blood. * Overt bleeding required the identification of the bleeding location and the hemoglobin drop and/or transfusion needed to be related to the bleeding.
次要结局
- Number of Participants With Composite of Disabling Stroke (mRS ≥ 3), Critical Bleeding, or All-cause Mortality(Approximately 12 months)
- Number of Participants With Composite of Ischemic Stroke or Systemic Embolism(Approximately 12 months)
- Number of Participants With All-cause Mortality(Approximately 12 months)
- Number of Participants With Ischemic Stroke(Approximately 12 months)
- Number of Participants With Cardiovascular (CV) Death(Approximately 12 months)
- Number of Participants With Composite of CV Death, Stroke, or Myocardial Infarction (MI)(Approximately 12 months)
- Number of Participants With Composite of ISTH Major or Clinically Relevant Non-major Bleeding(Approximately 12 months)
- Number of Participants With Clinically Relevant Non-major Bleeding(Approximately 12 months)
- Number of Participants With Hemorrhagic Stroke(Approximately 12 months)
- Number of Participants With Intracranial Hemorrhage(Approximately 12 months)
- Number of Participants With Fatal Bleeding(Approximately 12 months)
- Number of Participants With Minor Bleeding(Approximately 12 months)
- Number of Participants With Composite of Stroke, Systemic Embolism, ISTH Major Bleeding, or All-cause Mortality(Approximately 12 months)