Recombinant Human C1 Esterase Inhibitor (Conestat Alfa) in the Prevention of Acute Ischemic Cerebral and Renal Events After Transcatheter Aortic Valve Implantation: a Multi-center, Randomized, Double-blind, Placebo-controlled Investigational Study (PAIR-TAVI).
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 141
- 试验地点
- 4
- 主要终点
- Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)
研究概览
简要总结
The aim of this trial is to assess the safety and efficacy of conestat alfa (Ruconest®, Pharming Technologies B.V.) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic aortic stenosis (AS) compared to placebo.
详细描述
Severe aortic stenosis (AS) is a frequent valvular heart disease in the elderly with a prevalence of 4 to 10% and a mean survival of only 0.5 to 5 years if left untreated. Transcatheter aortic valve implantation (TAVI) has evolved as standard of care for high-, intermediate and potentially even low surgical risk candidates due to a lower perioperative risk compared to surgical aortic valve replacement (SAVR). Despite its relative safety compared to SAVR, embolic events originating from the calcified valve and leading to ischemic stroke and acute renal injury are major complications following TAVI in the acute and subacute period, and are associated with increased morbidity including cognitive decline and mortality. While cerebral embolic protection devices (CEPD) such as the Sentinel® CEPD (Boston Scientific) were designed to reduce the burden of cerebral embolic events, their impact on clinical events has yet to be determined, and other prophylactic options are currently not available. Ischemia/reperfusion injury (IRI) is a key pathophysiological mechanism involved in cerebral and renal embolic events after TAVI resulting in activation of endothelial cells, the contact activation and the complement system and attraction of neutrophils to the site of injury. In this regard, recombinant human C1 esterase inhibitor (rhC1INH, conestat alfa), a potent inhibitor of the complement and the contact system has been shown to reduce the size of cerebral ischemic damage and of renal injury in experimental IRI models, and has successfully been investigated in a pilot study of acute kidney injury following the administration of contrast media. The aim of the current trial is to assess the safety and efficacy of conestat alfa (Ruconest®, Pharming Technologies B.V.) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic AS compared to placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
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
- •Informed consent as documented by signature
- •Severe AS and scheduled for transfemoral TAVI
排除标准
- •Contraindications to the class of drugs under study (C1INH), e.g., known hypersensitivity or allergy to class of drugs or the investigational product
- •History of allergy to rabbits (as rhC1INH is derived from the breast milk of transgenic rabbits)
- •Women who are pregnant or breast feeding
- •Hemodynamic instability requiring emergency TAVI
- •Valve-in-valve procedure
- •Other access route than transfemoral
- •Non-cardiac co-morbidity with expected survival <6 months
- •Ischemic or hemorrhagic stroke within 30 days before TAVI
- •Dialysis or estimated glomerular filtration rate (eGFR) <20 ml/min/1.73m2
- •Contraindication for MRI such as a permanent non-MRI compatible pacemaker or severe claustrophobia
- •Liver cirrhosis (any Child-Pugh score)
- •Incapacity or inability to provide informed consent
- •Participation in another study with investigational drug or medical device within the 30 days preceding and during the present study
- •Previous enrolment into the current study
- •Any uncontrolled or significant concurrent illness that would put the patient at a greater risk or limit compliance with the study requirements at the discretion of the investigator
研究组 & 干预措施
Conestat alfa (Ruconest®) intervention group
The intervention group will receive conestat alfa (Ruconest®) as a 10-minute slow intravenous injection (up to 56 ml) once during the TAVI procedure followed by a second administration (up to 28 ml) again three hours later. The first administration will include a dosage of 100 U/kg (maximum 8400 U) conestat alfa. The dosing of the second administration will be 50 U/kg (maximum 4200 U).
干预措施: Conestat alfa (Ruconest®) (Drug)
saline injection placebo group
Subjects randomized into the placebo group will receive an intravenous normal saline injection with corresponding volume over 10 minutes during the TAVI procedure and three hours later after the first administration.
干预措施: NaCl 0.9%) (Drug)
结局指标
主要结局
Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)
时间窗: on day 4 (+/-1 day) after transfemoral TAVI
Total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI)
次要结局
- Maximum new lesion volume as measured by MRI (i.e. volume of the largest new lesion)(on day 4 (+/-1 day) after transfemoral TAVI)
- Number of new cerebral ischemic lesions as measured by MRI(on day 4 (+/-1 day) after transfemoral TAVI)
- Number (incidence) of clinically manifest ischemic stroke(within 48 hours after TAVI)
- Change in secondary brain atrophy at 3-months follow-up(at baseline and at 3-months follow-up)
- Change in secondary infarct growth at 3-months follow-up (defined as the difference between the infarct volumes)(at day 4 and at 3-months)
- Total brain damage (defined as the sum of secondary brain atrophy and final infarct volume)(at 3 months)
- Change in National Institutes of Health Stroke Scale Score (NIHSS)(at baseline and at 3-months follow-up)
- Change in modified Rankin scale(at baseline and at 3-months follow-up)
- Change in trail making test(at baseline and at 3-months follow-up)
- Change in Montreal Cognitive Assessment test (MOCA)(at baseline and at 3-months follow-up)
- Incidence of acute kidney injury (AKI) defined according to the Kidney Disease: Improving Global Outcomes criteria (any stage)(within 3 days after TAVI)
- Peak increase of urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL)(within 48 hours after TAVI)
- Incidence of significant increase in serum cystatin C (>10%)(within 48 hours after TAVI)