Vorapaxar in the Human Endotoxemia Model A Randomized, Double-Blind, Crossover Study
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Changes in Prothrombin Fragments F1+2
研究概览
简要总结
Vorapaxar is a recently approved protease activated receptor - 1 (PAR-1) inhibitor. Platelet inhibition may also exert positive results on coagulation activation and may beneficially influence the inflammatory response. Since vorapaxar is the first available substance of a new class of platelet inhibitors its effects on the human coagulation system and the inflammatory response will be assessed in the well-established human endotoxemia model.
详细描述
Vorapaxar is a novel platelet inhibitor inhibiting PAR-1. It is the first available substance of a new class of platelet inhibitors blocking the activation of platelets via thrombin or thrombin receptor activating peptides via PAR-1. As platelets contribute to the coagulation activation, i.e. by providing the surface for the assembly of the Tenase complex, and furthermore to the inflammatory response by releasing their stored granula containing promotors of both, inflammation and coagulation, we want to assess the effects of vorapaxar on these in the human endotoxemia model. Sixteen healthy volunteers will be included in this randomized, double-blind, placebo-controlled, single center, crossover trial with a washout period of 8 weeks. This wash out period was chosen based on the long elimination half-life of vorapaxar and to prevent any carry-over effects. After intake of 10mg vorapaxar (-24h) the degree of platelet inhibition will be assessed by whole bood aggregometry and, in case of insufficient platelet inhibition, subjects may receive another 10mg of vorapaxar. A bolus of 2ng/kg bodyweight lipopolysaccharide (LPS) will be infused and blood sampling will be performed at pre-defined time-points. After the washout-period the respective other treatment will be given to subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 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 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •≥18 years of age
- •≥60 kg bodyweight
- •Normal findings in medical history and physical examination unless the investigator considers the abnormality to be clinically irrelevant
- •Normal laboratory values unless the investigator considers abnormalities to be clinically irrelevant
- •Willingness to comply with the trial's safety demands (to refrain from excessive sporting activities two weeks after Vorapaxar intake, i.e. full contact sports, climbing, mountain biking etc.)
- •Ability to understand the purpose and nature of the study, as well as the associated risks No planned surgeries or other medical interventions in the planned study period
排除标准
- •Intake of any drugs that may interfere with the trial's endpoints or drugs (i.e. platelet inhibitors, anticoagulants, CYP3A4 inhibitors, NSAIDs, selective serotonin reuptake inhibitors, selective noradrenaline and serotonin reuptake inhibitors)
- •Positive results of HIV or hepatitis virology
- •Acute illness with systemic inflammatory reactions
- •Known allergies, hypersensitivities or intolerances to any of the used substances
- •Acute or recent bleeding episodes, increased risk of bleeding at the discretion of the investigator
- •History of stroke, transient ischemic attacks or intracerebral hemorrhage
- •Known coagulation or platelet disorders
- •Participation in an LPS trial within 6 weeks of the first study day
- •Severe liver or kidney dysfunction
- •Pregnancy or breastfeeding
研究组 & 干预措施
Vorapaxar
subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules
干预措施: Vorapaxar (Drug)
Vorapaxar
subjects will be treated with 4x2,5mg vorapaxar in empty lactose-starch capsules
干预措施: LPS (Other)
Placebo
subjects will be treated with 4 empty lactose-starch capsules
干预措施: Placebo (Drug)
Placebo
subjects will be treated with 4 empty lactose-starch capsules
干预措施: LPS (Other)
结局指标
主要结局
Changes in Prothrombin Fragments F1+2
时间窗: Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h
prothrombin fragment F1+2 concentrations, individual maxima were compared between both study periods
次要结局
- Protease Activated Receptor (PAR)-1 Expression on Platelets(Time points for evaluation were: baseline, 0h, 4h, 24h)
- P-Selectin(Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration)
- Thrombin-Antithrombin Complexes(Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h)
- E-Selectin(Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration)
- Plasmin-Antiplasmin Complexes(Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h)
- Von Willebrand Factor(Time points for evaluation were baseline, 2h, 4h, 6h, 24h after LPS administration)
- Interleukin 6(Time points for evaluation were baseline, 2h, 4h, 6h 24h after LPS administration)
- Tumor Necrosis Factor Alpha(Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h)
- Platelet Factor 4(Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h)
- Thrombomodulin(Time points for evaluation were: baseline, 0h, 2h, 4h, 6h, 24h)
- C-reactive Protein(Time points for evaluation were: baseline, and 24h after LPS administration)
研究者
Bernd Jilma
Ao.Univ.Prof.Dr.med
Medical University of Vienna