A Phase I Study to Determine the Pharmacokinetic Profile, Safety and Tolerability of Sildenafil (REVATIO®) in Cardiac Surgery
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Area under the plasma concentration versus time curve and Plasma Concentration of Sildenafil
研究概览
简要总结
The objectives of the study are the following:
- To evaluate the pharmacokinetic profile of Sildenafil in cardiac surgery patients at risk of acute kidney injury
- To determine the safety and tolerability of Sildenafil in cardiac surgery patients at risk of acute kidney injury
详细描述
Acute kidney injury occurs in up to one third of all patients following cardiac surgery. It is manifested by an acute decline in kidney function and results in significant increases in postoperative complications as well as an almost fourfold increase in the risk of postoperative death. Our understanding of the underlying processes is poor and recent systematic reviews have concluded that there is no effective treatment.
Experimental studies have demonstrated that preservation of endogenous Nitric Oxide (NO) bioavailability is reno-protective in response to a variety of injurious stimuli. Endogenous NO activity is increased by administration of the phosphodiesterase type 5 (PDE-5) inhibitor sildenafil citrate. This is used clinically in the treatment of erectile dysfunction (Viagra®, Pfizer) and more recently, pulmonary hypertension and acute right ventricular failure (Revatio®, Pfizer). We have developed a preclinical swine model of extracorporeal circulation (cardiopulmonary bypass) mediated acute kidney injury that shows significant homology to that which occurs in post cardiac surgery patients. Administration of intravenous sildenafil prevents acute kidney injury in this model in association with an increase in NO bioavailability. There is a recognized clinical need for developing prevention and treatment strategies for AKI and results obtained in this preclinical study indicate that Sildenafil is suitable for further development as a potential prevention strategy for post cardiac surgery AKI.
Prior to conducting a safety and efficacy trial however we intend to first establish a dose of Sildenafil that is tolerated by cardiac surgery patients and compare the pharmacokinetics of this dose to the effective dose identified in our preclinical work. We therefore propose to evaluate the pharmacokinetic profile, safety and tolerability of sildenafil in 36 patients undergoing cardiac surgery, in an open label, dose escalation Phase I study. This study will inform the design of a subsequent randomized Phase IIb trial that will determine efficacy and safety
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
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
- •Adult cardiac surgery patients (>18 years) undergoing cardiac surgery with moderately hypothermic CPB (32-34°C) and blood cardioplegia
- •Identified as representing a high risk group for acute kidney injury using a modified risk score based on the variables of Age, Sex, BMI, Smoking Status, NHYA class, Previous Operations, Peripheral Vascular Disease, Diabetes, Hypertension, Pre-operative Haemoglobin level, Pre-operative eGFR, Operative Priority, Operation Type, Ejection Fraction and Presence of Pre-Operative Critical Events.
- •Female subjects of childbearing potential are not to be pregnant (to be confirmed by urine human chorionic gonadotropin pregnancy test prior to dosing). Women are considered not to be of childbearing potential if they have been surgically sterilised (eg, tubal ligation, oophorectomy or hysterectomy) or are postmenopausal (defined as serum follicle-stimulating hormone level of ≥30 IU/mL) in the absence of hormone replacement therapy and complete absence of menses for at least 24 consecutive months.
排除标准
- •Emergency or salvage procedure
- •Ejection fraction <30%
- •CKD Stage 5, defined as eGFR<15ml/min or renal replacement therapy.
- •Administration of potent CYP 3A4 inhibitors within 1 month prior to study participation (e.g. HIV protease inhibitors, imidazole antifungals and erythromycin, please see Appendix 1 for a full list of prohibited medications).
- •Administration of nitrate medicines (e.g. glyceryl trinitrate within 24 hours of surgery.
- •Any ongoing malignancy, or prior malignancy that currently requires treatment.
- •Patients allergic to any other PDE-5 Inhibitor
- •Patients who are participating in another interventional clinical study
研究组 & 干预措施
Sildenafil
All subjects in groups 1-6 will receive SIldenafil but in escalating doses.
干预措施: Sildenafil (Drug)
结局指标
主要结局
Area under the plasma concentration versus time curve and Plasma Concentration of Sildenafil
时间窗: 48 Hours
There will be Pharmacokinetic sample collection pre and post dose to look at plasma concentration of sildenafil. Sample collection timepoints are post dose at 10 mins, 15 mins, 30 mns, 45 mins 2 hours, 4 hours, 12 hours, 24 hours and 48 hours.
次要结局
- Serum creatinine and Biochemical markers of AKI(5 Days)