A Multi-Center, Parallel-Group, Randomized, Double Blind, Adaptive Study Investigating the Safety and Efficacy of THR-184 in Patients at Increased Risk of Developing Cardiac Surgery Associated-Acute Kidney Injury (CSA-AKI)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 452
- 试验地点
- 41
- 主要终点
- Incidence of Acute Kidney Injury (AKI)
研究概览
简要总结
The purpose of this study is to determine whether THR-184 when administered around the time of cardiac surgery that requires cardiopulmonary bypass can prevent or ameliorate the development of acute kidney injury.
详细描述
The study has been designed to include patients scheduled for cardiac surgery who are considered at increased risk for developing CSA-AKI. The eligibility criteria are intended to enrich the study population with such patients.
Stage 1 consisted of 140 patients randomized in a 1:1:1:1 ratio (approximately 35 patients per treatment arm) to Placebo or to one of three (3) THR-184 dose arms:
- initial pre-surgery low dose of THR-184 by three (3) post-surgery doses at the low dose, or
- initial pre-surgery middle dose of THR-184 followed by three (3) post-surgery doses at the low dose, or
- initial pre-surgery high dose of THR-184 followed by three (3) post-surgery doses at the low dose
An interim analysis (IA) was performed by the Independent Statistical Center (ISC) and presented to the Independent Data Monitoring Committee (IDMC). The IDMC indicated no safety concerns and recommended that the study continue with the placebo arm and the initial pre-surgery high dose arm. Additionally, another dosing arm will be added, which will increase the dose post-surgery.
Stage 2 will consist of approximately 270 patients randomized in a 1:1:2 ratio to Placebo or to a dose selected from one of the two (2) THR-184 dose arms:
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 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female and >18 years of age.
- •Scheduled for a non-emergent coronary and/or valve surgery procedure requiring CPB, to include:
- •coronary artery bypass graft (CABG) alone;
- •aortic valve replacement or repair alone, with or without aortic root repair;
- •mitral, tricuspid, or pulmonic valve replacement or repair alone;
- •simultaneous replacement of several cardiac valves;
- •CABG with aortic, mitral, tricuspid, or pulmonic valve replacement or repair;
- •CABG with combined cardiac valve replacement or repair.
- •Have the following risk factors for CSA-AKI:
- •eGFR ≥ 20 and < 30 ml/min/1.73m2 OR
- •eGFR ≥ 30 and < 60 ml/min/1.73m2 and ONE of the following additional risk factors (other than age ≥ 75 years) OR
- •eGFR ≥ 60 ml/min/1.73m2 and TWO of the following additional risk factors
- •Additional Risk Factors:
- •Age ≥ 75 years;
- •Combined valve & coronary surgery;
- •Previous cardiac surgery with sternotomy;
- •Documented NYHA Class III or IV within 1 year prior to surgery;
- •Left ventricular ejection fraction (LVEF) ≤ 35% by invasive or noninvasive diagnostic cardiac imaging - echocardiography, nuclear imaging, computed tomography, magnetic resonance imaging or angiography performed within 90 days prior to surgery. (If LVEF ≤ 35% by any invasive or noninvasive imaging procedure, patient meets the risk factor.)
- •Insulin-requiring diabetes;
- •Non-insulin-requiring diabetes and the presence of ≥+2 proteinuria on urinalysis (medical history or dipstick);
- •Preoperative anemia (hemoglobin <11g/dl for men and women).
排除标准
- •If any of the following criteria apply prior to surgery, the patient will be excluded from the study:
- •Age > 85 years;
- •Weight >174 kg or 383 lbs;
- •The presence of AKI (KDIGO criteria) at the time of screening ;
- •Surgery to be performed without CPB;
- •Surgery to be performed under conditions of circulatory arrest or hypothermia with rectal temperature < 28°Celsius (82.4° Fahrenheit);
- •eGFR (MDRD) <20 ml/min/1.73m2;
- •Surgery for aortic dissection;
- •Surgery to correct a major congenital heart defect (e.g., Tetralogy of Fallot, transposition of the great vessels, single ventricle, Ebsteins anomaly. Bicuspid aortic valve is not to be considered a congenital heart defect.);
- •Prior organ transplantation;
- •Dialysis-dependence;
- •Administration of iodinated contrast media within 24 hours prior to cardiac surgery;
- •If received contrast media prior to 24 hours and have AKI as defined by KDIGO criteria;
- •Cardiogenic shock or haemodynamic instability within the 24 hours prior to surgery, including the anesthesia induction period; as defined by a systolic BP <80 mm Hg and pulse >120 beats per minute (bpm) and requirement for inotropes or vasopressors or other mechanical devices such as intra-aortic balloon counter-pulsation (IABP);
- •Requirement for any of the following within seven (7) days prior to cardiac surgery:
- •defibrillator or permanent pacemaker,
- •mechanical ventilation,
- •intra-aortic balloon counter-pulsation (IABP),
- •left ventricular assist device (LVAD),
- •other forms of mechanical circulatory support (MCS);
- •Cardiopulmonary resuscitation within 14 days prior to cardiac surgery;
- •Known history of cancer within the past 5 years, except for carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin;
- •Known or suspected sepsis at time of screening;
- •Known or suspected glomerulonephritis or interstitial nephritis at time of screening;
- •Confirmed or treated endocarditis within previous 30 days prior to cardiac surgery;
- •Other current active infection requiring antibiotic treatment;
- •Patients with known active human immunodeficiency virus infection;
- •Documented history of HIV antibodies;
- •Patients with known active Hepatitis B (HBV) or Hepatitis C (HCV) infection;
- •Documented history of HCV antibodies;
- •Documented history of HBV antigens;
- •Patients on immunosuppressant drugs or prednisone over the dose of 20 mg per day;
- •Inadequate hepatic function, defined as total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper limit of normal (ULN) at time of screening or Child Pugh Class C liver disease ( see appendix 6) or higher;
- •Any congenital coagulation disorder;
- •Pregnancy or lactation;
- •If patient has "Do Not Resuscitate" (DNR) status;
- •Known hypersensitivity to the study drug or any of its excipients;
- •Treatment with an investigational drug or participation in an interventional trial within 60 days prior to 1st dose of study drug;
- •In the opinion of the investigator any disease processes or confounding variables that would inappropriately alter the outcome of the study;
- •Inability to comply with the requirements of the study protocol.
研究组 & 干预措施
Placebo
An identical appearing placebo will be administered.
干预措施: Placebo (Drug)
THR-184 Dose 1
THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose.
干预措施: THR-184 (Drug)
THR-184 Dose 2
THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose.
干预措施: THR-184 (Drug)
THR-184 Dose 3
THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose.
干预措施: THR-184 (Drug)
THR-184 Dose 4
THR-184 initial pre-surgery high dose followed by (3) post surgery doses ~80% of the pre-surgery dose.
干预措施: THR-184 (Drug)
结局指标
主要结局
Incidence of Acute Kidney Injury (AKI)
时间窗: 7 days
Acute kidney injury (AKI) is defined using the KDIGO criteria, in which AKI is defined as any of the following: * Increase in SCr by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours; or * Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or * Urine volume \<0.5 ml/kg/h for 6 hours.
次要结局
- Incidence of AKI(7 days)
- Severity of AKI(7 days)
- Duration of AKI(7 days OR up to discharge after surgery)