A Study of THR-184 in Patients at Risk of Developing Cardiac Surgery Associated-Acute Kidney Injury (CSA-AKI)

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:

• initial pre-surgery high dose of THR-184, followed by (3) post-surgery doses at the original low dose;
• initial pre-surgery high dose of THR-184, followed by (3) post-surgery doses at ~80% of the pre-surgery dose

Study treatment (THR-184 or placebo) will consist of one 60-minute IV infusion administered prior to surgery, followed by a 60-minute IV infusion administered, beginning in the early post-operative period, and followed by two (2) additional 60-minute IV infusions administered, on consecutive days post-cardiac surgery.

The primary endpoint for the evaluation of efficacy in patients receiving THR-184, as compared to patients receiving Placebo, will be the proportion of patients developing CSA-AKI as measured by the Kidney Disease Improving Global Outcomes (KDIGO) criteria, as follows:

• Increase in Serum creatinine (SCr) by ≥0.3 mg/dl (>26.5 µmol/l) within 48 hours post-surgery; or
• Increase in SCr to ≥1.5 times a baseline which has been measured in the previous 7 days; or
• Urine volume <0.5 ml/kg/h for 6 hours post-operatively

If at least one of these measures is present by the 7 day assessment, a patient will be considered to have developed CSA-AKI.

Inclusion criteria

• 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).

Exclusion criteria

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.