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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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)

Conditions
-----------------
Acute Kidney Injury

Intervention / Treatment
-----------------
* Drug: THR-184
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>An identical appearing placebo will be administered. | Drug: Placebo<br>* A normal saline solution identical in appearance to the active drug solution<br>* Other names: Saline solution;|
| Experimental: THR-184 Dose 1<br>THR-184 initial pre-surgery low dose followed by (3) post surgery doses at the low dose. | Drug: THR-184<br>* THR-184 is a synthetic oligopeptide administered intravenously.<br>* Other names: Synthetic oligopeptide;|
| Experimental: THR-184 Dose 2<br>THR-184 initial pre-surgery mid-dose followed by (3) post surgery doses at the low dose. | Drug: THR-184<br>* THR-184 is a synthetic oligopeptide administered intravenously.<br>* Other names: Synthetic oligopeptide;|
| Experimental: THR-184 Dose 3<br>THR-184 initial pre-surgery high dose followed by (3) post surgery doses at the low dose. | Drug: THR-184<br>* THR-184 is a synthetic oligopeptide administered intravenously.<br>* Other names: Synthetic oligopeptide;|
| Experimental: THR-184 Dose 4<br>THR-184 initial pre-surgery high dose followed by (3) post surgery doses  80% of the pre-surgery dose. | Drug: THR-184<br>* THR-184 is a synthetic oligopeptide administered intravenously.<br>* Other names: Synthetic oligopeptide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Acute Kidney Injury (AKI) | 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. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AKI | AKI is defined using the SCr-KDIGO criteria, defined as 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. | 7 days | 
| Severity of AKI | 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. Staging of AKI is defined as the following: Stage 1: SCr 1.5 - 1.9 times baseline OR ≥0.3 mg/dL (≥26.5 µmol/L) increase, Urine output <0.5 ml/kg/hr for 6-12 hours Stage 2: SCr 2.0-2.9 times baseline, Urine output <0.5 ml/kg/h for ≥ 12 hours Stage 3: SCr 3.0 times baseline OR Increase in SCr to ≥5.0 mg/dL (≥353.6 µmol/L) OR Initiation of renal replacement therapy OR In patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m^2, Urine output <0.3 ml/kg/h for ≥24 hours OR Anuria for ≥12 hours. No AKI is considered the best outcome, and Stage 3 the worst outcome. | 7 days | 
| Duration of AKI | AKI is defined using the Scr-KDIGO criteria. Duration of AKI is defined as the number of days from start of AKI (SCr-KDIGO) where either SCr increase ≥ 0.3 mg/dL above pre-AKI reference point (if the value exists) or if SCr increase ≥1.5 times baseline or dialysis in the first 7 days up to discharge if prior to 7 days. | 7 days OR up to discharge after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Acute Kidney Injury, AKI, Cardiac surgery