Study of the Relaxin Agonist R2R01 in Patients at High Risk for Cardiac Surgery Associated- Acute Kidney Injury

Overview

This is a Phase 2, dose-ranging, double-blind, double-dummy, placebo-controlled, randomized study preceded by an open label safety run-in, in patients at high risk for Cardiac Surgery Associated - Acute Kidney Injury (CSA-AKI) following coronary artery bypass graft (CABG), valve surgery, aortic surgery, or a combination of the above, involving cardiopulmonary bypass (CPB). Subjects are eligible for screening if they are scheduled for non-emergent CABG, valve surgery, surgery of the ascending part of the aorta, or a combination of the above, involving CPB, within 4 weeks after screening. In addition, subjects are eligible if AKI risk factors are present (at screening): a. If isolated surgery (CABG, single valve surgery, or of the ascending part of the aorta surgery) is scheduled, at least two AKI risk factors should be present b. If combined surgery is scheduled, at least one AKI risk factor should be present Risk factors for AKI are defined below: • Chronic kidney disease (CKD) stage III • Diabetes mellitus on pharmacological treatment • Confirmed diagnosis of hypertension • Documented history of Chronic Heart Failure with New York Heart Association (NYHA) class III or higher * Left ventricular ejection fraction (LVEF) ≤40% * Peripheral vascular disease defined as one or more of the following: claudication, carotid occlusion or \>50% stenosis, amputation for arterial disease, previous or planned intervention on the abdominal aorta, limb arteries or carotids. * Stroke/transient ischemic attack (TIA) defined as sudden onset of focal or global brain, spinal cord, or retinal vascular damage, resulting in symptoms and signs of acute nervous system defects, which is associated with cerebral circulation disorders * Documented atrial fibrillation (AF) on the ECG performed at the screening visit * Anemia with hemoglobin ≤11 g/dL at any time during the 3-month period before or at the time of screening * Body Mass Index (BMI) ≥ 30 kg/m2 * Age ≥70 years at the time of screening The first dose of Investigational Medicinal Product (IMP: R2R01 or Placebo) will be administered subcutaneously (SC) the day before surgery at 06:00 PM (+/- 30 min); the second dose will be administered SC on the day of surgery between 07:00 and 08:00 AM when the surgery is scheduled for the morning, or between 11:00 AM and 12:00 PM when the surgery is scheduled for the afternoon; subsequent doses will be administered SC every 24 hours (+/- 90 min.) starting 24 hours after the second dose, and will continue to be administered until postoperative Day 5 or discharge, whichever occurs first. The follow-up period extends until postoperative Day 30. The study consists of: A. An Open-Label Safety Run-In Part, followed by B. A Double-Blind, Placebo-Controlled, Randomized Part A. An Open-Label Safety Run-In Part The first 10 subjects will be treated with R2R01 5.0 mg SC to ascertain its safety in this population. The Safety Run-In part will be run at the San Raffaele Hospital in Milan (PI Dr. Landoni). Data collected will include but will not be limited to: (1) detailed hemodynamic parameters; (2) use of vasopressors and/or inotropic agents during surgery and in the postoperative period; (3) incidence, severity, and relationship of adverse events (AEs), including serious adverse events (SAEs); (4) postoperative clinical course; (5) available PK data. A Scientific Review Committee (SRC), consisting of three CSA-AKI experts and at least one medical representative of the Sponsor, will review the data from the 5.0 mg dose cohort (open-label Part), based on the safety and available pharmacokinetic data collected from the 10 enrolled patients through postoperative Day 7 or discharge, whichever occurs first. If the SRC agrees to proceed with the 5.0 mg dose, enrollment will open to the randomized part B of the study. If instead, the SRC determines that the 5.0 mg dose is not appropriate, a new dose (i.e., 2.5 mg) will be selected by the SRC for evaluation in 10 additional subjects enrolledin the open-label safety run-in part. Upon completion of the Open-Label Safety Run-In Part, and once the SRC has determined the appropriate R2R01 dose(s) to be tested, enrollment will open to the Double-Blind, Placebo-Controlled, Randomized Part. B. Double-Blind, Placebo-Controlled, Randomized Part Approximately 430 patients will be randomly assigned in a 1:1:1 manner to receive one of the two doses of R2R01or placebo. At randomization, patients will be stratified by presence of CKD stage III (strata: eGFR 59-30 ml/min/1.73m2 vs. eGFR ≥60 ml/min/1.73m2). The randomized part will be conducted at all investigational sites. AKI will be staged according to KDIGO as follows: Stage 1: increase in SCr ≥0.3 mg/dL or an increase in serum creatinine ≥1.5-fold to 2-fold from baseline. Stage 2: incrincrease in SCr \>2-fold to 3-fold from baseline. Stage 3: increase in SCr \>3-fold or SCr ≥4.0 mg/dl or initiation of renal replacement therapy (RRT)