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

A Phase 2, Multi-center, Randomized, Dose-Ranging, Placebo-Controlled, Double-blind Study of the Relaxin Agonist R2R01 in Patients at High Risk for Cardiac Surgery Associated- Acute Kidney Injury

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)

Inclusion Criteria:

• Patient is able to communicate well with the Investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF).

• At least 18 years of age.

• Subject is scheduled for non-emergent CABG (single or multiple vessels), valve surgery (single or multiple valves), surgery of the ascending part of the aorta, or a combination of the above, involving cardiopulmonary bypass (CPB), AND risk factors for acute kidney injury (AKI) are present (at screening) as specified below:

  1. If only one type of surgery is scheduled at least two AKI risk factors should be present
  2. If any combined surgery is scheduled at least one AKI risk factor should be present

• Have stable renal function per Investigator assessment.

• Subject agrees not to participate in another interventional study after signing the ICF and until the end of study (EoS) visit has been completed.

• Both female patients, as well as female partners of male patients who are of childbearing potential must be willing to not become pregnant for the complete duration of the study until 90 days after the last dose of study drug.

Exclusion Criteria:

• Patient currently enrolled into another interventional clinical trial.
• Subject is scheduled for emergent surgery.
• Cardiac surgery planned to be performed "off-pump" without CPB.
• Expected CPB duration <60 minutes.
• Body weight <50 kg; >120 kg.
• Presence of AKI (KDIGO criteria) at the time of randomization.
• Current, prior, or scheduled renal replacement therapy.
• Patients who are post-nephrectomy.
• Patients with CKD of equal or more than stage IV (GFR≤30 ml/min/1.73 m2).
• Patient with a kidney transplant.
• Subject has a known or suspected glomerulonephritis at the time of randomization.
• Cardiogenic shock, hemodynamic instability, mechanical ventilation, intra-aortic balloon pump (IABP), left ventricular assist device (LVAD) or other forms of mechanical circulatory support (MCS), within 7 days prior to surgery.
• Patient received inotropes or vasopressors within 48 hours prior to the day of surgery.
• Known or suspected sepsis.
• Confirmed or suspected endocarditis
• Other current active infection requiring antibiotic treatment.
• Patient has severe liver disease (Child-Pugh score >7 points).
• Recently received (within the last 4 weeks) or is anticipated to receive before the end of the study chemotherapy which can interfere with kidney function (e.g. Platinum agents).
• Preoperative frailty (impaired mobility defined as patients requiring a wheelchair; and severe malnutrition defined as BMI <16 kg/m²).
• Patient previously enrolled and randomized into this study.
• Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestate, confirmed by a positive human chorionic gonadotropin laboratory.
• Known hypersensitivity to the study drug or any of its excipients.
• Any medical or social condition deemed by the investigator to be likely to interfere with a patient's ability to give informed consent, cooperate, and participate in the study or to be likely to interfere with the interpretation of the results.
• Patient who is in a relationship of dependency with the sponsor, investigator or trial site, or committed to an institution by virtue of an order issued by judicial or administrative authorities.