Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute Kidney Injury Following Open-Chest Cardiac Surgery

Study Overview
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Brief Summary
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This study evaluates RMC-035 compared to placebo for the prevention of acute kidney injury (AKI) in subjects who are at high risk for AKI following cardiac surgery. Half of the subjects will receive RMC-035 and the other half will receive placebo.

Detailed Description
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This is a Phase 2, randomized, double-blind, adaptive, parallel group clinical study that will evaluate RMC-035 compared to placebo in subjects at high risk for acute kidney injury (AKI) following cardiac surgery. Subjects are randomized in a 1:1 ratio.

Official Title
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A Phase 2, Randomized, Placebo-Controlled, Double-Blind, Adaptive, Parallel Group Clinical Study to Evaluate the Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute Kidney Injury Following Open-Chest Cardiac Surgery

Conditions
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Acute Kidney Injury

Intervention / Treatment
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* Drug: RMC-035
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Institutional Review Board/ International Ethics Committee approved Informed Consent obtained Ability to understand and comply with the study requirements and able to provide written informed consent Age ≥18 and <85 years Estimated glomerular filtration rate (eGFR) is ≥30 mL/min/1.73 m2 Subject is scheduled for non-emergent coronary artery bypass grafting (CABG) surgery and/or valve surgery and/or ascending aorta aneurysm surgery with use of cardiopulmonary bypass (CPB), and AKI risk factors are present at screening Female subject is not of child-bearing potential, or agreeing not to become pregnant Female subject must not be breastfeeding Female subject must not donate ova Male subject and their female spouse/partner(s) who are of childbearing potential must be using a highly effective form of birth control Male subjects must not donate sperm Subject agrees not to participate in another interventional study Exclusion Criteria: Medical condition that makes the subject unsuitable for study participation Scheduled for emergent surgeries (eg, aortic dissection) Scheduled for CABG and/or valve surgery and/or ascending aorta aneurysm surgery combined with additional non-emergent cardiac surgeries (eg, congenital heart defects) Scheduled to undergo transcatheter aortic valve implantation (TAVI) or transcatheter aortic valve replacement (TAVR), or off-pump surgeries or left ventricular assist device (LVAD) implantation Experiences a cardiogenic shock or hemodynamic instability which require inotropes or vasopressors or other mechanical devices within 24 hours prior to surgery Requirement for defibrillator or permanent pacemaker, mechanical ventilation, intraaortic balloon pumping (IABP), LVAD, or other forms of mechanical circulatory support (MCS) Diagnosed with AKI (as defined by KDIGO criteria) within 3 months prior to surgery Required cardiopulmonary resuscitation within 14 days prior to cardiac surgery Ongoing sepsis or an untreated diagnosed clinically significant infection (viral or bacterial) Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 times the upper limit of normal (ULN) History of solid organ transplantation History of renal replacement therapy (RRT) Medical condition which requires active immunosuppressive treatment Severe allergic asthma Ongoing chemotherapy or radiation therapy for malignancy that may have an impact on kidney function Received an investigational medicinal product within the last 90 days (or within 5 half-lives of the investigational drug, whichever is longer) Subject has a known allergy to RMC-035 or one of its constituents, or has previously received RMC-035

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, adaptive, parallel group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RMC-035<br>RMC-035 is a concentrate (6.0 mg/mL) for solution for infusion for IV administration. Dosing will be based on renal function at Day -1: Subjects with eGFR ≥60 mL/min/1.73m2 will receive 1.3 mg/kg (per dose) for the first and second dose, followed by 0.65 mg/kg (per dose) for the third, fourth and fifth dose, while subjects with eGFR >30 and <60 mL/min/1.73m2 will receive 0.65 mg/kg (per dose) for all five doses Dosing occurs at time 0 and then after 6, 12, 24 and 48 hours. | Drug: RMC-035<br>* Concentrate for Solution for Infusion<br>* Other names: ROSgard;|
| Placebo Comparator: Placebo<br>Identical to RMC-035 arm except that the placebo contains no active ingredient. | Drug: Placebo<br>* Concentrate for Solution for Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects developing AKI, as defined per Kidney Disease Improving Global Outcomes (KDIGO) criteria | AKI based on Serum Creatinine and/or Urine Output per KDIGO definition | 72 hours | 
| Safety and Tolerability | Nature, frequency and severity of treatment-emergent adverse events | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of Serum creatinine (SCr) | Time-corrected area under the curve (AUC) of serum creatinine | 72 hours | 
| Duration of AKI | Duration of AKI defined as the number of days meeting the definition of AKI (KDIGO definition) starting within 72 hours after first dose of IMP until resolution | 90 days | 
| Post-baseline changes in renal function: SCr and cystatin C values | SCr and cystatin C (and corresponding eGFR values) at 12, 24, 48, and 72 hours, respectively, and at Day 7/discharge, Day 30 and Day 90 | 90 days | 
| Post-baseline changes in renal function: Peak SCr and cystatin C values | Change from baseline of peak SCr and cystatin C | 7 days | 
| Post-baseline changes in renal function: AUC of cystatin C | Time-corrected AUC of cystatin C for Day 1 to Day 4 (72 hours after first dose of IMP) | 72 hours | 
| Need for renal replacement therapy: Dialysis treatment | Dialysis treatment (for any reason) | 7 days | 
| Need for renal replacement therapy: Dialysis free | Dialysis free days | 90 days | 
| Major adverse kidney event (MAKE) | MAKE at Day 30 and Day 90, defined as death, any dialysis, or ≥25% reduction of eGFR compared to baseline Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (either SCr, cystatin C, or both) | 90 days | 
| AKI Characteristics: AKI within 72 hours based on cystatin C and UO | AKI based on cystatin C and/or urine output (UO) | 72 hours | 
| AKI Characteristics: AKI within 7 days | AKI based on SCr and/or UO criteria, or cystatin C and/or UO criteria | 7 days | 
| AKI Characteristics: Persistence | AKI persistence, defined as an AKI (KDIGO definition) developing within 72 hours after first dose of IMP and with a duration of ≥72 hours | 7 days | 
| AKI Characteristics: Severity | AKI severity stage per KDIGO criteria | 7 days | 
| Change in urine albumin to creatinine ratio (UACR) and urine protein to creatinine ratio (UPCR) | Post-baseline changes in UACR and UPCR at Day 4, Day 30, and Day 90 | 90 days | 
| Pharmacokinetics of RMC-035 | AUC of RMC-035 concentrations in plasma | 7 days | 
| Pharmacokinetics of RMC-035 | Cmax of RMC-035 concentrations in plasma | 7 days | 
| Presence and titers of anti-drug antibodies (ADA) | Presence and titers of ADA at Day 1 (pre-surgery), Day 30, and Day 90 | 90 days | 
| Characteristics of ADA | Characteristics of ADA developed at Day 30 and Day 90 with regards to isotype, neutralizing capacity, and cross-reactivity with endogenous alpha-1-microglobulin (A1M) | 90 days |