Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute Kidney Injury Following Open-Chest Cardiac Surgery
- Registration Number
- NCT05126303
- Lead Sponsor
- Guard Therapeutics AB
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 177
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Identical to RMC-035 arm except that the placebo contains no active ingredient. RMC-035 RMC-035 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.
- Primary Outcome Measures
Name Time Method Percentage of Subjects Developing AKI, as Defined Per Kidney Disease Improving Global Outcomes (KDIGO) Criteria 72 hours Percentage of subjects developing AKI based on Serum Creatinine and/or Urine Output per KDIGO definition
- Secondary Outcome Measures
Name Time Method Characteristics of ADA (Cross-reactivity) 90 days Characteristics of ADA developed at Day 30 and Day 90 with regards cross-reactivity with endogenous alpha-1-microglobulin (A1M)
Peak SCr Value 7 days Change from baseline of peak SCr from baseline to Day 7
Major Adverse Kidney Event (MAKE) - Cystatin C 90 days MAKE at Day 30 and Day 90, defined as death, any dialysis, or ≥25% reduction of eGFR compared to baseline.
eGFR calculated based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using Cystatin C.Major Adverse Kidney Event (MAKE) - SCr and Cystatin C 90 days MAKE at Day 30 and Day 90, defined as death, any dialysis, or ≥25% reduction of eGFR compared to baseline.
eGFR calculated based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using SCr and Cystatin C.Change in Serum Cystatin C Values Over Time 90 days Cystatin C measurement in serum at 12, 24, 48, and 72 hours, respectively, and at Day 7/discharge, Day 30 and Day 90
Area Under the Curve (AUC) of Serum Creatinine (SCr) 72 hours Time-corrected area under the curve (AUC) of serum creatinine calculated as follows:
The area under the SCr concentration versus time curve following drug administration were calculated using timepoints at Day 1 (12 hour), Day 2 (24 hour), Day 3 (48 hour) and Day 4 (72 hour). The individual log-transformed SCr values were determined, and the AUC (utilizing planned times) were calculated using the right Riemann sum: AUC = 0.5 x SCr(12h) + 0.5 x SCr(24h) + 1 x SCr(48h) + 1 x SCr(72h) The time-corrected AUC (log-scale) was then calculated as AUC/3Duration of AKI 90 days 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
Change in SCr Values Over Time 90 days SCr at 12, 24, 48, and 72 hours, respectively, and at Day 7/discharge, Day 30 and Day 90
Peak Cystatin C Value 7 days Change from baseline of peak cystatin C from baseline to Day 7
AKI Within 7 Days 7 days AKI based on SCr and/or UO criteria, or cystatin C and/or UO criteria
Persistence of AKI 7 days AKI persistence, defined as an AKI (KDIGO definition) developing within 72 hours after first dose of IMP and with a duration of ≥72 hours
Change in Urine Albumin to Creatinine Ratio (UACR) and Urine Protein to Creatinine Ratio (UPCR) 90 days Post-baseline changes in UACR and UPCR at Day 4, Day 30, and Day 90
Pharmacokinetics of RMC-035 (AUC) 4 days AUC(0-24) of RMC-035 concentrations in plasma (Day 3)
Pharmacokinetics of RMC-035 (Cmax) 7 days Cmax of RMC-035 concentrations in plasma Day 3
Presence of Anti-drug Antibodies (ADA) 90 days Presence of ADA at Day 1 (pre-surgery), Day 30, and Day 90; positive samples
AUC of Cystatin C 72 hours Time-corrected AUC of cystatin C for Day 1 to Day 4 (72 hours after first dose of IMP) calculated as follows:
The area under the cystatin C concentration versus time curve following drug administration were calculated using timepoints at Day 1 (12 hour), Day 2 (24 hour), Day 3 (48 hour) and Day 4 (72 hour). The individual log-transformed cystatin C values were determined, and the AUC (utilizing planned times) were calculated using the right Riemann sum: AUC = 0.5 x cystatin C(12h) + 0.5 x cystatin C(24h) + 1 x cystatin C(48h) + 1 x cystatin C(72h) The time-corrected AUC (log-scale) was then calculated as AUC/3Number of Participants Requiring Renal Replacement Therapy (Dialysis) 7 days Renal replacement therapy (dialysis treatment) required by any participant for any reason
Number of Days Without Need for Dialysis 90 days Number of days that participants were not requiring dialysis
Major Adverse Kidney Event (MAKE) - SCr 90 days MAKE at Day 30 and Day 90, defined as death, any dialysis, or ≥25% reduction of eGFR compared to baseline.
eGFR calculated based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using SCr.AKI Within 72 Hours Based on Cystatin C and UO 72 hours AKI based on cystatin C and/or urine output (UO)
Severity of AKI 7 days AKI severity stage 1, 2 or 3 per KDIGO criteria, with 1 being mildest stage and 3 being most severe stage.
Reference: KDIGO (2012). "Clinical Practice Guideline for Acute Kidney Injury." JOURNAL OF THE INTERNATIONAL SOCIETY OF NEPHROLOGY 2(1).
Trial Locations
- Locations (29)
Rochester Regional Health - Rochester General Hospital
🇺🇸Rochester, New York, United States
University of Virginia (UVA) Health - University Hospital
🇺🇸Charlottesville, Virginia, United States
Aurora Health Care - Aurora St. Luke's Medical Center
🇺🇸Milwaukee, Wisconsin, United States
Institut Universitaire de Cardiologie et de Pneumologie de Québec
🇨🇦Québec, Canada
Münster University Hospital
🇩🇪Münster, Germany
Duke University Hospital
🇺🇸Durham, North Carolina, United States
University Hospital Hradec Kralove
🇨🇿Hradec Kralove, Czechia
MUHC - Royal Victoria Hospital
🇨🇦Montréal, Canada
University of Wisconsin
🇺🇸Madison, Wisconsin, United States
Hamilton Health Sciences
🇨🇦Hamilton, Canada
CHUM
🇨🇦Montréal, Canada
Herz- und Diabeteszentrum Nordrhein-Westfalen (NRW)
🇩🇪Bad Oeynhausen, Germany
Reina Sofia University Hospital
🇪🇸Córdoba, Spain
Herzzentrum Dresden GmbH
🇩🇪Dresden, Germany
University Hospital Motol - Charles University Prague
🇨🇿Praha 5, Czechia
Bryan Heart
🇺🇸Lincoln, Nebraska, United States
Indiana Ohio Heart
🇺🇸Fort Wayne, Indiana, United States
Baylor Scott and White Research Institute - Dallas
🇺🇸Dallas, Texas, United States
St. John Regional Hospital
🇨🇦Saint John, Canada
Saint Michael's Hospital
🇨🇦Toronto, Canada
Universitätsklinikum Köln
🇩🇪Köln, Germany
Hospital Universitario Central de Asturias
🇪🇸Oviedo, Spain
Hospital de La Princesa
🇪🇸Madrid, Spain
Complejo Hospitalario Universitario de Santiago (CHUS)
🇪🇸Santiago de Compostela, Spain
Deutsches Herzzentrum München
🇩🇪München, Germany
Hospital Sant Pau
🇪🇸Barcelona, Spain
Westdeutsches Herzzentrum Essen
🇩🇪Essen, Germany
Universitätsklinikum Giessen und Marburg - Standort Giessen
🇩🇪Gießen, Germany
Universitätsklinikum Halle (Saale)
🇩🇪Halle, Germany