*Randomisation must occur on day 1, that is, the day before surgery is intended. All screening assessments may be performed on day 1 prior to surgery, including randomisation. These assessments must be completed prior to any presurgical activities, such as administration of fluids or medications, including anaesthesia.

†Visit 5 must occur at 72 hours from start of first infusion of IMP, with a scheduling window of ±2 hours.

‡Visit 6 and all associated assessments should occur on the day of hospital discharge. In case subject is discharged on day 4, discharge (visit 6) assessments performed prior to discharge on that day are acceptable.

§Visit may be performed by qualified and trained study staff at the subject's home or other suitable location, where appropriate.

¶In case of subject withdrawal, subject should be encouraged to undergo all EOS assessments as an early termination visit.

**Only required as long as Foley catheter is in place.

††Assessments must be performed prior to IMP administration.

‡‡Height only measured at screening (visit 1). Weight during ICU stay only required if possible.

§§The initial physical examination performed at screening should be comprehensive; all other physical examinations may be abbreviated and symptom driven.

¶¶A serum pregnancy test completed during the screening period within 48 hours prior to surgery does not need to be repeated on the day of surgery. If the serum pregnancy test occurs more than 48 hours prior to the date of surgery, a serum or urine pregnancy test will also be performed on day 1 prior to surgery.

***Haematology labs: haematocrit, haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, red cell distribution width, red blood cells, platelets, leucocytes (including neutrophils, monocytes, lymphocytes, eosinophils, basophils) clinical chemistry labs: albumin, calcium, chloride, SCr, C reactive protein, sodium, estimated glomerular filtration rate, magnesium, phosphate, potassium, blood urea nitrogen, uric acid, glucose liver function labs: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin (total and conjugated), gamma glutamyltransferase.

†††The screening sample for SCr must be collected on day −1 (or day of surgery, see footnote ‡‡) and will be analysed locally (to evaluate eligibility and determine correct start dose of RMC-035 according to renal function) and centrally (as baseline for endpoint assessment). All SCr samples collected during hospital stay will be analysed both locally (to support AKI evaluation) and in a central lab (for the purpose of endpoint assessments). Days 30 and 90 samples will be analysed centrally.

‡‡‡Cystatin C samples will be collected and analysed in a central lab only for the purpose of endpoint assessments.

§§§UACR: screening sample will be collected as a spot urine sample and analysed locally to evaluate albuminuria as an eligibility criterion (in the absence of historical albuminuria data within 3 months prior to randomisation). UACR and UPCR: In-hospital samples (day 1, visit 2 and day 4, visit 5) will be collected either as a first morning void (FMV) sample or drawn directly from a Foley catheter and analysed in a central lab only. Follow-up samples (day 30, visit 7 and day 90, visit 8) will be collected as FMV samples as possible and analysed in a central lab only.

¶¶¶All 5 doses to be calculated using the same weight measurement that is used for randomisation/stratification. IMP will be permanently discontinued in subjects developing AKI stage 2 or higher as per KDIGO guidelines.

****Intravenous infusion over 60 min, first infusion should start approximately 10 min before expected onset of CPB (time point 0 is defined as start of IMP administration).

††††Intravenous infusion over 60 min at 6 hours (±30 min) after the start of first infusion.

‡‡‡‡ Intravenous infusion over 30 min at 12 hours, 24 hours and 48 hours (±30 min) after the start of first infusion.

§§§§PK sampling at day 2 and 3 should occur 30 min (±5 min) and 90 min (±15 min) from start of IMP infusion (see table 4).

¶¶¶¶Vital signs: body temperature, blood pressure, heart rate, respiratory rate, SpO2.

*****Data points to collect are type of CPB pump (pulsatile or non-pulsatile, if applicable) and duration of CPB (exact time of initiation and end of CPB), duration of surgery (beginning of surgery defined as exact time of initial skin incision, end of surgery defined as exact time of skin closure), blood loss volume, administration of any fluids during surgery (blood products (red blood cells, plasma, cryoprecipitate, platelets, etc), crystalloids, colloids and others), target body temperature during CPB and time at temperature range, duration of cross clamp (minutes), number, position and graft source bypasses performed, length of time with mean arterial pressure <50 mm Hg, valve surgery type (replacement or repair), replacement valve origin (bioprosthetic or mechanical), aortic repair type and time of admission to the ICU.

†††††Time of discharge from ICU to hospital ward, another treatment facility or home.

‡‡‡‡‡Urine samples for evaluation of exploratory urinary (kidney) biomarkers and plasma/serum samples for evaluation of cardiac biomarkers will be collected at the intervals described below, respectively (see table 5).

§§§§§PRO HRQoL assessment: SF-36 and EQ-5D-5L. PRO HRQoL assessments to be performed as early as possible in the screening period.

¶¶¶¶¶Medications taken within 30 days prior to the day surgery is intended are to be collected. Use of contrast agent within 72 hours prior to the day surgery is intended should be documented as a prior/concomitant medication. When possible, type and quantity of contrast agent should be recorded.

ADA, antidrug antibodies; AE, adverse event; CPB, cardiopulmonary bypass; EQ-5D-5L, European Quality of Life 5 Domain 5-Level Score; HRQoL, health-related quality of life; ICU, intensive care unit; KDIGO, Kidney Disease Improving Global Outcomes; PK, pharmacokinetics; PROs, patient-reported outcomes; SAE, serious AE; SAEs, serious adverse events; SF-36, 36-Item Short Form Survey; UACR, urine albumin to creatinine ratio; UPCR, urine protein to creatinine ratio.