POINTER: study protocol for a phase 2b, randomised, placebo-controlled, double-blind, parallel group dose-finding clinical study to evaluate the efficacy of RMC-035 on renal function and safety, in participants at high risk for kidney injury, following open-chest cardiac surgery.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass invariably induces renal stress and risk of irreversible kidney function loss, with no approved drug treatments. RMC-035, a recombinant human alpha-1-microglobulin with potent heme-binding and antioxidant capacity, has shown promising long-term kidney-protective effects in a phase 2a trial of patients undergoing cardiac surgery. The primary objective of this phase 2b dose-optimisation trial is to demonstrate that RMC-035 (pooled dose groups) is superior to placebo in preserving renal function at 90 days after surgery. METHODS: This randomised, blinded, placebo-controlled, multicentre study evaluates the efficacy and safety of RMC-035 among approximately 161 high-risk patients undergoing cardiac surgery who are randomised into one of three treatment groups in a 2:2:3 ratio: RMC-035 (30 mg or 60 mg) or placebo. The study drug is administered via three intravenous infusions, with the first dose given intraoperatively, followed by additional doses at 6 and 24 h, respectively. The primary endpoint is the change in estimated glomerular filtration rate (eGFR) from baseline (pre-surgery) to Day 90. Important secondary endpoints include the incidence of major adverse kidney events at Day 90 and short-term outcomes reflecting changes in renal filtration markers up to Day 7. Safety assessments encompass adverse events, vital signs, electrocardiograms and routine safety laboratory tests. Additional evaluations include pharmacokinetics, anti-drug antibodies and immunological biomarkers. DISCUSSION: This multicentre, multinational phase 2b trial, will assess the change in eGFR within 90 days of the first dose, providing additional evidence of the long-term kidney-protective potential of RMC-035 in patients undergoing cardiac surgery at high risk for kidney injury. Trial outcomes will inform the preferred dose, dosing regimen, and benefit-risk profile related to cardiac surgery for a future pivotal phase 3 trial. TRIAL REGISTRATION: The trial was registered June 20, 2024, at Clinicaltrials.gov (NCT06475274 https://clinicaltrials.gov/study/NCT06475274 ). The trial including the participating EU countries is also registered with the EUCT number 2024-510658-28 under https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-510658-28-00 . The first patient was enrolled August 26, 2024.