CMX-2043, a new, potent chemical entity, failed to reduce the incidence of acute kidney injury (AKI) in patients at elevated risk for contract-induced AKI.
“[AKI] is a major problem in contemporary percutaneous coronary intervention… with an incidence of about 20% to 25% in high-risk patients,” Deepak L. Bhatt, MD, MPH, study investigator from Brigham and Women’s Hospital in Boston, said during a press conference at the 2016 American College of Cardiology Scientific Sessions & Expo. “Unfortunately, this particular approach … did not reduce [AKI].”
To date, a number of different approaches have been attempted for reducing contrast-induced nephropathy, Dr Bhatt noted. “But from a bottom-line perspective, other than just giving patients saline water before the procedure by the vein … nothing else has clearly been demonstrated to reduce that risk. Therefore, we need new therapies.”
Results of an earlier study, SUPPORT-1, found that a single intravenous bolus of CMX-2043—a derivative of alpha-lipoic acid plus a chemical moiety for potency—reduced the mean peak rise in concentrations of creatine kinase-myocardial band (CK-MB) and troponin T, with no serious drug-related adverse events.
To better understand the drug’s potential efficacy, Dr Bhatt and colleagues conducted the randomized, double blind, placebo-controlled, phase 2a CARIN trial, enrolling 361 patients with acute coronary syndrome (ACS) or non-ACS from 31 centers in the United States and Canada.
Patients underwent elective coronary angiography, excluding ST-segment elevation myocardial infarction (STEMI), and were randomly assigned into 1 of 4 arms: 2.4-mg/kg CMX-2043 (n=87); 3.6-mg/kg CMX-2043 (n=94); 2 x 2.4-mg/kg CMX-2043 (n=87); or placebo (n=93).
Reduction in the incidence of AKI, defined as serum creatinine change from baseline of ≥0.3 mg/dL at 72 hours after administration of the first study drug dose, served as the primary efficacy end point. Key secondary end points included incidence of major adverse cardiovascular events (MACE) or major adverse kidney events (MAKE), reduction in cardiac injury, and reduction in the incidence of type 4a MI.
At day 4, there were no significant differences in the rate of the primary efficacy end point between the 3 study drug doses and placebo: 2.4-mg/kg, 25.6%; 3.6-mg/kg, 25.3%; 2 x 2.4-mg/kg, 18.9%; and placebo, 18.6% (P>.1 for all comparisons).
Similarly, differences in the rates of MACE, MAKE, and their component endpoints did not reach statistical significance (P>.1 for all comparisons).
“There still remains an unmet clinical need to find agents that reduce contrast nephropathy and protect kidneys during angiographic procedures,” Dr Bhatt concluded.
He added that the trial’s design might serve as a useful template for future trials to efficiently determine whether novel agents that appear promising in animal studies are worth examining in larger, more expensive phase 3 evaluations.
“In this case, we did prevent a large, 10 000-patient study that would have likely been negative from happening by efficiently studying this in about 300 patients,” he said.
Bhatt DL. LBCT IV. CARIN: a prospective, comparative, randomized, multi-center, double-blinded, placebo-controlled, phase 2a study of the safety and efficacy of CMX-2043 for periprocedural injury protection in subjects undergoing coronary angiography at risk of radio-contrast induced nephropathy. Presented at the 65th Annual Scientific Session and Expo of the American College of Cardiology. April 2-4, 2016; Chicago, IL.