Verified Hepatorenal Syndrome Reversal As A Robust Multi-Component Primary End Point: The CONFIRM Study Trial Design

Abstract

Background: Hepatorenal syndrome type 1 (HRS-1) is an uncommon, rapidly progressing, potentially fatal renal failure if left untreated. Terlipressin is a vasopressin analog that is fi rst-line therapy in combination with albumin for treatment of HRS-1 in countries outside of North America. In two previous Phase III clinical trials, terlipressin showed favorable effects on improvement in renal function compared with placebo; however, neither study showed a signi fi cant between-group difference in the primary end point. CONFIRM (NCT02770716) is an ongoing clinical trial designed to address operational challenges observed in the previous studies by using a novel, more clinically relevant primary end point than the previous studies. Methods: This Phase III, randomized, double-blind, multicenter study is expected to enroll about 300 patients at approximately 70 sites in the US and Canada. Patients with cirrhosis and ascites demonstrating renal impairment via rapidly progressive worsening of serum creatinine (SCr) level ( ≥ 199 μ mol/L [ ≥ 2.25 mg/dL] with a trajectory of SCr doubling over 2 weeks) are randomized 2:1 to receive either terlipressin 1 mg every 6 hrs as an IV bolus injection or placebo. The design of the study is generally similar to previous terlipressin prospective studies in the setting of HRS-1. A key feature differentiating this study from the previous ones centers around a novel, multi-component ef fi cacy variable that extends beyond the traditional outcome of improvement in renal function to include durability of treatment-related effects on renal replacement therapy (RRT) requirements and survival. To meet criteria for the primary ef fi cacy end point in CONFIRM, patients must show not only HRS reversal con fi rmed by two SCr values ≤ 1.5 mg/dL, but also survive, without RRT, for at least 10 days after achieving it. Conclusion: Data from this pivotal study will demonstrate whether terlipressin treatment is effective as measured by a new, clinically meaningful, multi-component primary ef fi cacy end point.