Design and population of the VALOR-CKD study: a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of veverimer in slowing progression of chronic kidney disease in patients with metabolic acidosis

Abstract

Background Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD. Methods The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12-20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20-40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of > 40% from baseline, or death due to kidney failure. Key secondary endpoints include effects on physical function. Results Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 24%. Diabetes and hypertension were present in 56% and 98% of participants, respectively. Conclusions VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function.

Effect of Treatment of Metabolic Acidosis in Chronic Kidney Disease (Ckd) : a Systematic Review

“…Mathur, et al (2023) 12 showed the patients' mean age was 65.1 years old, and female patients made up 42% of the total.…”

VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis

“…The statistical analysis plan and power calculations have been published previously, 10 and the complete prespecified statistical analysis plan is provided with the protocol (Supplemental Appendix). In brief, VALOR-CKD was an event-based trial that was designed to terminate when the independent blinded Clinical Events Adjudication Committee had positively adjudicated the requisite number of primary end point events.…”

“…The VALOR-CKD study was a randomized, double-blind, placebo-controlled, multicenter clinical trial; details regarding the trial design and baseline characteristics of the participants have been published previously, 10 and the protocol is available in the Supplemental Appendix. The trial was sponsored by Tricida, Inc. and conducted at 346 sites in 35 countries from September 2018 through September 2022.…”

“…The full design and methods for VALOR-CKD have been previously reported. 10 After enrollment into part A (run-in period) of the study and 4-8 weeks of treatment with veverimer, patients with an increase from baseline in serum bicarbonate by $4 mEq/L or a serum bicarbonate $22 mEq/L progressed to the next stage of the trial (randomized treatment [part B]) after randomization to veverimer or placebo. The active treatment run-in period was designed to maximize the separation in serum bicarbonate levels between treatment groups after randomization.…”

A basic solution for a complex problem: does treatment of metabolic acidosis slow CKD progression?

“…A prespecified exploratory analysis demonstrated that veverimer was associated with improved time to the composite clinical endpoint of death, KRT, or a decline in eGFR of at least 50% in the 196 participants included in the cumulative 52 weeks treatment period. This culminated in the randomized multicenter randomized placebo-controlled VALOR-CKD trial, which recruited over 1400 patients [29 ▪ ]. Topline results were released by the parent company Tricida indicating that the study did not meet its primary endpoint, which was defined as time to first occurrence of any event in the composite of renal death, ESKD or greater than or equal to 40% reduction in eGFR.…”