Phase 3 Randomized Study Comparing Vadadustat with Darbepoetin Alfa for Anemia in Japanese Patients with Nondialysis-Dependent CKD

Abstract

BackgroundStandard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo.MethodsIn this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs.ResultsA total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0–13.0 g/dl), and the lower 95% confidence limit for the difference between groups (−0.50 g/dl) was above the predefined noninferiority margin (−0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation.ConclusionsIn Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.

Efficacy and Safety of Vadadustat for Anemia in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis

“…Of these, 23 were excluded, most often because the records found in the international trial register were regarded as duplicate records of available published papers ( n = 11) or the study had an ineligible design ( n = 4). Finally, 7 articles that included 10 RCTs were selected for analysis ( Pergola et al, 2016 ; Martin et al, 2017 ; Nangaku et al, 2020 ; Chertow et al, 2021 ; Eckardt et al, 2021 ; Nangaku et al, 2021a ; Nangaku et al, 2021b ) ( Figure 1 ).…”

“…A total of 8,438 participants diagnosed with CKD-related anemia were enrolled. Of the 10 trials, 6 investigated the effect and safety of vadadustat versus placebo/ESA (darbepoetin alfa) for the treatment of anemia in NDD-CKD subjects ( Pergola et al, 2016 ; Martin et al, 2017 ; Nangaku et al, 2020 ; Chertow et al, 2021 ; Nangaku et al, 2021a ). Another 4 trials investigated the effect and safety of vadadustat versus placebo/ESA (darbepoetin alfa) for the treatment of anemia in DD-CKD subjects ( Nangaku et al, 2020 ; Eckardt et al, 2021 ; Nangaku et al, 2021b ).…”

“…All trials inadequately reported randomization, allocation concealment and blinding of outcome assessment, which was regarded as having a low risk of bias. Five trials in 3 studies had an unclear risk of bias related to participant and personnel blinding because an open-label design carries an inherent bias that might affect AE reporting ( Chertow et al, 2021 ; Eckardt et al, 2021 ; Nangaku et al, 2021a ). In terms of incomplete outcome data, 3 trials had a high risk of bias because missing data were not balanced between the intervention group and the control group and missing outcomes differed ( Pergola et al, 2016 ; Nangaku et al, 2021a ; Nangaku et al, 2021b ).…”

“…Five trials in 3 studies had an unclear risk of bias related to participant and personnel blinding because an open-label design carries an inherent bias that might affect AE reporting ( Chertow et al, 2021 ; Eckardt et al, 2021 ; Nangaku et al, 2021a ). In terms of incomplete outcome data, 3 trials had a high risk of bias because missing data were not balanced between the intervention group and the control group and missing outcomes differed ( Pergola et al, 2016 ; Nangaku et al, 2021a ; Nangaku et al, 2021b ). Nine trials had a low risk of bias in selective reporting, and only one have a high risk of bias ( Pergola et al, 2016 ).…”

“…Previous phase 2 trials have shown that vadadustat significantly elevates and maintains Hb concentrations compared with placebo in nondialysis-dependent CKD (NDD-CKD) patients ( Pergola et al, 2016 ; Martin et al, 2017 ). Recently, multicenter randomized controlled trials (RCTs) on vadadustat versus placebo or an ESA in both dialysis-dependent (DD-CKD) and NDD-CKD patients have been completed ( Nangaku et al, 2020 ; Nangaku et al, 2021a ; Nangaku et al, 2021b ; Chertow et al, 2021 ; Eckardt et al, 2021 ), but no rigorous systematic synthesis of all relevant data is available to date. To provide more evidence for vadadustat in the treatment of anemia in CKD, we incorporated phase 2 and 3 RCTs comparing vadadustat with placebo or ESAs and performed a systematic review to comprehensively evaluate the efficacy and safety of vadadustat for anemia in CKD patients compared with placebo or ESAs.…”