Risk factors for progression of chronic kidney disease in the EPPIC trials and the effect of AST-120

Abstract

Background: Two randomized, double-blind, placebo-controlled trials (EPPIC-1 and EPPIC-2) investigated the efficacy and safety of AST-120, an oral spherical carbon adsorbent, in adults with chronic kidney disease (CKD). While the benefit of adding AST-120 to standard therapy was not supported by these trials, we performed a post hoc analysis to focus on CKD progression and to determine the risk factors for the primary endpoint in the EPPIC trial population.

Methods: In the EPPIC trials, patients were randomly assigned 1:1 to treatment with AST-120 or placebo. The primary endpoint was a composite of dialysis initiation, kidney transplantation, or doubling of serum creatinine. The EPPIC trial pooled population was evaluated with the same statistical methods used for analysis of the primary and secondary efficacy endpoints. The trials were registered on ClinicalTrials.gov (NCT00500682 [EPPIC-1] and NCT00501046 [EPPIC-2]).

Results: An analysis of the placebo population suggested baseline urinary protein to urinary creatinine ratio (UP/UCr) ≥1.0 and hematuria were independent risk factors for event occurrence and eGFR lowering. Analysis of the high risk patients revealed a difference in the primary endpoint occurrence between treatment groups, if angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers were administered (hazard ratio 0.74, 95% confidence interval 0.56-0.96). Also, the eGFR changes from baseline in the AST-120 group were smaller than that in the placebo group (P = 0.035).

Conclusions: CKD progression may have an association with baseline UP/UCr and hematuria. Treatment with AST-120 may delay the time to the primary endpoint in patients with progressive CKD receiving standard therapy, thus warranting further investigation.

Keywords: AST-120; CKD; CKD progression; Clinical trial; Spherical carbon adsorbent; Uremic toxins.

Conflict of interest statement

Conflict of interest

The EPPIC trials were sponsored by Mitsubishi Tanabe Pharma Corporation and Kureha Corporation. Gerald Schulman, Tomas Berl, Gerald Beck, Giuseppe Remuzzi and Eberhard Ritz report having received consulting fees from Kureha Corporation and Mitsubishi Tanabe Pharma Corporation as a steering committee member for EPPIC-1 and -2. Tomas Berl reports having received consultancy fees from Sanofi, fees for expert testimony from AstraZeneca, and payment for lectures including service on speakers’ bureaus from Otsuka. Giuseppe Remuzzi reports his institution has received payment for consultancy work from Alexion Pharmaceuticals, AstraZeneca, Pharmanet, and Reata Pharmaceuticals. Eberhard Ritz reports receiving payment for lectures including service on speakers’ bureaus from AbbVie, Amgen, Daiichi Sankyo, and Medice. Miho Shimizu reports employment with Mitsubishi Tanabe Pharma Corporation. Mami Kikuchi and Yuko Shobu report employment with Kureha Corporation.

Research involving human participants

The EPPIC trials were conducted in accordance with the tenets of the Declaration of Helsinki (2004) and with applicable legal and regulatory requirements, and their design was approved by the appropriate institutional review boards for 239 sites (e.g. IRB#: 07-3493-0 and 07-3495-0). The trials were registered on ClinicalTrials.gov (NCT00500682 [EPPIC-1] and NCT00501046 [EPPIC-2]).

Informed consent

All patients provided written informed consent before participation.

Figures

Fig. 1

Distribution of baseline eGFR and eGFR change populations (pooled placebo ITT population). a Percentage of patients in terms of baseline eGFR, b event rates and baseline eGFR, c percentage of patients in terms of % change from baseline in eGFR, d event rates and % change from baseline in eGFR. eGFR estimated glomerular filtration rate, ESRD end stage renal disease

Fig. 2

Effect of AST-120 on endpoint achievement. N number of patients in the respective population, n number of patients who had primary endpoint achievement, ACEI/ARB angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, CI confidence interval, HR hazard ratio, UP/UCr urinary protein to urinary creatinine ratio. Patients without UP/UCr or hematuria data were excluded from the subgroup analysis

Fig. 3

Kaplan–Meier analysis (a) and eGFR relative change from baseline (b) (UP/UCr ≥1.0, hematuria positive and baseline ACEI/ARB use). a Stratified Cox analysis, stratified factors: region, DN/non-DN, baseline sCr (3 mg/dL above or below). N number of patients in the respective population, HR hazard ratio. b Mixed-effects model was applied (ANCOVA). ACEI/ARB angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, eGFR estimated glomerular filtration rate, UP/UCr urinary protein to urinary creatinine ratio