Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD

Abstract

Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0-5.0 mg/dl for men and 1.5-5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.

Keywords: CKD; GFR; creatinine; randomized controlled trials.

Copyright © 2015 by the American Society of Nephrology.

Figures

Figure 1.

Structural features of AST-120 and activated charcoal (United States Pharmacopeia). High-resolution transmission electron microscopy studies demonstrate that AST-120 differs structurally from activated charcoal (United States Pharmacopeia). AST-120, spherical carbon adsorbent, presents as black, odorless, spherical particles approximately 0.2–0.4 mm in diameter. Composed mainly of carbon (approximately 96%), AST-120 exhibits adsorption ability similar or superior to that of activated charcoal for certain acidic and basic organic compounds known to be increased in renal failure; however, AST-120 has lower adsorption ability than activated charcoal for digestive enzymes.

Figure 2.

Patient disposition. The ITT population includes all randomly assigned patients who received ≥1 doses of study drug and had ≥1 postbaseline measurements of sCr.

Figure 3.

Primary efficacy end point (triple composite end point). (A) EPPIC-1 and EPPIC-2 trials. (B) Pooled analysis of both trials. Kaplan–Meier analysis and eGFR relative change from baseline analyzed using a mixed-effect model for repeated measures and analysis of covariance in the ITT population.

Figure 4.

Subgroup analysis by Cox proportional hazards regression in the ITT population. (A) EPPIC-1 and EPPIC-2 trials. (B) Pooled analysis of both trials. Men with hemoglobin levels3.0 mg/dl], and CKD cause [diabetic or nondiabetic nephropathy] status as covariates.) Patients not reaching the primary end point are censored at the time of their last contact. N, number of patients in the respective population; n, number of patients who had an event; N/A, not applicable.

Figure 5.

CKD progression. (A) Evaluation of eGFR decline distribution based on baseline eGFR (pooled placebo ITT population). (B) Event rate based on eGFR decline (pooled placebo ITT population). The cumulative probability of remaining free of renal disease progression (as defined by the primary end point) is estimated and plotted graphically with the Kaplan–Meier method for two groups (eGFR slow decline and eGFR fast decline, respectively) divided in the pooled placebo group. Stratified Cox proportional hazards regression is used to compare time to onset of renal disease progression between the slow and fast decline placebo groups. DN, diabetic nephropathy.

Figure 6.

Effect of UP/UCr and hematuria status on renal disease progression. (A) Event rate based on baseline UP/UCr level or hematuria status (pooled placebo ITT population). (B) Mean eGFR decline based on baseline UP/UCr level or hematuria status (pooled placebo ITT population). (C) Event rate based on combined baseline UP/UCr level and hematuria status (pooled placebo ITT population). K-M, Kaplan–Meier.