Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD

Abstract

Background and objectives: Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis.

Design, setting, participants, & measurements: One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-unit study (designated the TRCA-101 Study). Patients had a mean baseline eGFR of 35 ml/min per 1.73 m², a mean baseline serum bicarbonate of 17.7 mEq/L, and comorbidities, including hypertension (93%), diabetes (70%), and heart failure (21%). Patients ate a controlled diet and were treated for 14 days with placebo or one of four TRC101 dosing regimens (1.5, 3, or 4.5 g twice daily or 6 g once daily). After treatment, patients were discharged and followed for 7-14 days.

Results: All TRC101 treatment groups had a mean within-group increase in serum bicarbonate of ≥1.3 mEq/L (P<0.001) within 72 hours of the first dose and a mean increase in serum bicarbonate of 3.2-3.9 mEq/L (P<0.001) at the end of treatment compared with placebo, in which serum bicarbonate did not change. In the combined TRC101 treatment group, serum bicarbonate was normalized (22-29 mEq/L) at the end of treatment in 35% of patients and increased by ≥4 mEq/L in 39% of patients. After discontinuation of TRC101, serum bicarbonate decreased nearly to baseline levels within 2 weeks. All adverse events were mild or moderate, with gastrointestinal events most common. All patients completed the study.

Conclusions: TRC101 safely and significantly increased the level of serum bicarbonate in patients with metabolic acidosis and CKD.

Keywords: Diabetes Mellitus; Double-Blind Method; Heart Failure; Hydrochloric Acid; Renal Insufficiency, Chronic; acidosis; bicarbonates; chronic kidney disease; comorbidity; diet; humans; hypertension; kidney; metabolic acidosis, chronic; sodium.

Figure 1.

Study design schematic. Overall study design for the TRCA-101 Study, including screening, treatment, and follow-up. The first 60 patients had follow-up from day 15 to day 21, whereas patients 60–101 had follow-up from day 15 to day 28. CRU, clinical research unit; n, number of patients in each treatment group; R, randomization.

Figure 2.

Disposition of study participants. Consort diagram of patient flow through the TRCA-101 Study detailing profile and disposition of study participants during screening, randomization, and participation in the trial. Of 154 patients screened, 135 were enrolled and randomized, with screen failure due to bicarbonate or eGFR eligibility accounting for most enrollment exclusions. All 135 randomized study participants completed treatment and follow-up, and their data were analyzed for efficacy and safety of TRC101. N, number of patients screened or number of patients in each treatment group.

Figure 3.

TRC101 significantly increased mean serum bicarbonate (SBC) throughout the 2-week treatment period, with serum bicarbonate returning to baseline after treatment discontinuation. Mean SBC response with treatment over the 14-day intervention period (days 1–14) and during the 7- to 14-day off-treatment follow-up period (days 15–28) by dose group. Treatment with TRC101 caused a steady increase in mean SBC in all TRC101 dose groups during the on-treatment period. During the off-treatment period, a decrease in SBC from the end of treatment value was observed in all TRC101 dose groups, with SBC levels returning nearly to the baseline (BL) values. N, number of patients in each treatment group; SE, SEM.

Figure 4.

Serum bicarbonate increased by ≥3, ≥4, and ≥5 mEq/L in 52%, 39%, and 22% of patients, respectively, in the combined TRC101 dose group compared with 6%, 3% and 0% of placebo-treated patients, respectively. Category of change from baseline in serum bicarbonate at day 15. Percentages of patients (y axis), including the percentages of patients (above bars) in the respective treatment groups, achieving defined increases of serum bicarbonate from baseline (x axis) corresponding to <2, ≥2, ≥3, ≥4, ≥5, ≥6, and ≥7 mEq/L are shown. The percentage of patients in the respective treatment groups achieving a defined increase of serum bicarbonate from baseline was calculated on the basis of the number of patients who reached the given value divided by the total number of patients in the treatment group (summarized in Figures 1 and 2). The numbers of patients in each treatment group attaining the given change from baseline in serum bicarbonate were <2 mEq/L (pooled placebo =27, TRC101 1.5 g twice daily =7, TRC101 6 g once daily =5, TRC101 3 g twice daily =11, TRC101 4.5 g twice daily =7), ≥2 mEq/L (pooled placebo =4, TRC101 1.5 g twice daily =18, TRC101 6 g once daily =23, TRC101 3 g twice daily =14, TRC101 4.5 g twice daily =19), ≥3 mEq/L (pooled placebo =2, TRC101 1.5 g twice daily =14, TRC101 6 g once daily =14, TRC101 3 g twice daily =10, TRC101 4.5 g twice daily =16), ≥4 mEq/L (pooled placebo =1, TRC101 1.5 g twice daily =8, TRC101 6 g once daily =12, TRC101 3 g twice daily =10, TRC101 4.5 g twice daily =11), ≥5 mEq/L (pooled placebo =0, TRC101 1.5 g twice daily =3, TRC101 6 g once daily =6, TRC101 3 g twice daily =6, TRC101 4.5 g twice daily =8), ≥6 mEq/L (pooled placebo =0, TRC101 1.5 g twice daily =3, TRC101 6 g once daily =5, TRC101 3 g twice daily =3, TRC101 4.5 g twice daily =4), and ≥7 mEq/L (pooled placebo =0, TRC101 1.5 g twice daily =1, TRC101 6 g once daily =1, TRC101 3 g twice daily =2, TRC101 4.5 g twice daily =2).