Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial

Abstract

Background: Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD.

Methods: To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations.

Results: Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms.

Conclusions: LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.

Keywords: clinical trial; fibroblast growth factor; kidney disease; mineral metabolism; phosphate; pilot study.

Copyright © 2019 by the American Society of Nephrology.

Figures

Figure 1.

CONsolidated Standards of Reporting Trials diagram depicting consent, randomization, and dropout in the COMBINE trial. CK, creatine kinase.

Figure 2.

Changes in serum phosphate and FGF23 over 12 months in response to nicotinamide and lanthanum carbonate in nondialysis CKD. (A) Changes in serum phosphate by treatment arm in the COMBINE trial are presented as means with error bars reflecting ±1 SD. (B) Changes in intact FGF23 (B) by treatment arm are presented as medians; error bars depict interquartile ranges. N-L, nicotinamide active/lanthanum carbonate active; N-p, nicotinamide active/lanthanum carbonate placebo; p-L, nicotinamide placebo/lanthanum carbonate active; p-p, nicotinamide placebo/lanthanum carbonate placebo.

Figure 3.

Change in 24-hour urine phosphate-to-creatinine ratio over 12 months in response to nicotinamide and lanthanum carbonate in nondialysis CKD. Changes in 24-hour urine phosphate-to-creatinine ratio in milligrams per gram by treatment arm in the COMBINE trial, presented as means with error bars reflecting ±1 SD. N-L, nicotinamide active/lanthanum carbonate active; N-p, nicotinamide active/lanthanum carbonate placebo; p-L, nicotinamide placebo/lanthanum carbonate active; p-p, nicotinamide placebo/lanthanum carbonate placebo.