Efficacy and Safety of a Novel Nicotinamide Modified-Release Formulation in the Treatment of Refractory Hyperphosphatemia in Patients Receiving Hemodialysis—A Randomized Clinical Trial

Abstract

Introduction Despite widespread use of phosphate binders (PBs), phosphate control is insufficient in many hemodialysis patients. Preliminary clinical observations suggest that nicotinamide may act synergistically with PBs to improve phosphate control. Methods This multinational, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of nicotinamide modified release (NAMR) in combination with oral PB in a large cohort of hemodialysis patients with abnormal serum phosphate concentration (>4.5 mg/dl) despite treatment with PB. Patients entered a proof-of-efficacy phase (12 weeks [W12]) in which adjustments of relevant comedication were not permitted, followed by a safety extension phase for up to 52 weeks. Here, we report the results of the first phase. Results The intention-to-treat (ITT) population consisted of 539 patients in the NAMR and 183 patients in the placebo group. NAMR and placebo were orally administered once daily (250–1500 mg/d). Mean age of patients was 61.8 years, and 63.0% were men. In the confirmatory analysis that estimated the difference in serum phosphate concentration after 12 weeks, NAMR proved superior over placebo with a significant difference of –0.51 mg/dl (95% confidence interval [CI] –0.72, –0.29; P < 0.0001). This effect was associated with significantly lower intact parathyroid hormone (iPTH) values (NAMR: 292.4±300.4 pg/ml vs. placebo: 337.0±302.7 pg/ml; P = 0.04) and an improved calcification propensity (T50 time; NAMR: 23.8±97.1 minutes vs. placebo: 2.3±100.7 minutes; P = 0.02). Diarrhea and pruritus were more frequent in the NAMR group. Conclusion NAMR combined with oral PB significantly improved phosphate control in hemodialysis patients.

Effects of pharmacological inhibition of the sodium‐dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models

“…1,25‐dihydroxyvitamin D, which has been shown to upregulate intestinal NPT2b in preclinical models, 24,25,50 also increases phosphate absorption 11,51 and transporter‐mediated phosphate absorption 16 in ESRD patients, suggesting a role for NPT2b in human phosphate absorption. Nicotinamide therapy reduces hyperphosphatemia in patients on dialysis 52 . Preclinical studies indicate the effect of nicotinamides is through decreased NPT2b mediated transport, 20,53 providing additional evidence for an appreciable role of NPT2b in human phosphate absorption.…”

“…Nicotinamide therapy reduces hyperphosphatemia in patients on dialysis. 52 Preclinical studies indicate the effect of nicotinamides is through decreased NPT2b mediated transport, 20 , 53 providing additional evidence for an appreciable role of NPT2b in human phosphate absorption. Two NPT2b inhibitors that were reported to decrease phosphate absorption in preclinical models recently advanced to the clinic.…”

NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease

“…However, the study that did not observe a decrease in serum phosphate levels, the COMBINE trial (NCT02258074), had a dropout rate of 25% in the NAM group due to pill burden and gastrointestinal symptoms [191]. In the NICOREN (NCT01011699) and NOPHOS trials, the majority of reported adverse events are also gastrointestinal upset, as well as thrombocytopenia, anemia and pruritus [193,194]. However, a meta-analysis of the efficacy and safety of NAM on phosphate metabolism in hemodialysis patients revealed that thrombocytopenia was the only significant adverse effect caused by NAM [195].…”

Nicotinamide and acute kidney injury

“…The dose-limiting adverse effect of niacin is skin flushing, caused by an increase in the vasodilator prostacyclin. Additional adverse effects of niacin and NAM include pruritus, skin rash, gastrointestinal disturbances and thrombocytopaenia [ 18 , 19 ]. Liver cell damage has been observed at intakes of niacin as little as 750 mg/day [ 20 ].…”

“…Vitamin B3 vitamers have been tested in clinical trials for the treatment of hyperphosphataemia in CKD ( Figure 3B and Table 1 ). In CKD, niacin [ 26 ] or NAM [ 18 , 19 , 30 ], either alone or in combination with other phosphate binders, reduced serum phosphate levels in most trials through inhibition of the expression of the intestinal phosphate transporter NaPi2b by poorly characterized mechanisms. The main metabolite of NAM, N-methyl-2-pyridone-5-carboxamide, may accumulate in haemodialysis patients [ 19 ].…”