Abstract
Background and Aims
Despite the introduction of several new phosphate binders over the last decades, adequate control of hyperphosphatemia in haemodialysis (HD) patients still remains a crucial challenge as more than half of the population still remains hyperphosphataemic in daily practice. A growing amount of clinical data suggests that nicotinamide (NA) represents a complementary and effective treatment option for hyperphosphataemia. Efficacy and safety of once daily intake of modified release (MR) NA were investigated for fixed doses between 250 and 1,000 mg in hyperphosphatemic HD patients. Additionally, the MR formulation was compared to trice daily intake of an immediate release (IR) formulation of NA.
Method
This multicenter, controlled trial included HD patients with serum phosphate concentrations between 4.7 and 7.5 mg/dL after initial discontinuation of phosphate binder treatment. Patients were randomized to either once daily intake of 250 mg (N=48), 500 mg (N=50), 750 mg (N=50) or 1,000 mg of MR NA (N=53) in a double-blind setting, or intake of 1,000 mg of IR NA (N=51), divided over three daily doses in an open-label setting over a treatment period of 8 weeks.
Results
Based on the ITT population the study revealed a highly significant (p<0.001) dose-response relationship between dose of MR NA and serum phosphate concentrations in week 4 (primary endpoint). At this time point, significant reductions of serum phosphate concentrations were observed only for the 750 and 1,000 mg dose groups. Between week 5 and 8, all dose groups revealed significant reductions of serum phosphate. The different formulations exhibited a comparable phosphate lowering capacity (mean change from baseline until week 4: MR -1.07 mg/dL, IR -1.12 mg/dL; p=0.8163).
The most frequently reported adverse events were gastrointestinal symptoms in 31.4% of patients and skin reactions in 19.8% of patients. The study also revealed a nonsignificant decrease in mean platelet count. Overall, the number of adverse events increased in the 750 and both 1,000 mg dosage groups. For individual adverse events, dose dependency was observed for diarrhea, headache, vomiting and nausea.
NA treatment resulted in a dose dependent increase of plasma concentrations of NA and its terminal metabolites (N-methyl-2-pyridone-5-carboxamide, N-methyl-4-pyridone-5-carboxamide, Nicotinamide-N-oxide).
The tolerability profile as well as the plasma concentrations of NA metabolites were similar for both formulations although the proportion of patients that terminated treatment due to adverse events was higher in the IR arm compared to the MR formulation (33.5% versus 26.4% of patients). However, this study was not powered to reliably assess clinical superiority with regard to AE.
Conclusion
Our study characterised the NA modified release preparation NoPhos as an effective novel therapeutic option for the treatment of hyperphosphatemia in HD patients. In the monotherapy setting a clear dose-response relationship was revealed for daily doses between 250 and 1,000 mg, while best tolerability was observed at a dose of 500 mg/d.
P1386EFFICACY AND SAFETY OF MODIFIED RELEASE NICOTINAMIDE IN THE TREATMENT OF HYPERPHOSPHATEMIA IN HEMODIALYSIS PATIENTS