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Clinical Trial
. 2023 Mar 31;38(4):982-991.
doi: 10.1093/ndt/gfac206.

Modified-release nicotinamide for the treatment of hyperphosphataemia in haemodialysis patients: 52-week efficacy and safety results of the phase 3 randomized controlled NOPHOS trial

Markus Ketteler  1   2 , Andrzej Wiecek  3 , Alexander R Rosenkranz  4 , Claudia Ose  5   6 , Jan Rekowski  5   6 , Horst Lorenz  7 , Burkhard Hellmann  8 , Michael Karus  8 , Michaela Ruhmann  8 , Richard Ammer  8   9
Affiliations
Clinical Trial

Modified-release nicotinamide for the treatment of hyperphosphataemia in haemodialysis patients: 52-week efficacy and safety results of the phase 3 randomized controlled NOPHOS trial

Markus Ketteler et al. Nephrol Dial Transplant. .

Abstract

Background: We previously reported that modified-release nicotinamide (NAMR) was superior to placebo in reducing serum phosphate concentrations over 12 weeks in a large cohort of haemodialysis patients with hyperphosphataemia. Here we report outcomes after 52 weeks of treatment.

Methods: NOPHOS was a phase 3, international, randomized, controlled, double-blind trial with a parallel group design. NAMR (250-1500 mg/day) was investigated in comparison to placebo as an add-on therapy to an individual therapy with approved phosphate binders.

Results: In the intention-to-treat population (NAMR: n = 539; placebo: n = 183), serum phosphate was significantly lower in the NAMR group compared with the placebo group at week 24 (5.40 ± 1.55 versus 5.79 ± 1.37 mg/dl, P < .001) with a mean difference of -0.39 mg/dl [95% confidence interval (CI) -0.66 to -0.13], but was comparable between the groups at week 52 [mean difference -0.08 (95% CI -0.36-0.20)]. In the completer population (n = 358), statistical significance in favour of NAMR was reached at weeks 24 and 52. The treatment effect was reduced in patients with high baseline serum intact parathyroid hormone (iPTH) compared with patients with low baseline serum iPTH. Compliant patients in the NAMR group had a more pronounced and sustained reduction in serum phosphate than non-compliant patients. NAMR treatment was associated with a significantly increased risk of thrombocytopenia, pruritus, anaemia, and diarrhoea. Herpes zoster occurred exclusively in patients randomized to NAMR.

Conclusions: NAMR combined with phosphate binders significantly reduced serum phosphate over the first 24 weeks of treatment, but the treatment effect was not maintained up to week 52. Non-compliance may have contributed to reduced long-term efficacy. Several newly identified safety signals warrant further evaluation.

Keywords: haemodialysis; hyperphosphataemia; mineral and bone disease; nicotinamide; randomized controlled trial.

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Conflict of interest statement

M.Ke. has received lecture and consulting honoraria from Amgen, FMC, MEDICE, Sanofi, Vifor Fresenius Medical Care Renal Pharma and Vifor Pharma. A.W. has received honoraria for lectures from Fresenius, Bayer AG and MEDICE and for participation in Scientific Advisory Boards from GlaxoSmithKline. C.O. reports grants from MEDICE. A.R.R., J.R. and H.L. have no conflicts of interests to declare. B.H., M.Ka. and M.R. are employees of MEDICE Arzneimittel Pütter GmbH & Co. KG. R.A. is chief executive officer and owner of MEDICE Arzneimittel Pütter GmbH & Co. KG. The 52-week efficacy and safety results presented in this paper have not been published previously in whole or part. We previously reported the 12-week results from this trial in Ketteler M, Wiecek A, Rosenkranz A et al. Efficacy and safety of a novel nicotinamide modified-release formulation in the treatment of refractory hyperphosphatemia in patients receiving hemodialysis-a randomized clinical trial. Kidney Int Rep 2021; 6: 594–604.

Figures

Graphical Abstract
Graphical Abstract
FIGURE 1:
FIGURE 1:
Time course of serum phosphate based on a longitudinal analysis using a linear mixed model with maximum likelihood (ML) estimator (ITT population). ML estimators and raw mean values for serum phosphate concentration are shown.
FIGURE 2:
FIGURE 2:
Time course of serum phosphate in patients with low and high baseline serum iPTH concentrations (ITT population). Maximum likelihood (ML) estimators and raw mean values for serum phosphate concentration are shown for patients with baseline iPTH concentrations (A) <248 pg/ml and (B) ≥248 pg/ml.
FIGURE 3:
FIGURE 3:
Time course of serum phosphate in compliant and non-compliant patients (completer population). (A) Mean serum phosphate concentration in the NAMR and placebo groups [data given as mean ± standard error of the mean (SEM); *P < .05, ***P < .001]. (B) Mean serum 2PY and NNO concentrations in compliant and non-compliant patients based on week-52 data (data given as mean ± SEM). (C) Mean serum phosphate concentration stratified according to compliance at week 52. Scr., screening.
See this image and copyright information in PMC

References

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