Efficacy and safety of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease
Treatment for hyperphosphatemia in chronic kidney disease (CKD) involves dietary control of phosphorus intake, dialysis, and treatment with oral phosphate binders, none of which were approved by the Federal Food and Drug Administration in pediatric patients at the time of this study.
This was a phase 2, multicenter study (NCT01574326) with a 2-week, randomized, placebo-controlled, fixed-dose period (FDP) followed by a 6-month, single-arm, open-label, dose-titration period (DTP), with the aim to evaluate the safety and efficacy of sevelamer carbonate (SC) in hyperphosphatemic pediatric patients with CKD. Following a 2–4 week screening phase, pediatric patients with a serum phosphorus level higher than age-appropriate levels were randomized to receive either SC or placebo as powder/tablets in 0.4–1.6 g doses, based on body surface area. The primary efficacy outcome was the change in serum phosphorus from baseline to end of the FDP in the SC versus placebo arms (analysis of covariance). The secondary outcome was mean change in serum phosphorus from baseline to end of DTP by treatment group and overall. Treatment-emergent/serious adverse events (AEs) were recorded.
Of 101 enrolled patients (29 centers), 66 completed the study. The majority of patients were adolescents (74%; mean age 14.1 years) and on dialysis (77%). Renal transplant was the main reason for discontinuation. SC significantly reduced serum phosphorus from baseline levels (7.16 mg/dL) during the FDP compared to placebo (least square mean difference − 0.90 mg/dL, p = 0.001) and during the DTP (− 1.18 mg/dL, p < 0.0001). The safety and tolerability of SC and placebo were similar during the FDP, with patients in both groups reporting mild/moderate gastrointestinal AEs during the DTP.
Sevelamer carbonate significantly lowered serum phosphorus levels in hyperphosphatemic children with CKD, with no serious safety concerns identified.
KeywordsChronic kidney disease Hyperphosphatemia Pediatric patients Sevelamer carbonate Phosphate binder
The authors acknowledge Mark Benfield MD, Pediatric Nephrology of Alabama, Phenix City, AL, for his contributions to the study, and Gill Sperrin, CBiol, MRSB, CMPP, and Priyanka Narang, PhD, of Envision Scientific Solutions, for editorial support in the preparation of this publication, sponsored by Sanofi. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication. This study was funded by Sanofi.
Interested researchers may request access to anonymized patient-level data and clinical study documents related to this publication at www.clinicalstudydatarequest.com.
Compliance with ethical standards
The first patient signed informed consent on 11 May 2012, and the last patient completed the last visit on 16 June 2015.
The trial was conducted in accordance with the International Conference on Harmonization/Good Clinical Practice guidelines. The protocol also complied with the laws and regulations of the countries where the study was conducted. The study received approval from local Institutional Review Boards/Independent Ethics Committees.
Conflict of interest
This study was funded by Sanofi. JF, SFS, DD and SJS have no conflict to declare. RJ receives research funding from Arbor Pharmaceuticals and is a scientific advisor for The Mike Program, Portland, OR. KWP receives research funding from Sanofi and Genentech. CW receives honoraria from UpToDate®. BA is currently employed by Sanofi. GFC was employed by Sanofi at the time of the study. He is currently employed by Editas Medicine. BAW is a consultant for Amgen, Baxter, Keryx, and Rockwell; receives research funding from Baxter and NIH; receives honoraria from Amgen, Rockwell, and UpToDate®, and is a board member of the North American Pediatric Renal Trials and Collaborative Studies, and the National Kidney Foundation.
- 1.Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31:607–617Google Scholar
- 5.Klaus G, Watson A, Edefonti A, Fischbach M, Ronnholm K, Schaefer F, Simkova E, Stefanidis CJ, Strazdins V, Vande Walle J, Schroder C, Zurowska A, Ekim M (2006) Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol 21:151–159CrossRefPubMedGoogle Scholar
- 11.Fan S, Ross C, Mitra S, Kalra P, Heaton J, Hunter J, Plone M, Pritchard N (2009) A randomized, crossover design study of sevelamer carbonate powder and sevelamer hydrochloride tablets in chronic kidney disease patients on haemodialysis. Nephrol Dial Transplant 24:3794–3799CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Ferreira A, Frazao JM, Monier-Faugere MC, Gil C, Galvao J, Oliveira C, Baldaia J, Rodrigues I, Santos C, Ribeiro S, Hoenger RM, Duggal A, Malluche HH (2008) Effects of sevelamer hydrochloride and calcium carbonate on renal osteodystrophy in hemodialysis patients. J Am Soc Nephrol 19:405–412CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Fishbane S, Delmez J, Suki WN, Hariachar SK, Heaton J, Chasan-Taber S, Plone MA, Moe S (2010) A randomized, parallel, open-label study to compare once-daily sevelamer carbonate powder dosing with thrice-daily sevelamer hydrochloride tablet dosing in CKD patients on hemodialysis. Am J Kidney Dis 55:307–315CrossRefPubMedGoogle Scholar
- 22.Moustafa M, Lehrner L, Al-Saghir F, Smith M, Goyal S, Dillon M, Hunter J, Holmes-Farley R (2014) A randomized, double-blind, placebo-controlled, dose-ranging study using Genz-644470 and sevelamer carbonate in hyperphosphatemic chronic kidney disease patients on hemodialysis. Int J Nephrol Renov Dis 7:141–152Google Scholar
- 29.Rees L, Azocar M, Borzych D, Watson AR, Buscher A, Edefonti A, Bilge I, Askenazi D, Leozappa G, Gonzales C, van Hoeck K, Secker D, Zurowska A, Ronnholm K, Bouts AH, Stewart H, Ariceta G, Ranchin B, Warady BA, Schaefer F (2011) Growth in very young children undergoing chronic peritoneal dialysis. J Am Soc Nephrol 22:2303–2312CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Fabio M (2013) Hyperphosphataemia: treatment options. Drugs:1–16Google Scholar
- 32.Sekercioglu N, Thabane L, Diaz Martinez JP, Nesrallah G, Longo CJ, Busse JW, Akhtar-Danesh N, Agarwal A, Al-Khalifah R, Iorio A, Guyatt GH (2016) Comparative effectiveness of phosphate binders in patients with chronic kidney disease: a systematic review and network meta-analysis. PLoS One 11:e0156891CrossRefPubMedPubMedCentralGoogle Scholar