TY - JOUR
T1 - Effects of nicotinamide and lanthanum carbonate on serum phosphate and fibroblast growth factor-23 in CKD
T2 - The COMBINE trial
AU - Ix, Joachim H.
AU - Isakova, Tamara
AU - Larive, Brett
AU - Raphael, Kalani L.
AU - Raj, Dominic S.
AU - Cheung, Alfred K.
AU - Sprague, Stuart M.
AU - Fried, Linda F.
AU - Gassman, Jennifer J.
AU - Middleton, John P.
AU - Flessner, Michael F.
AU - Block, Geoffrey A.
AU - Wolf, Myles
N1 - Funding Information:
Nicotinamide and placebo were donated by Endurance Products Company, Tigard, Oregon; and lanthanum carbonate and placebo were donated by Shire Pharmaceuticals, Wayne, Pennsylvania. The investigators wish to thank the study participants and many individuals who made the trial possible, including National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Flessner, J.W. Kusek, K.C. Abbott, P.L. Kimmel, S. Mendley, Fried (Steering Committee Chair); Data Coordinating Center (Cleveland Clinic): Gassman, G.J. Beck, K. Brittain, S. Sherer, B. Hu, C. Kendrick, A. Larive, K. Wiggins, J. MacKrell, V. Konig; Laboratory Medicine Research Testing Services (FGF23), University of Washington: A. Hoofnagle, K. Van Leuven, D. Landicho, H. Pflaum, J. Wallace, T. Nguyen; George Washington University: Raj, S. Sharma, A. Ramezani, M. Wing, C. Franco, A. Dumadag, S. Andrews; Northwestern University School of Medicine: Isakova, R. Mehta, M. Bradley, G. Schwartz, C. Martinez, P. Fox, A. Stump, A. Hodakowski, D. Lipiszko; NorthShore University Health System: Sprague, S. Fettman, J. Rubens, S. Rao, S. Lewis; Veterans Medical Research Foundation: Ix, D. Rifkin, U. Selamet, C. Ginsberg, E. Castro, B. Thomas, C. Fernandes, L. Frank, A. Chostner, D. Walpole; Denver Nephrology Research: Block, L. Kooienga, M. Baltazar, M. Persky, B. Shamblin, M. Chonchol, MSedlacek, R. Hoehler, B. Farmer; University of Utah: Cheung, C. Orme, Raphael, A. Balch, T. Greene, J. Zitterkoph, M. Varner, S. Neagle, H. Buswell; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah: Cheung, C. Orme, Raphael, A. Balch, T. Greene, J. Zitterkoph, M. Varner, S. Neagle, H. Buswel l; Duke University: Wolf, Middl eton, and Data Safety and Moni tory Board members D. Warnock, J. Bonventre, D. Coyne, L. Dworkin, R. Glassock, J. Hodges, A. Thompson, M. Leonard, M. Pahl, A.K. Singh, JR Landis, D. Bluemke. Designed the study: Dr. Ix, Dr. Isakova, Dr. Gassman, Dr. Flessner, Dr. Block, and Dr. Wolf. Conducted the experiment: Dr. Ix, Dr. Isakova, Dr. Raphael, Dr. Raj, Dr. Cheung, Dr. Sprague, Dr. Block, and Dr. Wolf. Data analysis: Dr. Larive, Dr. Gassman, and Dr. Middleton. Interpreted study findings: Dr. Ix, Dr. Isakova, Dr. Larive, Dr. Raphael, Dr. Raj, Dr. Cheung, Dr. Sprague, Dr. Fried, Dr. Gassman, Dr. Middleton, Dr. Flessner, Dr. Block, and Dr. Wolf. Drafted first and subsequent versions of the manuscript: Dr. Ix. Critically revised the manuscript: Dr. Ix, Dr. Isakova, Dr. Larive, Dr. Raphael, Dr. Raj, Dr. Cheung, Dr. Sprague, Dr. Fried, Dr. Gassman, Dr. Middleton, Dr. Flessner, Dr. Block, and Dr. Wolf. Secured funding: Dr. Ix, Dr. Isakova, Dr. Raphael, Dr. Raj, Dr. Cheung, Dr. Gassman, Dr. Block, and Dr. Wolf. This trial was sponsored by the NIDDK Pilot Clinical Trials consortium (contracts U01DK097093, U01DK099877, U01DK099924, U01DK099930, and U01DK099933) with additional support from an ancillary study grant to Isakova (R01DK102438).
Funding Information:
This trial was sponsored by the NIDDK Pilot Clinical Trials consortium (contracts U01DK097093, U01DK099877, U01DK099924, U01DK099930, and U01DK099933) with additional support from an ancillary study grant to Isakova (R01DK102438).
Funding Information:
Dr. Ix reports grants from NIDDK during the conduct of the study and grants from Baxter International outside the submitted work. Dr. Isakova reports other from Shire, personal fees from Bayer, personal fees from Eli Lilly, outside the submitted work. Dr. Raphael reports grants from NIH, during the conduct of the study. Dr. Cheung reports grants from NIDDK, during the conduct of the study. Dr. Sprague reports grants from NIH, during the conduct of the study; grants and personal fees from Vifor, grants and personal fees from Opko, grants and personal fees from Amgen, grants from Reata, outside the submitted work. Dr. Fried reports other from NIDDK, during the conduct of the study. Dr. Gassman reports grants from NIH/NIDDK, during the conduct of the study. Dr. Block reports personal fees, nonfinancial support and other from Ardelyx, Inc., grants, personal fees and non-financial support from Keryx, Inc., outside the submitted work. Dr. Wolf reports personal fees from Keryx, during the conduct of the study; personal fees from Amgen, personal fees from Diasorin, personal fees from Akebia, personal fees from AMAG, personal fees from Ardelyx, personal fees from Lutipold, personal fees from SANOFI, grants from SHIRE, outside the submitted work.
Publisher Copyright:
Copyright © 2019 by the American Society of Nephrology.
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85066968906&partnerID=8YFLogxK
U2 - 10.1681/ASN.2018101058
DO - 10.1681/ASN.2018101058
M3 - Article
C2 - 31085679
AN - SCOPUS:85066968906
VL - 30
SP - 1096
EP - 1108
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 6
ER -