FGF23 Reduction : Efficacy of a New Phosphate Binder in CHronic Kidney Disease

Chronic Renal Failure Clinical Trial

— FRENCH  

Official title:

Randomized Placebo Controlled Double-blind Trial in CKD Patients Not on Dialysis to Evaluate the Effect of Sevelamer Carbonate in the Control of FGF-23 Serum Levels and Its Consequences in the Evolution of PTH, Calcitriol and Mineral Metabolism Parameters Levels

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01220843
• Other study ID #: PI10-PR-CHOUKROUN-1
• Secondary ID: 2010-020872-49
• Status: Completed
• Phase: Phase 3
• First received: October 12, 2010
• Last updated: April 27, 2016
• Start date: October 2010
• Est. completion date: April 2013

Study information

• Verified date: April 2016
• Source: Centre Hospitalier Universitaire, Amiens
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate in Chronic Kidney Disease (CKD) patients not on dialysis and who have an Fibroblast growth factor 23 (FGF23) serum levels elevated, the effect of non calcic phosphate binder: sevelamer carbonate. This treatment could lead to a diminution of FGF23 serum levels due to the diminution of intestinal absorption of dietary phosphate. In addition, the investigators will describe the impact of the FGF23 level monitoring on the main phosphocalcium metabolism markers as phosphatemia, intact parathyroid hormone (iPTH), serum calcitriol and phosphaturia.

Description:

The total length of the study is 14 weeks divided in 2 parts the first part is the screening period she will stay 1 to 2 weeks and the second period with the treatment with permanent dosage during 12 weeks.

During the screening visit (Vo) inclusion and non inclusion criteria will be checked and the patient consent will be collected. Biological analysis will be performed.

If the patient still eligible after the reception of biological results, he will be randomized and will received, either sevelamer carbonate, either placebo. The study treatment will be begun at the randomisation visit (V1) the dosage will be 2 tablets 3 times per day (corresponding to 4.8g/d sevelamer carbonate for patient taken active medication).

Patient will be seen every 2 weeks after the first visit (+/-5days) during 6 weeks (visit2/day15, visit3/day30, visit4/day45) and 12 weeks after the randomisation visit (visit5/day90). This visits will include biological analysis, compliance evaluation, adverse events report, concomitant treatments reports.

After the consent signature, all the adverse events will be collected until the end of the study for the patient (Visit5 or end of the study visit). Serious adverse events will be collected until 30 days after the date of the end of the study.

The same dosage of the study treatment will be followed during all the study period except if the phosphatemia (evaluated during one analysis) is found above the normal range planned by the protocol. In this case, the dosage adaptations will be :

• If during a visit the phosphatemia is above or equal to 0.8 mmol/l and superior to 0.5 mmol/l, the study treatment dosage need to be reduce to 2 tablets 3 times per day to 1 tablet 3 times per day.

• If during the next blood punction, the phosphatemia still or equal to 0.8 mmol/l and superior to 0.5 mmol/l, the study treatment will be stopped and a "end of study" visit will be performed.

• If during one study visit, the phosphatemia is above or equal to 0.5 mmol/l,the study treatment will be stopped immediately and a end of study visit will be performed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: April 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients who gave their written consent

• Women or men over 18 years

• No concomitant treatment with phosphate binders

• CKD patients not on dialysis stage 3b or 4, as a GFR (glomerular filtration rate) between 15 and 45 ml/min/1.73m2, using simplified MDRD formula

• At the inclusion visit,patients with blood results as levels of C-terminal FGF-23 > 120 rU/ml and fasting phosphatemia > 1.0 mmol/l

• Able to comply with the study procedures during all the study period

• Willing to abstain from taking any following medication during all the study period :antiacid and phosphate binders with aluminium, magnesium, calcium or lanthanum;Treatment for hyperparathyroid : active vitamin D and calcimimetic ; native vitamin D

• Female subjects who are of childbearing potential must have a reliable contraceptive methods during all the study period (hormonal, barrier methods or intrauterine device)

• No Participation in any clinical trial using an investigational product or device during the 30 days preceding the first protocol visit

• Informed patient who agreed with the utilisation of his data for the study

• Able to read and understand french and study objectives

• Inscription to medical assurance

Exclusion Criteria:

• predisposition with or presence of intestinal or ileus obstruction or severe gastrointestinal motility disorder(like severe constipation)

• Antecedent of major gastrointestinal surgery

• Abusive consumption of alcohol and drug (exclude tabacco) according the investigator

• Arrythmia treated by antiarrythmic agent or epilepsia treated by anticonvulsant

• Antecedent of kidney transplantation

• Antecedent of parathyroidectomy

• At the inclusion visit,patients with blood results as fasting phosphatemia > 1.78 mmol/l or serum 25(OH)D3< 20 ng/ml (<50 nmol/)

• Pregnancy or breastfeeding

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Renal Failure
• Kidney Failure, Chronic
• Renal Insufficiency

Intervention

Drug:
• Placebo
dosage : 2 tablets 3 times per day corresponding taken during meals during 12 weeks
• Sevelamer carbonate
dosage : 2 tablets 3 times per day corresponding taken during meals during 12 weeks ( each tablet :800mg sevelamer carbonate

Locations

Country	Name	City	State
France	CHU Amiens service de nephrologie	Amiens
France	CHU de Bordeaux Service de néphrologie	Bordeaux
France	CHU Caen service de néphrologie	Caen
France	CHU Lyon service de néphrologie	Lyon
France	CHU Marseille Service de néphrologie	Marseille
France	CHU de Montpellier Hôpital Lapeyronie Service de Néphrologie	Montpellier
France	CHU de Nice Service de néphrologie	Nice
France	Hôpital Européen Georges Pompidou Service de Nephrologie	Paris
France	Hôpital Tenon Service de Nephrologie	Paris
France	CHU Reims service de néphrologie	Reims
France	Clinique du Landy Centre de dialyse	Saint Ouen
France	CHU St Etienne Hopital Nord Service de néphrologie	St Etienne
France	Néphrologie - Dialyse Centre de Rein Artificiel	TASSIN la Demi Lune
France	CH Valenciennes hémodialyse	Valenciennes
France	CHU de Nancy service de néphrologie	Vandeuvre les Nancy

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire, Amiens	Genzyme, a Sanofi Company

Country where clinical trial is conducted

France, 

References & Publications (21)

Danziger J. The bone-renal axis in early chronic kidney disease: an emerging paradigm. Nephrol Dial Transplant. 2008 Sep;23(9):2733-7. doi: 10.1093/ndt/gfn260. Epub 2008 May 9. — View Citation

Fliser D, Kollerits B, Neyer U, Ankerst DP, Lhotta K, Lingenhel A, Ritz E, Kronenberg F; MMKD Study Group, Kuen E, König P, Kraatz G, Mann JF, Müller GA, Köhler H, Riegler P. Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol. 2007 Sep;18(9):2600-8. Epub 2007 Jul 26. — View Citation

Gutiérrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Jüppner H, Wolf M. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008 Aug 7;359(6):584-92. doi: 10.1056/NEJMoa0706130. — View Citation

Inaba M, Okuno S, Imanishi Y, Yamada S, Shioi A, Yamakawa T, Ishimura E, Nishizawa Y. Role of fibroblast growth factor-23 in peripheral vascular calcification in non-diabetic and diabetic hemodialysis patients. Osteoporos Int. 2006 Oct;17(10):1506-13. Epub 2006 Aug 5. — View Citation

Jean G, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B, Chazot C. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant. 2009 Sep;24(9):2792-6. doi: 10.1093/ndt/gfp191. Epub 2009 Apr 25. — View Citation

JP Cristol, AS Bargnoux, AM Dupuy, M Morena, A Avignon and B Canaud. Biological markers of vascular calcifications in uremia. Médecine Nucléaire 2009; 33, 53-61.

Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, Sherrard DJ, Andress DL. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005 Feb;16(2):520-8. Epub 2004 Dec 22. — View Citation

Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009 Aug;(113):S1-130. doi: 10.1038/ki.2009.188. — View Citation

Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F; Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-54. Erratum in: Ann Intern Med. 2008 Oct 7;149(7):519. — View Citation

Levin A, Djurdjev O, Beaulieu M, Er L. Variability and risk factors for kidney disease progression and death following attainment of stage 4 CKD in a referred cohort. Am J Kidney Dis. 2008 Oct;52(4):661-71. doi: 10.1053/j.ajkd.2008.06.023. — View Citation

Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M. Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int. 2006 Feb;69(3):531-7. — View Citation

National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002 Feb;39(2 Suppl 1):S1-266. — View Citation

Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, Carvalho AB, Jorgetti V, Canziani ME, Moysés RM. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol. 2010 Feb;5(2):286-91. doi: 10.2215/CJN.05420709. Epub 2009 Nov 12. — View Citation

Peiskerová M, Kalousová M, Kratochvílová M, Dusilová-Sulková S, Uhrová J, Bandúr S, Malbohan IM, Zima T, Tesar V. Fibroblast growth factor 23 and matrix-metalloproteinases in patients with chronic kidney disease: are they associated with cardiovascular disease? Kidney Blood Press Res. 2009;32(4):276-83. doi: 10.1159/000243050. Epub 2009 Oct 1. — View Citation

Shigematsu T, Kazama JJ, Yamashita T, Fukumoto S, Hosoya T, Gejyo F, Fukagawa M. Possible involvement of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism associated with renal insufficiency. Am J Kidney Dis. 2004 Aug;44(2):250-6. — View Citation

Stubbs JR, Quarles LD. Fibroblast growth factor 23: uremic toxin or innocent bystander in chronic kidney disease? Nephrol News Issues. 2009 May;23(6):33-4, 36-7. Review. — View Citation

Tanaka H, Hamano T, Fujii N, Tomida K, Matsui I, Mikami S, Nagasawa Y, Ito T, Moriyama T, Horio M, Imai E, Isaka Y, Rakugi H. The impact of diabetes mellitus on vitamin D metabolism in predialysis patients. Bone. 2009 Nov;45(5):949-55. doi: 10.1016/j.bone.2009.07.016. Epub 2009 Jul 23. — View Citation

Urena Torres P, Friedlander G, de Vernejoul MC, Silve C, Prié D. Bone mass does not correlate with the serum fibroblast growth factor 23 in hemodialysis patients. Kidney Int. 2008 Jan;73(1):102-7. Epub 2007 Oct 17. — View Citation

Vassalotti JA, Uribarri J, Chen SC, Li S, Wang C, Collins AJ, Calvo MS, Whaley-Connell AT, McCullough PA, Norris KC; Kidney Early Evaluation Program Investigators. Trends in mineral metabolism: Kidney Early Evaluation Program (KEEP) and the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Am J Kidney Dis. 2008 Apr;51(4 Suppl 2):S56-68. doi: 10.1053/j.ajkd.2007.12.018. — View Citation

Voormolen N, Noordzij M, Grootendorst DC, Beetz I, Sijpkens YW, van Manen JG, Boeschoten EW, Huisman RM, Krediet RT, Dekker FW; PREPARE study group. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant. 2007 Oct;22(10):2909-16. Epub 2007 May 21. — View Citation

Westerberg PA, Linde T, Wikström B, Ljunggren O, Stridsberg M, Larsson TE. Regulation of fibroblast growth factor-23 in chronic kidney disease. Nephrol Dial Transplant. 2007 Nov;22(11):3202-7. Epub 2007 Jun 13. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of the serum levels of C terminal segment of fibroblast growth factor 23 (FGF23) and evaluation of sevelamer carbonate effect on this levels in comparison with placebo	Indeed the sevelamer carbonate could lead to a diminution of FGF23 serum levels due to the diminution of intestinal absorption of dietary phosphate.	12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the serum levels of iPTH		12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the serum levels of calcitriol (1 25(OH)2D3)		12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the serum levels of others mineral metabolism parameters (phosphore, calcium, intact FGF-23 , 25(OH)D3, bone specific alkaline phosphatases, osteocalcin, collagen crosslink, C reactive protein)		12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the urinary levels of phosphate		12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the urinary levels of calcium		12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the urinary levels of creatinine		12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the urinary levels of urea		12 weeks after the beginning of treatment	No
Secondary	Evaluation of sevelamer carbonate effect on the serum and urinary levels of specific biomarkers (serum : fetuin A, para-cresyl sulfate, osteopontin)		12 weeks after the beginning of treatment	No