Sevelamer and Secondary Hyperparathyroidism in Chronic Kidney Disease

NCT ID: NCT01191762

Last Updated: 2016-11-01

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

30 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-04-30

Study Completion Date

2013-04-30

Brief Summary

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The hypothesis underlying this study is that phosphate interferes with PTH-mediated calcium reabsorption in the distal nephron and thereby necessitates supranormal \[PTH\]to maintain normocalcemia in chronic kidney disease. This study will examine the hypothesis with measures of phosphate homeostasis and calcium reabsorption. A double-blind trial of the intestinal phosphate binder sevelamer carbonate will be employed to examine whether reductions in phosphate influx alter distal nephron phosphate concentration and the \[PTH\] required for calcium reabsorption in the expected manner.

Detailed Description

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The parathyroid hormone concentration (\[PTH)\] rises as glomerular filtration rate (GFR) falls. This almost universal phenomenon is called secondary hyperparathyroidism (SHPT). \[PTH\] rises with dietary phosphate in chronic kidney disease. \[PTH\] also rises with stable dietary phosphate as GFR falls. The mechanism underlying these phenomena is unknown.

We hypothesize that phosphate exerts its effect on \[PTH\] in the cortical distal nephron (CDN). Ordinarily, intestinal phosphate absorption does not fall in proportion to GFR as chronic kidney disease (CKD) progresses. Consequently, the concentration of phosphate increases in the cortical distal nephron (CDN), where PTH regulates tubular calcium reabsorption. We speculate that increased \[P\]cdn reduces the concentration of free calcium through complexation, and thereby necessitates high \[PTH\] for achievement of calcium reabsorption sufficient to maintain normocalcemia. We can show algebraically that \[P\]cdn is proportional to the ratio EP/Ccr, where EP is the urinary excretion rate of phosphate and Ccr is creatinine clearance, a surrogate for GFR. EP/Ccr can be calculated from measurements in aliquots of serum and urine as \[P\]u\[cr\]s/\[cr\]u. If our hypothesis is correct, we anticipate that \[PTH\] will be proportional to EP/Ccr in CKD, and that delta \[PTH\] will be proportional to delta EP/Ccr obtained with sequential determinations.

We will study 30 patients with CKD and a comparable number of controls. All subjects will have normocalcemia. Controls will be seen once for informed consent, and once in the fasting state between 8:00 a.m. and 10:00 a.m. for collection of urine and blood specimens.

Patients with CKD will be seen at five visits at intervals of four weeks. At the first visit, we will obtain informed consent and obtain a specimen for measurement of 25-hydroxyvitamin D (25OHD). At visits 2-5, we will obtain necessary specimens to measure concentrations of PTH, fibroblast growth factor 23 (FGF23), 25OHD, and 1,25-dihyroxyvitamin D (1,25(OH)2D). We will also measure ionized and ultrafilterable calcium, creatinine, and phosphorus in serum and calcium, phosphorus, and creatinine in urine. These measurements will enable us to follow the effects of interventions on hormone concentrations and parameters of calcium and phosphorus homeostasis.

At visit 2 we will prescribe vitamin D in accordance with \[25OHD\] obtained at visit 1. For \[25OHD\] \< 32 ng/mL, doses will be 50,000 units/d of D2 for one week, followed by 2000 mg/d of D2 for 3 weeks. For \[25OHD\] \> 32 ng/mL, the dose will be D3 2000 mg/d for four weeks. The purpose of this intervention is to minimize the likelihood that vitamin D insufficiency or deficiency contributes to SHPT.

At visit 3, we will instruct patients in a phosphate-restricted diet. At visit 4 we will quantify the metabolic effects of the diet, and will randomly assign patients to receive either placebo or sevelamer carbonate 800 mg tablets, 3 with each meal. At visit 5, we will quantify the effects of the two interventions on parameters of calcium and phosphate homeostasis and on hormone concentrations. We will view positive regressions of \[PTH\] on EP/Ccr and of ∆\[PTH\] on ∆EP/Ccr as evidence for our hypothesis.

Conditions

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Hyperparathyroidism Chronic Kidney Disease

Keywords

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secondary hyperparathyroidism phosphate calcium chronic kidney disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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sevelamer carbonate

2400 mg (3 pills) with each meal

Group Type ACTIVE_COMPARATOR

sevelamer carbonate

Intervention Type DRUG

2400 mg with each meal for 4 weeks

placebo control

3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets.

Group Type PLACEBO_COMPARATOR

placebo

Intervention Type DRUG

3 tablets with each meal

Interventions

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sevelamer carbonate

2400 mg with each meal for 4 weeks

Intervention Type DRUG

placebo

3 tablets with each meal

Intervention Type DRUG

Other Intervention Names

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Renvela (Genzyme)

Eligibility Criteria

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Inclusion Criteria

* eGFR \< 60 ml/min
* age at least 18 years

Exclusion Criteria

* any primary parathyroid disease
Minimum Eligible Age

18 Years

Maximum Eligible Age

120 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role collaborator

Kenneth R. Phelps, M.D.

INDIV

Sponsor Role lead

Responsible Party

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Kenneth R. Phelps, M.D.

Principal Investigator

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Kenneth R. Phelps, M.D.

Role: PRINCIPAL_INVESTIGATOR

Stratton VAMC, Albany, NY

Locations

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Stratton Veterans Affairs Medical Center

Albany, New York, United States

Site Status

Countries

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United States

References

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Natale P, Green SC, Ruospo M, Craig JC, Vecchio M, Elder GJ, Strippoli GF. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD). Cochrane Database Syst Rev. 2025 Jun 27;6(6):CD006023. doi: 10.1002/14651858.CD006023.pub4.

Reference Type DERIVED
PMID: 40576086 (View on PubMed)

Phelps KR, Mason DL. Parathyroid Hormone, Fibroblast Growth Factor 23, and Parameters of Phosphate Reabsorption. Am J Nephrol. 2018;47(5):343-351. doi: 10.1159/000489270. Epub 2018 May 18.

Reference Type DERIVED
PMID: 29779023 (View on PubMed)

Phelps KR, Mason DL, Stote KS. Phosphate homeostasis, parathyroid hormone, and fibroblast growth factor 23 in stages 3 and 4 chronic kidney disease. Clin Nephrol. 2016 May;85(5):251-61. doi: 10.5414/CN108686.

Reference Type DERIVED
PMID: 26951967 (View on PubMed)

Phelps KR, Mason DL. Parameters of phosphorus homeostasis at normal and reduced GFR: theoretical considerations. Clin Nephrol. 2015 Mar;83(3):167-76. doi: 10.5414/cn108367.

Reference Type DERIVED
PMID: 25685872 (View on PubMed)

Other Identifiers

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PhelpsK

Identifier Type: -

Identifier Source: org_study_id