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Sevelamer and Secondary Hyperparathyroidism in Chronic Kidney Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01191762
Recruitment Status : Completed
First Posted : August 31, 2010
Results First Posted : July 31, 2014
Last Update Posted : November 1, 2016
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Kenneth R. Phelps, M.D., Phelps, Kenneth R., M.D.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hyperparathyroidism Chronic Kidney Disease Drug: sevelamer carbonate Drug: placebo Phase 3

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of Sevelamer Carbonate on Critical Variables in the Pathogenesis of Secondary Hyperparathyroidism
Study Start Date : April 2010
Actual Primary Completion Date : August 2012
Actual Study Completion Date : April 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Active Comparator: sevelamer carbonate
2400 mg (3 pills) with each meal
Drug: sevelamer carbonate
2400 mg with each meal for 4 weeks
Other Name: Renvela (Genzyme)

Placebo Comparator: placebo control
3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets.
Drug: placebo
3 tablets with each meal

Primary Outcome Measures :
  1. Fractional Change in [PTH] in CKD After a 4-week Course of Sevelamer Carbonate [ Time Frame: 4 weeks ]
    This outcome measure documented the effect of intestinal phosphate-binding on [PTH]. Fractional change was calculated as ([PTH]post - [PTH]pre)/[PTH]pre, where 'pre' and 'post' referred respectively to baseline [PTH] (before treatment) and [PTH] after four weeks of treatment. Reductions were cited as negative numbers, and increments were cited as positive numbers.

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • eGFR < 60 ml/min
  • age at least 18 years

Exclusion Criteria:

  • any primary parathyroid disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01191762

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United States, New York
Stratton Veterans Affairs Medical Center
Albany, New York, United States, 12208
Sponsors and Collaborators
Kenneth R. Phelps, M.D.
Genzyme, a Sanofi Company
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Principal Investigator: Kenneth R. Phelps, M.D. Stratton VAMC, Albany, NY

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Kenneth R. Phelps, M.D., Principal Investigator, Phelps, Kenneth R., M.D. Identifier: NCT01191762     History of Changes
Other Study ID Numbers: PhelpsK
First Posted: August 31, 2010    Key Record Dates
Results First Posted: July 31, 2014
Last Update Posted: November 1, 2016
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Kenneth R. Phelps, M.D., Phelps, Kenneth R., M.D.:
secondary hyperparathyroidism
chronic kidney disease
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Hyperparathyroidism, Secondary
Urologic Diseases
Renal Insufficiency
Parathyroid Diseases
Endocrine System Diseases
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action