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Sevelamer and Secondary Hyperparathyroidism in Chronic Kidney Disease

This study has been completed.
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Kenneth R. Phelps, M.D., Phelps, Kenneth R., M.D.
ClinicalTrials.gov Identifier:
NCT01191762
First received: August 27, 2010
Last updated: September 26, 2016
Last verified: September 2016

August 27, 2010
September 26, 2016
April 2010
August 2012   (final data collection date for primary outcome measure)
Fractional Change in [PTH] in CKD After a 4-week Course of Sevelamer Carbonate [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
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.
Fractional reduction in [PTH] in CKD after a 4-week course of sevelamer carbonate [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01191762 on ClinicalTrials.gov Archive Site
Not Provided
Correlation of [PTH] to phosphate excretion per volume of glomerular filtrate [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Sevelamer and Secondary Hyperparathyroidism in Chronic Kidney Disease
The Effect of Sevelamer Carbonate on Critical Variables in the Pathogenesis of Secondary Hyperparathyroidism
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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Hyperparathyroidism
  • Chronic Kidney Disease
  • Drug: sevelamer carbonate
    2400 mg with each meal for 4 weeks
    Other Name: Renvela (Genzyme)
  • Drug: placebo
    3 tablets with each meal
  • Active Comparator: sevelamer carbonate
    2400 mg (3 pills) with each meal
    Intervention: Drug: sevelamer carbonate
  • Placebo Comparator: placebo control
    3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets.
    Intervention: Drug: placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
30
April 2013
August 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

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

Exclusion Criteria:

  • any primary parathyroid disease
Both
18 Years to 120 Years   (Adult, Senior)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01191762
PhelpsK
No
No
Not Provided
Kenneth R. Phelps, M.D., Phelps, Kenneth R., M.D.
Kenneth R. Phelps, M.D.
Genzyme, a Sanofi Company
Principal Investigator: Kenneth R. Phelps, M.D. Stratton VAMC, Albany, NY
Phelps, Kenneth R., M.D.
September 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP