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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
  Purpose
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 Intervention Phase
Hyperparathyroidism
Chronic Kidney Disease
Drug: sevelamer carbonate
Drug: placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effect of Sevelamer Carbonate on Critical Variables in the Pathogenesis of Secondary Hyperparathyroidism

Resource links provided by NLM:


Further study details as provided by Phelps, Kenneth R., M.D.:

Primary Outcome Measures:
  • 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.


Enrollment: 30
Study Start Date: April 2010
Study Completion Date: April 2013
Primary Completion Date: August 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 120 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • any primary parathyroid disease
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01191762

Locations
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
Investigators
Principal Investigator: Kenneth R. Phelps, M.D. Stratton VAMC, Albany, NY
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Kenneth R. Phelps, M.D., Principal Investigator, Phelps, Kenneth R., M.D.
ClinicalTrials.gov Identifier: NCT01191762     History of Changes
Other Study ID Numbers: PhelpsK 
Study First Received: August 27, 2010
Results First Received: November 13, 2013
Last Updated: September 26, 2016
Health Authority: United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Phelps, Kenneth R., M.D.:
secondary hyperparathyroidism
phosphate
calcium
chronic kidney disease

Additional relevant MeSH terms:
Kidney Diseases
Renal Insufficiency, Chronic
Hyperparathyroidism, Secondary
Hyperparathyroidism
Urologic Diseases
Renal Insufficiency
Parathyroid Diseases
Endocrine System Diseases
Sevelamer
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 02, 2016