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| Name | Class |
|---|---|
| Genzyme, a Sanofi Company | INDUSTRY |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| sevelamer carbonate | Active Comparator | 2400 mg (3 pills) with each meal |
|
| placebo control | Placebo Comparator | 3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| sevelamer carbonate | Drug | 2400 mg with each meal for 4 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Fractional Change in [PTH] in CKD After a 4-week Course of Sevelamer Carbonate | 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. | 4 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kenneth R. Phelps, M.D. | Stratton VAMC, Albany, NY | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stratton Veterans Affairs Medical Center | Albany | New York | 12208 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40576086 | Derived | 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. | |
| 29779023 | Derived | 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. |
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Randomization was preceded by a 4-week course of vitamin D (dose determined by plasma [25OHD]) and then by a 4-week period of dietary phosphate restriction. The phosphate restriction was continued through the therapeutic trial.
Patients with eGFR < 60 were recruited from renal clinics and randomized to receive 3 tablets of sevelamer or placebo with each meal for four weeks.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sevelamer Carbonate | 2400 mg (3 pills) with each meal sevelamer carbonate : 2400 mg with each meal for 4 weeks |
| FG001 | Placebo Control | 3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. placebo : 3 tablets with each meal |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Post-treatment data were not obtained from patient who withdrew on third treatment day.
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| ID | Title | Description |
|---|---|---|
| BG000 | Sevelamer Carbonate | 2400 mg (3 pills) with each meal sevelamer carbonate : 2400 mg with each meal for 4 weeks |
| BG001 | Placebo Control | 3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. placebo : 3 tablets with each meal |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Fractional Change in [PTH] in CKD After a 4-week Course of Sevelamer Carbonate | 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. | Posted | Mean | Standard Error | percentage of baseline [PTH] | 4 weeks |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sevelamer Carbonate | 2400 mg (3 pills) with each meal sevelamer carbonate : 2400 mg with each meal for 4 weeks |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| nausea | Gastrointestinal disorders | Systematic Assessment | The patient complained of nausea and upset stomach from the inception of his treatment. |
All intended measurements were made. The desired number of participants was recruited.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kenneth R. Phelps, M.D. | Kenneth R. Phelps, M.D. | 518-626-5641 | kenneth.phelps@va.gov |
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| ID | Term |
|---|---|
| D006961 | Hyperparathyroidism |
| D051436 | Renal Insufficiency, Chronic |
| D006962 | Hyperparathyroidism, Secondary |
| ID | Term |
|---|---|
| D010279 | Parathyroid Diseases |
| D004700 | Endocrine System Diseases |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
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| ID | Term |
|---|---|
| D000069603 | Sevelamer |
| ID | Term |
|---|---|
| D011073 | Polyamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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| placebo | Drug | 3 tablets with each meal |
|
| 26951967 | Derived | 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. |
| 25685872 | Derived | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| 0 |
| 15 |
| 1 |
| 15 |
| EG001 | Placebo Control | 3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. placebo : 3 tablets with each meal | 0 | 15 | 0 | 15 |
|
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| D014570 |
| Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |