Sevelamer and Secondary Hyperparathyroidism in Chronic Kidney Disease

• Sponsor: Kenneth R. Phelps, M.D. (Other)
• Overall Status: Completed
• CT.gov ID: NCT01191762
• Collaborator: Genzyme, a Sanofi Company (Industry)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 36
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Apr 1, 2010
• Actual Primary Completion Date: Aug 1, 2012
• Actual Study Completion Date: Apr 1, 2013

Arms and Interventions

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 Names: 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

Outcome Measures

Primary Outcome Measures

1. Fractional Change in [PTH] in CKD After a 4-week Course of Sevelamer Carbonate [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kenneth R. Phelps, M.D., Principal Investigator, Phelps, Kenneth R., M.D.
• ClinicalTrials.gov Identifier: NCT01191762
• Other Study ID Numbers: PhelpsK
• First Posted: Aug 31, 2010
• Last Update Posted: Nov 1, 2016
• Last Verified: Sep 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Kenneth R. Phelps, M.D., Principal Investigator, Phelps, Kenneth R., M.D.: secondary hyperparathyroidism; phosphate; calcium; chronic kidney disease
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hyperparathyroidism; Hyperparathyroidism, Secondary; Sevelamer

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Sevelamer Carbonate	Placebo Control
Arm/Group Description	2400 mg (3 pills) with each meal sevelamer carbonate : 2400 mg with each meal for 4 weeks	3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. placebo : 3 tablets with each meal
Period Title: Overall Study
STARTED	15	15
COMPLETED	14	15
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Sevelamer Carbonate	Placebo Control	Total
Arm/Group Description	2400 mg (3 pills) with each meal sevelamer carbonate : 2400 mg with each meal for 4 weeks	3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. placebo : 3 tablets with each meal	Total of all reporting groups
Overall Participants	14	15	29
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 21.4%	6 40%	9 31%
>=65 years	11 78.6%	9 60%	20 69%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.7 (8.5)	70.1 (10.5)	71.8 (9.6)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	14 100%	15 100%	29 100%
Region of Enrollment (participants) [Number]
United States	14 100%	15 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Fractional Change in [PTH] in CKD After a 4-week Course of Sevelamer Carbonate
Description	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.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sevelamer Carbonate	Placebo Control
Arm/Group Description	2400 mg (3 pills) with each meal sevelamer carbonate : 2400 mg with each meal for 4 weeks	3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. placebo : 3 tablets with each meal
Measure Participants	14	15
Mean (Standard Error) [percentage of baseline [PTH]]	-11.7 (5.8)	16.4 (10.0)

Adverse Events

Arm/Group Title	Sevelamer Carbonate		Placebo Control
Arm/Group Description	2400 mg (3 pills) with each meal sevelamer carbonate : 2400 mg with each meal for 4 weeks		3 placebo tablets with each meal; tablets are identical to sevelamer carbonate 800 mg tablets. placebo : 3 tablets with each meal
All Cause Mortality
	Sevelamer Carbonate		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sevelamer Carbonate		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Sevelamer Carbonate		Placebo Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		0/15 (0%)
Gastrointestinal disorders
nausea	1/15 (6.7%)	1	0/15 (0%)	0

Limitations/Caveats

All intended measurements were made. The desired number of participants was recruited.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.