Phosphate Lowering in CKD Trial

Study Overview
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Brief Summary
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The proposed research is a randomized-controlled trial to determine the effectiveness of reducing serum phosphorus using a phosphate binder, lanthanum carbonate, for improving the function of arteries in adults with moderate to severe chronic kidney disease (CKD). [COMIRB 13-0328] Additionally, it will determine phosphorus balance among adults with CKD and whether there is a difference in phosphorus balance after three months of treatment with lanthanum carbonate. [COMIRB 15-0384]

Detailed Description
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Chronic kidney disease (CKD) is a major health concern both in the general and Veteran populations. Indeed, the prevalence of CKD in a large Veteran population is 20%. Cardiovascular disease (CVD) is significantly increased in CKD and is an important cause of morbidity and mortality. As much as 80% of all CVD is associated with vascular dysfunction, particularly impaired endothelium-dependent dilation (EDD), measured by brachial artery flow-mediate dilation (FMD), and stiffening of the large elastic arteries, measured by aortic pulse-wave velocity (aPWV). Not surprisingly, patients with CKD demonstrate these dysfunctional vascular phenotypes. Even in early stages of CKD, there is an increase in oxidative stress resulting in structural and functional vascular changes, which, in turn, contributes to vascular dysfunction (impaired EDD and large elastic artery stiffening). In CKD, phosphorus remains within the normal range (2.5-4.5 mg/dL) until late in the disease. However, elevated serum phosphorus, even within the normal range, is associated with impaired EDD and with indirect measures of arterial stiffness. Whether lowering serum phosphorus in patients with CKD will improve EDD and arterial stiffness is unknown. This study is a randomized-controlled trial of lanthanum carbonate, a non-calcium based phosphate binder, to treat vascular dysfunction. The efficacy of phosphate binding with lanthanum carbonate for treating vascular endothelial dysfunction and large elastic artery stiffness in patients with stage IIIb and IV CKD (estimated glomerular filtration rate 15-45 mL/min/1.73m2) with baseline serum phosphorus of 2.8-5.5 mg/dL will be assessed. The study will also determine if lowering serum phosphorus with lanthanum carbonate also reduces circulating and endothelial cell markers of oxidative stress. This study could shift clinical practice guidelines by establishing a novel therapy for reducing CVD risk in CKD patients not requiring chronic hemodialysis. [COMIRB 13-0328] Little is known about phosphorus balance in CKD. It is assumed that CKD patients remain in neutral phosphorus balance despite decreases in kidney function. Serum phosphorus remains in the normal range until late in CKD thus making it difficult to recognize perturbations in phosphorus balance. Indeed, among CKD patients treated with the non-calcium containing phosphate binder, sevelamer, serum phosphorus did not change after six weeks of treatment but urinary phosphate excretion, parathyroid hormone, and fibroblast growth factor-23 changed significantly, suggesting a shift in phosphorus homeostasis. However, two other studies found that patients with CKD III-IV treated with calcium-containing phosphate binders remained in neutral phosphorus balance. There are no studies evaluating the effects of non-calcium based phosphate binders on phosphorus balance among patients with CKD nor other studies examining the effect of changing phosphorus balance on vascular function. An extension of the above-described 12-week prospective randomized, placebo-controlled double-blind trial (COMIRB 13-0328) will be conducted in a subset of subjects. A total of 24 subjects from COMIRB 13-0328 will be recruited to participate in the Phosphorus Balance sub-investigation (12 subjects treated with lanthanum carbonate and 12 subjects treated with placebo). [15-0384] They will consume a diet with a fixed phosphorus content (1000 +/- 50 mg) for seven days. They will then be admitted to the inpatient Center for Translational Clinical Research at the University of Colorado Denver for 48 hours to accurately collect urine and stool samples. The goal of the Phosphorus Balance sub-investigation (COMIRB 15-0384) is to determine whether lowering serum phosphorus, accomplished during the parent phosphorus lowering randomized-controlled trial (COMIRB 13-0328), affects phosphorus balance compared to those subjects treated with placebo. A key secondary goal is to determine if differences in phosphorus balance affect vascular function as measured by FMD. [15-0384] To ensure adequate enrollment in the Phosphorus Balance Study (COMIRB 15-0384), an amendment was approved to recruit patients with stage IIIb and IV CKD with normal or modestly elevated serum phosphorus (2.8-5.5 mg/dL) who are not currently participating in the parent Phosphorus Lowering RCT (COMIRB 13-0328). Similar to the Phosphorus Lowering RCT, these patients will follow a low phosphorus diet and will be randomized to lanthanum carbonate or placebo for 12 weeks (run-in period) prior to beginning the current Phosphorus Balance protocol.

Official Title
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Phosphate Lowering to Treat Vascular Dysfunction in Chronic Kidney Disease

Conditions
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Chronic Kidney Disease, Cardiovascular Disease

Intervention / Treatment
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* Drug: Lanthanum carbonate
* Drug: placebo
* Drug: Ascorbic Acid
* Drug: Nitroglycerin
* Procedure: Flow-mediated dilation measurement
* Procedure: Aortic pulse-wave velocity
* Procedure: Endothelial cell collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40-79, women must be post-menopausal CKD stage IIIb or IV (estimated glomerular filtration rate by MDRD 15-45 mL/min/1.73m2), stable for 3 months Serum phosphorus 2.8-5.5 mg/dL, stable for 3 months Not using phosphate binders Albumin > 3.0 g/dL Free from alcohol dependence or abuse Ability to provide informed consent BMI < 40 kg/m2 Not taking medications that interact with agents administered during experimental sessions (e.g., sildenafil interacts with nitroglycerin) For COMIRB 15-0384, completion of the prospective, randomized, placebo-controlled double-blind trial, Phosphorus Lowering to Treat Vascular Dysfunction in Chronic Kidney Disease (COMIRB 13-0328) or completion of 12-week run-in phase Exclusion Criteria: Life expectancy <1 year Uncontrolled hypertension History of severe liver disease History of congestive heart failure (EF < 35%) History of hospitalizations within the last 3 months History of ileus or bowel obstruction Active infection or antibiotic therapy Expected kidney transplant in the next 6 months Active vitamin D analogue use (i.e. calcitriol, paricalcitol, doxercalciferol) Vasculitis requiring immunosuppressive therapy within the last year Current tobacco abuse

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lanthanum carbonate<br>Eligible subjects who are randomly assigned to the experimental arm will receive lanthanum carbonate (1500-4500 mg/day in divided doses) titrated to serum phosphorus levels. | Drug: Lanthanum carbonate<br>* Non-calcium containing phosphorus binder<br>* Other names: Fosrenol;Drug: Ascorbic Acid<br>* Intravenous administration during measurement of flow mediated dilation.<br>* Other names: Vitamin C;Drug: Nitroglycerin<br>* Drug that is administered under the tongue that relaxes blood vessels. To be administered during measurement of flow mediated dilation.<br>Procedure: Flow-mediated dilation measurement<br>* Measurement of the blood flow in the brachial artery, an artery in the upper arm, using ultrasound.<br>Procedure: Aortic pulse-wave velocity<br>* Measurement of the stiffness of the arteries using a transcutaneous tonometer, a small device placed over the skin over the carotid, brachial, radial and femoral arteries.<br>Procedure: Endothelial cell collection<br>* Collection of endothelial cells from vein in arm. A flexible wire is inserted through an IV into a forearm vein to collect endothelial cells for further study. This is performed at the baseline visit and and the final study visit.<br>|
| Placebo Comparator: placebo<br>Eligible subjects who are randomly assigned to the placebo arm will receive placebo tablets (identical to the active lanthanum carbonate tablets) to be taken 3 times daily and titrated to serum phosphorus levels. | Drug: placebo<br>* Table identical to lanthanum carbonate but with no active ingredient<br>Drug: Ascorbic Acid<br>* Intravenous administration during measurement of flow mediated dilation.<br>* Other names: Vitamin C;Drug: Nitroglycerin<br>* Drug that is administered under the tongue that relaxes blood vessels. To be administered during measurement of flow mediated dilation.<br>Procedure: Flow-mediated dilation measurement<br>* Measurement of the blood flow in the brachial artery, an artery in the upper arm, using ultrasound.<br>Procedure: Aortic pulse-wave velocity<br>* Measurement of the stiffness of the arteries using a transcutaneous tonometer, a small device placed over the skin over the carotid, brachial, radial and femoral arteries.<br>Procedure: Endothelial cell collection<br>* Collection of endothelial cells from vein in arm. A flexible wire is inserted through an IV into a forearm vein to collect endothelial cells for further study. This is performed at the baseline visit and and the final study visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brachial Artery Flow-mediated Dilation | Measurement of how well the brachial artery dilates in response to shear stress. It is a measure of endothelial function. It is reported as percent change, which represents the change in dilation of the artery before and after occlusion. Brachial artery flow-mediated dilation will be measured at baseline and at 12 weeks (end-of-study) in the treatment and placebo groups to determine if there is a change brachial artery flow mediated dilation from baseline to 12 weeks and if this change is significantly different between the treatment and placebo groups. | baseline and 12 weeks | 
| Aortic Pulse-wave Velocity | The speed that blood travels from the carotid artery to the femoral artery, expressed as cm/s (centimeters/second). It is a measure of arterial stiffness. Aortic pulse-wave velocity will be measured at baseline and at 12 weeks (end-of-study) in the treatment and placebo groups to determine if there is a change aortic pulse wave velocity from baseline to 12 weeks and if this change is significantly different between the treatment and placebo groups. | baseline and 12 weeks | 
| Phosphorus Balance Sub-study (COMIRB 15-0384) | Balance is defined as oral intake minus urine output minus stool output. | 9 days from the start of the sub-study, approximately 13 weeks and 2 days from the start of the Main/Parent Study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxidative Stress-associated Suppression of EDD | The influence of oxidative stress on FMD will be determined by infusing a supraphysiologic dose of ascorbic acid or isovolemic saline. The difference in FMD, expressed as percentage change in FMD, which represents the change in dilation of the artery before and after occlusion, during ascorbic acid vs. saline infusion will be taken as a measure of the modulation of EDD/stiffness by oxidative stress. | baseline and 12 weeks | 
| Vascular Endothelial Cell Protein Expression | Measures of different protein markers on endothelial cells. Will help understand the underlying pathophysiology of vascular dysfunction in chronic kidney disease. Vascular endothelial cell protein expression will be measured at baseline and at 12 weeks (end-of-study) in the treatment and placebo groups to determine if there is a change vascular endothelial cell protein expression from baseline to 12 weeks and if this change is significantly different between the treatment and placebo groups. The expression of endothelial cells collected from patients will be compared to the expression in HUVEC (human umbilical vein endothelial cell) controls and this ratio will be reported as the outcomes measure. | baseline and 12 weeks | 
| Interleukin-6 to Measure Systemic Inflammation | This is a blood test. Interleukin-6 and C-reactive protein will be measured at baseline and at 12 weeks (end-of-study) in the treatment and placebo groups to determine if there is a change in interleukin-6 and C-reactive protein from baseline to 12 weeks and if this change is significantly different between the treatment and placebo groups. | baseline and 12 weeks | 
| Oxidized Low-density Lipoprotein (Ox-LDL) to Measure Systemic Oxidized Stress | This is a blood test art. Oxidized low-density lipoprotein (ox-LDL) will be measured at baseline and at 12 weeks (end-of-study) in the treatment and placebo groups to determine if there is a change in ox-LDL from baseline to 12 weeks and if this change is significantly different between the treatment and placebo groups. | baseline and 12 weeks | 
| C-reactive Protein to Measure Systemic Inflammation | This is a blood test. C-reactive protein will be measured at baseline and at 12 weeks (end-of-study) in the treatment and placebo groups to determine if there is a change in C-reactive protein from baseline to 12 weeks and if this change is significantly different between the treatment and placebo groups. | baseline and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperphosphatemia, vascular dysfunction, chronic kidney disease, cardiovascular disease, endothelial dysfunction