Phosphate Lowering in CKD Trial

Phase 4

Completed

Conditions: Chronic Kidney Disease
Cardiovascular Disease

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

Registration Number: NCT02209636

Lead Sponsor: VA Office of Research and Development

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 66

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lanthanum carbonate	Aortic pulse-wave velocity	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.
placebo	Endothelial cell collection	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.
Lanthanum carbonate	Flow-mediated dilation measurement	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.
placebo	Aortic pulse-wave velocity	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.
Lanthanum carbonate	Endothelial cell collection	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.
placebo	placebo	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.
placebo	Flow-mediated dilation measurement	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.
Lanthanum carbonate	Lanthanum carbonate	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.
Lanthanum carbonate	Ascorbic Acid	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.
Lanthanum carbonate	Nitroglycerin	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.
placebo	Ascorbic Acid	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.
placebo	Nitroglycerin	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.

Primary Outcome Measures

Name	Time	Method
Brachial Artery Flow-mediated Dilation	baseline and 12 weeks	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.
Aortic Pulse-wave Velocity	baseline and 12 weeks	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.
Phosphorus Balance Sub-study (COMIRB 15-0384)	9 days from the start of the sub-study, approximately 13 weeks and 2 days from the start of the Main/Parent Study	Balance is defined as oral intake minus urine output minus stool output.

Secondary Outcome Measures

Name	Time	Method
Oxidative Stress-associated Suppression of EDD	baseline and 12 weeks	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.
Vascular Endothelial Cell Protein Expression	baseline and 12 weeks	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.
Oxidized Low-density Lipoprotein (Ox-LDL) to Measure Systemic Oxidized Stress	baseline and 12 weeks	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.
C-reactive Protein to Measure Systemic Inflammation	baseline and 12 weeks	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.
Interleukin-6 to Measure Systemic Inflammation	baseline and 12 weeks	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.