CARE-2 (Calcium Acetate [PhosLo®]/Sevelamer[Renagel®] Evaluation Study 2) for Heart Calcification in Dialysis Patients

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the effects of two phosphate binders, PhosLo and sevelamer, on heart calcification in dialysis patients. The study will use a non-invasive technique, electron beam computed tomography (CT) scanning, to measure calcium in the coronary arteries, the aortic valve, and the mitral valve.

Detailed Description
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Cardiovascular disease is the major cause of death and disability in patients with end-stage renal disease on hemodialysis. It has been hypothesized that ingestion of calcium-based phosphate binders results in net positive calcium balance and vascular calcium deposition. Chertow et al. tested the role of ingested calcium in the progression of cardiovascular calcification in the Treat-To-Goal study (Kidney International 62:245, 2002). They reported that patients treated with calcium-based phosphate binders demonstrated progressive cardiovascular calcification, while patients treated with a calcium-free binder, sevelamer, showed stabilization or improvement in calcification scores. However, the protocol did not prohibit intake of supplemental oral calcium in the sevelamer group, which confounded their ability to accurately test the calcium hypothesis. Moreover, due to the cholesterol sequestering activities of sevelamer, the low-density lipoprotein (LDL) cholesterol was lower among sevelamer-treated patients than the calcium treated patients, resulting in a major imbalance in a cardiovascular risk factor. Lowering LDL level reduces progression of CVC and therefore confounds interpretation of the study. Subsequently, it has been reported in the lay press that patients randomized to sevelamer or calcium-based binders in the Dialysis Clinical Outcomes Revisited (DCOR) study have failed to show a difference in mortality or major secondary endpoints (Suki et al., To be presented American Society of Nephrology November 2005). To circumvent these limitations, the CARE-2 study will test the hypothesis that if LDL levels are lowered to a similar level in calcium acetate and sevelamer-treated patients, there will be no difference in the progression of cardiac calcification. CARE-2 will randomize patients with elevated LDL to calcium acetate or sevelamer. Atorvastatin is added to achieve LDL < 70 mg/dL in both treatment groups. The primary endpoint is change in cardiac calcification scores, determined by electron beam scanning after 1 year. Secondary endpoints include the ability of calcium acetate and sevelamer to control phosphorus and meet NKF-K/DOQI guidelines.

Official Title
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CARE-2 (Calcium Acetate (PhosLo®)/Sevelamer(Renagel®) Evaluation Study 2)

Conditions
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Calcinosis, Arteriosclerosis, Hyperparathyroidism, Secondary

Intervention / Treatment
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* Drug: calcium acetate
* Drug: sevelamer
* Drug: atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible subjects will be male or female patients with end-stage renal disease on maintenance hemodialysis for less than 5 years, with elevated LDL cholesterol Currently treated with oral phosphate binders Coronary artery calcium scores of 30 to 5000 Agatston units measured by electron beam CT scanning Written informed consent Negative serum pregnancy test if appropriate Expect to comply with protocol procedures and schedule Exclusion Criteria: Unstable angina pectoris Severe congestive heart failure Severe obstructive pulmonary disease requiring supplemental oxygen Severe liver dysfunction Severe malnutrition Severe hyperparathyroidism Known HIV Active malignancy for which the subject is receiving chemotherapy or radiation Planned renal transplant within the next year Clinical evidence of calciphylaxis or recent history of hypercalcemia History of obstructed bowels Hypersensitivity to any of the components of the study medication History of swallowing disorders Weight > 300 pounds Any condition which makes patient participation not in the patient's best interest

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>PhosLo + atorvastatin | Drug: calcium acetate<br>* 667 mg gelcap, 2-4 t.i.d titrated to serum phosphorus level<br>* Other names: PhosLo;Drug: atorvastatin<br>* 20 mg PO qD (in PhosLo group), or held until D60 (sevelamer group); titrate by LDL levels and liver function tests<br>* Other names: Lipitor;|
| Active Comparator: 2<br>Sevelamer + atorvastatin | Drug: sevelamer<br>* 1-3 tablets t.i.d, titrated to serum phosphorus level<br>* Other names: Renagel;Drug: atorvastatin<br>* 20 mg PO qD (in PhosLo group), or held until D60 (sevelamer group); titrate by LDL levels and liver function tests<br>* Other names: Lipitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| electron-beam CT coronary artery calcification AGATSTON score |  | change at 12 mo from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| serum phosphorus |  | Days 30-365 | 
| calcium x phosphorus product |  | Days 30-365 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PhosLo (Calcium acetate), Renagel (sevelamer, polyallylamine HCL), kidney dialysis, hyperphosphatemia, Kidney failure