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

Sponsor

Nabi Biopharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT00211939

Collaborator

(none)

203

Enrollment

Location

Arms

25.9

Duration (Months)

7.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Calcinosis Arteriosclerosis Hyperparathyroidism, Secondary	Drug: calcium acetate Drug: sevelamer Drug: atorvastatin	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

203 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 2005

Actual Primary Completion Date :

Dec 1, 2006

Actual Study Completion Date :

Mar 1, 2007

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: 1

PhosLo + atorvastatin

Drug: calcium acetate

667 mg gelcap, 2-4 t.i.d titrated to serum phosphorus level

Other Names:

PhosLo

Drug: atorvastatin

20 mg PO qD (in PhosLo group), or held until D60 (sevelamer group); titrate by LDL levels and liver function tests

Other Names:

Lipitor

Active Comparator: 2

Sevelamer + atorvastatin

Drug: sevelamer

1-3 tablets t.i.d, titrated to serum phosphorus level

Other Names:

Renagel

Drug: atorvastatin

20 mg PO qD (in PhosLo group), or held until D60 (sevelamer group); titrate by LDL levels and liver function tests

Other Names:

Lipitor

Outcome Measures

Primary Outcome Measures

electron-beam CT coronary artery calcification AGATSTON score [change at 12 mo from baseline]

Secondary Outcome Measures

serum phosphorus [Days 30-365]
calcium x phosphorus product [Days 30-365]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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