Grant Abstract: A Randomized, Controlled Trial for Homocysteine

Grant Number: 5U01DK061700-05
Project Title: A Randomized, Controlled Trial for Homocysteine

Abstract: DESCRIPTION (Adapted from the application) This multicenter, randomized, double-blind controlled clinical trial has been designed to determine whether total homocysteine (tHcy)-lowering treatment with a standard multivitamin augmented by a high dose combination of folic acid, vitamin B12, and vitamin B6, versus treatment with a standard multivitamin devoid of these three B-vitamins, reduces the pooled rate of recurrent and de novo cardiovascular disease outcomes (i.e., pooled occurrence of non-fatal and fatal arteriosclerotic outcomes, including coronary heart, cerebrovascular, and peripheral vascular disease events= primary outcome), among clinically stable renal transplant recipients who have mild to moderately elevated tHcy levels. The basic eligibility criteria are age 35 to 75 years old, functioning renal allograft for greater than six-months with serum creatinine based creatinine clearance greater than 30 mL/min, and a screening random tHcy level greater than12 uM/L. Patients will be stratified based on the presence/absence of clinical CVD, and randomly assigned to treatment with a standard multivitamin containing a high dose combination of folic acid, vitamin B6, and vitamin B12, or an identical multivitamin devoid of these three micronutrients. Randomized patients will also undergo a methionine loading test. All patients will receive standard clinical management for traditional CVD risk factor reduction. The study is designed to recruit 4000 patients (2000 in each group) over a two-year period for 83% power to detect a 25% treatment effect. Follow-up continues until occurrence of de novo or recurrent non-fatal CVD, or death, or a maximum of four-years. Data analysis will be performed on the basis of original randomization (intention to treat) using the log-rank test of difference in survival-without-endpoint curves. In the current era of cereal grain flour fortified with physiologic amounts of folic acid, RTRs comprise a patient population particularly well-suited to test the tenable hypothesis that tHcy-lowering treatment will reduce CVD outcomes, given: a) their persistent excess prevalence of mild hyperhomocysteinemia post-fortification, in contrast, for example, to coronary heart disease patients with normal renal function; b) the demonstrated capability of B-vitamin treatment regimens featuring supraphysiologic amounts of folic acid to successfully "normalize" tHcy levels in RTRs. Furthermore, overall "conditions" in the RTR population (i.e., renal impairment, mild to moderate hyperhomocysteinemia which can be normalized by supraphysiologic dose B-vitamin supplements, and high CVD event rates) are representative of the larger population of patients with chronic renal insufficiency, who are not yet dialysis-dependent. Accordingly, findings from the proposed trial are very likely to be generalizable to the much more sizable population of patients with renal insufficiency progressing to end-stage renal disease.

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