Healthy Combine Study

Healthy

Phosphorus Homeostasis, FGF23, Vitamin D

STUDY SUMMARY Title: EFFECTS OF NICOTINAMIDE AND LANTHANUM CARBONATE ON PHOSPHORUS HOMEOSTASIS Protocol Number:STU00090161 Phase: Phase 1, detailed physiologic study Methodology: double blind, randomized, placebo-controlled, 2x2 factorial Study Duration: 12-18 months (to complete the entire study protocol) Study Center: Single-center Objectives: Define short-term effects of the interventions (lanthanum carbonate and nicotinamide) on indices of phosphate handling Number of Subjects: 80 Diagnosis and Main Inclusion Criteria: Healthy volunteers Study Product(s), Dose,Route, Regimen: Nicotinamide, 750 mg by mouth twice daily, Lanthanum carbonate, Fosrenol, 1000 mg by mouth three times daily with meals Duration of administration: 2 weeks (length of time study participants are enrolled in study) Reference therapy: reference is a placebo Statistical Methodology: Repeated measures analysis using mixed linear models

Chronic kidney disease (CKD) is a growing public health problem that increases risks of endstage renal disease (ESRD), cardiovascular disease (CVD), fractures, and death, and it poses an enormous financial burden on the US health system. Existing therapies modestly impact outcomes. Novel strategies targeting CKD-specific mechanisms are urgently needed to improve health and reduce cost. CKD is complicated by disordered mineral metabolism, characterized by abnormal calcium and phosphate homeostasis, calcitriol and klotho deficiency, and elevated levels of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Elevated FGF23 is the earliest and most common manifestation of disordered mineral metabolism. Observational studies report independent associations between elevated phosphate and FGF23 blood levels and increased risks of ESRD, CVD and death. As potential explanatory mechanisms, phosphate excess induces arterial stiffness due to vascular calcification, and FGF23 excess contributes directly to the pathogenesis of left ventricular hypertrophy (LVH). Together, these effects promote CVD events and death. Dietary phosphate absorption is a modifiable determinant of phosphate and FGF23 levels. Small studies of short duration suggest that phosphate binders and dietary phosphate modification in CKD can lower phosphate and FGF23 blood levels by reducing paracellular absorption of phosphate in the gut. However, animal studies demonstrate that compensatory upregulation of transcellular phosphate absorption via the sodium phosphate co-transporter, NPT2b, reduces the efficacy of these approaches. Since nicotinamide lowers plasma phosphate by reducing gut expression of NPT2b,the investigators hypothesize that use of nicotinamide combined with phosphate binders on a background of dietary phosphate moderation will most effectively reduce phosphate and FGF23 blood levels in CKD. The investigators plan to advance this approach in future randomized clinical trials. The objective of this study is to perform a detailed physiologic study of healthy volunteers to assess the short-term effects of nicotinamide alone, lanthanum carbonate alone, or both in combination, on phosphate homeostasis. The results from healthy volunteers will provide information needed for optimal design of studies for patients with CKD.

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