Healthy Combine Study

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.

INCLUSION CRITERIA

Healthy volunteers

Age ≥ 18 years, at the time of screening

Normal renal function at screening, as defined by

- eGFR > 60

- no albuminuria

- normal urinalysis

- normotensive, defined as blood pressure <140/85mmHg

- no known history of CKD

Adequate organ and marrow function at screening as defined below:

- HCT ≥ 30%

- platelets ≥ 125,000/mm3

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit

- 25-hydroxyvitamin D ≥ 10mg/dL

Women of child-bearing potential and men must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation, and for 90 days following completion of therapy.

Ability to understand and the willingness to sign a written informed consent.

EXCLUSION CRITERIA:

History of allergic reaction to nicotinamide, niacin (excluding flushing), and/or
multivitamin preparations

Liver disease, defined as known cirrhosis by imaging or physician diagnosis.

- Documented alcohol use > 14 drinks/week

- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and/or alkaline
phosphatase concentrations > 2 times the upper limit of the local laboratory reference
range and/or total bilirubin concentration not within institutional limits.

Creatine kinase (CK) concentrations > 2 times the upper limit of the local laboratory
reference range at screening

Major hemorrhagic event within the past six months from screening requiring inpatient
admission.

Blood or platelet transfusion within the past six months from screening

History of primary hyperparathyroidism

Current, clinically significant malabsorption

Anemia (screening HCT < 30%) at screening

Plasma albumin < 2.5 mg/dl at screening

25-hydroxyvitamin D <10mg/dL at screening

Inability or unwillingness to provide consent

Current or recent treatment (within the last 14 days from screening) with
niacin/nicotinamide > 100 mg/day

Current or recent use of MVI containing niacin/nicotinamide > 100 mg/day

Current use of Tums (or calcium carbonate taken for indigestion) at a dose of >1000 mg
daily

Current participation in another clinical trial or other interventional research