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.

• Nicotinamide (Drug): Nicotinamide tablet
• Lanthanum Carbonate (Drug), also known as Fosrenol: Lanthanum Carbonate tablet
• Lanthanum Carbonate Placebo (Drug), also known as Placebo (for Lanthanum Carbonate 500mg tablet): Sugar pill manufactured to look like Lanthanum Carbonate tablet
• Nicotinamide Placebo (Drug), also known as Placebo (for Nicotinamide 750mg tablet): Sugar pill manufactured to look like Nicotinamide tablet

Primary outcomes

• Change in Intact FGF23 [Approximately 3 weeks.]: Longitudinal change in serum intact FGF23 levels from baseline visit through completion of study.

Secondary outcomes

• Change in Plasma Phosphorus Level [Approximately 3 weeks.]: Longitudinal change in plasma phosphorus levels from baseline visit through completion of study.
• Change in 24 Hour Urinary Phosphorus Level [Approximately 3 weeks.]: Longitudinal change in 24 hour urinary phosphorus levels from baseline visit through completion of study.

Sex: All, ages: 18 Years to 60 Years, accepts healthy volunteers

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

Participant flow

Outcome results

• Change in Intact FGF23 (Primary), Geometric mean, pg/ml: Lanthanum + Nicotinamide 1.001 (0.978 to 1.024); Lanthanum + Nicotinamide Placebo 1.006 (0.983 to 1.029); Lanthanum Placebo + Nicotinamide 1.009 (0.987 to 1.032); Lanthanum Placebo + Nicotinamide Placebo 1.005 (0.995 to 1.014) (p 0.3738)
• Change in Plasma Phosphorus Level (Secondary), Geometric mean, mg/dl: Lanthanum + Nicotinamide 0.0099 (-0.0407 to 0.0604); Lanthanum + Nicotinamide Placebo -0.0102 (-0.0596 to 0.0392); Lanthanum Placebo + Nicotinamide 0.0099 (-0.0395 to 0.0593); Lanthanum Placebo + Nicotinamide Placebo 0.0004 (-0.0202 to 0.0210) (p 0.854)
• Change in 24 Hour Urinary Phosphorus Level (Secondary), Geometric mean, mg: Lanthanum + Nicotinamide -10.24 (-33.94 to 13.47); Lanthanum + Nicotinamide Placebo -5.88 (-29.13 to 17.37); Lanthanum Placebo + Nicotinamide 1.29 (-22.11 to 24.69); Lanthanum Placebo + Nicotinamide Placebo -10.85 (-20.56 to -1.13) (p 0.0648)

Adverse events

Time frame: Duration of the study, which with study visit windows was approximately 3 weeks

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2017-02-15)

• Tamara Isakova, MD, MMSc, Principal investigator, Northwestern University