Healthy Combine Study

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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Short-Term Effects of Nicotinamide and Lanthanum Carbonate on Phosphorus Homeostasis in Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Nicotinamide
* Drug: Lanthanum Carbonate
* Drug: Lanthanum Carbonate Placebo
* Drug: Nicotinamide Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Double blind, randomized, placebo-controlled, 2x2 factorial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lanthanum + Nicotinamide<br>Lanthanum Carbonate 1000mg orally three times daily with meals for 2 weeks and Nicotinamide 750mg orally twice daily for 2 weeks | Drug: Nicotinamide<br>* Nicotinamide tablet<br>Drug: Lanthanum Carbonate<br>* Lanthanum Carbonate tablet<br>* Other names: Fosrenol;|
| Active Comparator: Lanthanum + Nicotinamide Placebo<br>Lanthanum Carbonate 1000mg orally three times daily with meals for 2 weeks and Nicotinamide Placebo orally twice daily for 2 weeks | Drug: Lanthanum Carbonate<br>* Lanthanum Carbonate tablet<br>* Other names: Fosrenol;Drug: Nicotinamide Placebo<br>* Sugar pill manufactured to look like Nicotinamide tablet<br>* Other names: Placebo (for Nicotinamide 750mg tablet);|
| Active Comparator: Lanthanum Placebo + Nicotinamide<br>Lanthanum Carbonate Placebo orally three times daily with meals for 2 weeks and Nicotinamide 750mg orally twice daily for 2 weeks | Drug: Nicotinamide<br>* Nicotinamide tablet<br>Drug: Lanthanum Carbonate Placebo<br>* Sugar pill manufactured to look like Lanthanum Carbonate tablet<br>* Other names: Placebo (for Lanthanum Carbonate 500mg tablet);|
| Placebo Comparator: Lanthanum Placebo + Nicotinamide Placebo<br>Lanthanum Carbonate Placebo orally three times daily with meals for 2 weeks and Nicotinamide Placebo orally twice daily for 2 weeks | Drug: Lanthanum Carbonate Placebo<br>* Sugar pill manufactured to look like Lanthanum Carbonate tablet<br>* Other names: Placebo (for Lanthanum Carbonate 500mg tablet);Drug: Nicotinamide Placebo<br>* Sugar pill manufactured to look like Nicotinamide tablet<br>* Other names: Placebo (for Nicotinamide 750mg tablet);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FGF23 | Longitudinal change in serum FGF23 levels from baseline visit through completion of study. | Approximately 3 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PTH | Longitudinal change in serum PTH levels from baseline visit through completion of study. | Approximately 3 weeks. | 
| Change in plasma phosphorus level | Longitudinal change in plasma phosphorus levels from baseline visit through completion of study. | Approximately 3 weeks. | 
| Change in urinary phosphorus level | Longitudinal change in urinary phosphorus levels from baseline visit through completion of study. | Approximately 3 weeks. | 
| Change in P1NP | Longitudinal change in serum P1NP levels from baseline visit through completion of study. | Approximately 3 weeks. | 
| Change in CTX | Longitudinal change in urinary phosphorus levels from baseline visit through | Approximately 3 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phosphorus Homeostasis, FGF23, Vitamin D