Clinical trial NCT03136705
Conditions: Healthy
Keywords: Phosphorus Homeostasis FGF23 Vitamin D
Sponsor: Northwestern University
Start date: 2016-02-03; Completion date: 2017-12-01
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
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:
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.

Arms: arm 1: Lanthanum Carbonate 1000mg orally three times daily with meals for 2 weeks and Nicotinamide 750mg orally twice daily for 2 weeks arm 2: Lanthanum Carbonate 1000mg orally three times daily with meals for 2 weeks and Nicotinamide Placebo orally twice daily for 2 weeks arm 3: Lanthanum Carbonate Placebo orally three times daily with meals for 2 weeks and Nicotinamide 750mg orally twice daily for 2 weeks arm 4: Lanthanum Carbonate Placebo orally three times daily with meals for 2 weeks and Nicotinamide Placebo orally twice daily for 2 weeks
Interventions: intervention 1: Nicotinamide intervention 2: Lanthanum Carbonate intervention 3: Lanthanum Carbonate Placebo intervention 4: Nicotinamide Placebo
Intervention descriptions: intervention 1: Nicotinamide tablet intervention 2: Lanthanum Carbonate tablet intervention 3: Sugar pill manufactured to look like Lanthanum Carbonate tablet intervention 4: Sugar pill manufactured to look like Nicotinamide tablet

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
SHORT-TERM EFFECTS OF NICOTINAMIDE AND LANTHANUM CARBONATE ON 
PHOSPHORUS HOMEOSTASIS IN HEALTHY VOLUNTEERS     
 
Detailed physiologic study of healthy volunteers  
 
Principal Investigator: 
 
 
 
 
 
Tamara Isakova, MD, MMSc 
 
                                   Northwestern University 
 
Address: 633 North St. Clair, 18th Floor   
                                               Room 18-083 
Chicago, IL 60611 
 
Phone # (312)-503-6921 
 
Fax # (312)-503-5656 
 
Email: tamara.isakova@northwestern.edu 
Biostatistician: 
 
Jungwha Lee, PhD 
  
 
 
 
Assistant Professor, Department of Preventative Medicine  
 
 
 
 
Northwestern University 
 
 
 
 
680 N Lake Shore Drive 
 
 
 
 
Suite 1400 
 
 
 
 
Chicago, IL 60611 
 
 
 
 
(312)-503-2292 
 
 
 
 
Fax: (312)-908-9588 
 
 
 
 
jungwha-lee@northwestern.edu 
 
Study Drug/Study Device: Nicotinamide 
 
 
 
 
Lanthanum carbonate, Fosrenol   
 
IND/IDE Number: 
 
IND exempt (see appendix for documentation)  
 
IND/IDE Holder Name: 
IND exempt (see appendix for documentation) 
 
Funding Source:  
NIDDK 
 
Initial version:  
 
May 6, 2014 
Amended: 
 
 
February 15, 2017  
 
                                               Research Office Address 
                                               633 North St. Clair, 18th Floor   
                                               Room 18-083 
Chicago, IL 60611 
 
Phone # (312)-503-6921 
 
Fax # (312)503-5656 
 
Email: tamara.isakova@northwestern.edu 
 


STU00090161 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................1 
STUDY SCHEMA..............................................................................................................2 
STUDY SUMMARY ..........................................................................................................2 
1.0 
BACKGROUND AND RATIONALE ...................................................................3 
1.1 
Disease Background........................................................................................................ 3 
1.2 
Study Agent(s)/Devices Background and Associated Known Toxicities ......................... 3 
1.3 
Other Agents/Devices ...................................................................................................... 4 
1.4 
Rationale .......................................................................................................................... 4 
2.0 
STUDY OBJECTIVES...........................................................................................5 
2.1 
Primary Objectives ........................................................................................................... 5 
2.2 
Secondary Objectives ...................................................................................................... 5 
2.3 
Endpoints ......................................................................................................................... 5 
3.0 
PATIENT ELIGIBILITY .........................................................................................5 
3.1 
Inclusion Criteria .............................................................................................................. 5 
3.2 
Exclusion Criteria ............................................................................................................. 6 
4.0 
TREATMENT PLAN ..............................................................................................7 
4.1 
Treatment Dosage and Administration ............................................................................ 7 
4.2 
Toxicities and Dosing Delays/Dose Modifications ........................................................... 7 
4.3 
Concomitant Medications/Treatments ............................................................................. 8 
4.4 
Other Modalities or Procedures ....................................................................................... 8 
4.5 
Duration of Therapy ......................................................................................................... 8 
4.6 
Duration of Follow Up ...................................................................................................... 8 
4.7 
Removal of Participants from Protocol Therapy .............................................................. 8 


STU00090161 
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4.8 
Participant Replacement ................................................................................................. 8 
5.0 
STUDY PROCEDURES ........................................................................................8 
5.1 
Recruitment…………….……………………………………………………………………….8 
5.2 
Screening Procedures ..................................................................................................... 9 
5.3 
Baseline Procedures........................................................................................................ 9 
5.4 
Procedures During Treatment ....................................................................................... 10 
5.5 
Time and Events Table .................................................................................................. 11 
5.6 
Removal of Subjects from Study ................................................................................... 11 
6.1   Safety/tolerability ................................................................................................................ 12 
7.1 
Adverse Event Monitoring ............................................................................................. 12 
7.2 
Definitions ...................................................................................................................... 12 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 13 
7.4 
Reporting Requirements for Adverse Events ................................................................ 14 
7.5 
Unblinding Procedures .................................................................................................. 15 
7.6 
Stopping Rules .............................................................................................................. 15 
8.0 
DRUG/DEVICE INFORMATION .......................................................................15 
8.1 
Lanthanum Carbonate ................................................................................................... 15 
8.2 
Nicotinamide .................................................................................................................. 16 
9.0 
CORRELATIVES/SPECIAL STUDIES ............................................................16 
9.1 
Sample Collection Guidelines ........................................................................................ 17 
9.2 
Assay Methodology ....................................................................................................... 17 
9.3 
Specimen Banking ......................................................................................................... 17 
10.0 
STATISTICAL CONSIDERATIONS .............................................................17 
10.1 
Study Design/Study Endpoints ...................................................................................... 17 
10.2 
Sample Size and Accrual .............................................................................................. 18 
10.3 
Data Analyses Plans...................................................................................................... 19 


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11.0 
STUDY MANAGEMENT .................................................................................19 
11.1 
Conflict of Interest .......................................................................................................... 19 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 19 
11.3 
Registration Procedures ................................................................................................ 20 
 
   11.4    Subject Compensation………………………………………………………………………..19 
11.5 
Data Management and Monitoring/Auditing .................................................................. 20 
11.6 
Adherence to the Protocol ............................................................................................. 20 
11.7 
Amendments to the Protocol ......................................................................................... 21 
11.8 
Record Retention ........................................................................................................... 21 
11.9 
Obligations of Investigators ........................................................................................... 21 
12.0 
REFERENCES .................................................................................................23 
13.0 
APPENDICES ...................................................................................................24 


STU00090161 
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LIST OF ABBREVIATIONS 
 
CKD  
chronic kidney disease   
CBC 
complete blood counts 
CVD 
cardiovascular disease 
ESRD 
end-stage renal disease  
FGF23 
fibroblast growth factor 23 hormone 
LVH 
left ventricular hypertrophy 
NPT2b 
sodium phosphate co-transporter 
PTH 
parathyroid hormone 
FEPi 
Fractional excretion of phosphate 
P1NP 
N terminal propeptide of Type 1 procollagen, bone formation marker 
CTX 
C terminal cross-linked peptide, bone resorption marker 
LC 
Lanthanum Carbonate 
N 
Nicotinamide 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LC, Lanthanum carbonate 
N, Nicotinamide 
STUDY SUMMARY 
Title 
EFFECTS OF NICOTINAMIDE AND LANTHANUM CARBONATE 
ON PHOSPORUS HOMEOSTASIS     
Short Title 
Nicotinamide, lanthanum carbonate and phosphate 
homeostasis     
Protocol Number 
The standard protocol number used to identify this study 
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(s) 
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 
 
 
 
LC
LC + N 
N
Placebo
Screen
Baseline
Randomize


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Chronic kidney disease (CKD) is a growing public health problem that increases risks of end-
stage renal disease (ESRD), cardiovascular disease (CVD), fractures, and death, and it poses 
an enormous financial burden on the US health system.1-3 Existing therapies modestly impact 
outcomes.4-8  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).9  Elevated FGF23 is the earliest and 
most common manifestation of disordered mineral metabolism.10  Observational studies report 
independent associations between elevated phosphate and FGF23 blood levels and increased 
risks of ESRD, CVD and death.11-13  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).14,15  Together, these effects promote 
CVD events and death.12        
Dietary phosphate absorption is a modifiable determinant of phosphate and FGF23 levels.16-18  
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.19  However, animal studies demonstrate that compensatory 
upregulation of transcellular phosphate absorption via the sodium phosphate co-transporter, 
NPT2b, reduces the efficacy of these approaches.20,21  Since nicotinamide lowers plasma 
phosphate by reducing gut expression of NPT2b,22 we 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.  We 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. 
1.2 
Study Agent(s)/Devices Background and Associated Known Toxicities 
Nicotinamide will be used at a dose of 750 mg twice daily.  Nicotinamide reduces plasma 
phosphate levels by blocking intestinal phosphate absorption through down-regulation of 
NPT2b,21 and it is well-tolerated and considered safe at high doses.23 Unlike niacin, 
nicotinamide does not cause flushing, and is thought to be less likely to cause liver test 
abnormalities, hyperuricemia, or insulin resistance.24 In a post-hoc analysis of a randomized 
study of niacin in 327 patients with CKD stages 2 and 3, Rao et al found that, in addition to 
reducing phosphate levels in the blood, niacin decreased FGF23 levels by 10.9% from baseline 
over 24 weeks, and that the magnitude of the decline in FGF23 was directly associated with the 
magnitude of decline in blood phosphate.25   
Lanthanum carbonate at a dose of 1000 mg twice daily with meals will be used.  Lanthanum 
carbonate is a phosphate binder that is approved for use in patients with ESRD undergoing 
dialysis. This fixed dose was chosen because we have demonstrated that this dose safely 
reduced urinary phosphate, signifying effective phosphate binding, in CKD stages 3−4.26,27  
Importantly, lanthanum carbonate has been used in the hemodialysis population, with 6-year 
long safety data demonstrating a good safety profile.28 Lanthanum carbonate has also been 


STU00090161 
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used in healthy volunteers in whom it has also been found to be safe.  As in patients with CKD, 
doses of 1000 mg three times daily in healthy volunteers achieve maximal reduction in 24-hour 
urine.29  
1.3 
Other Agents/Devices 
N/A 
1.4 
Rationale 
The justification for the combined approach of binders with nicotinamide to modify plasma 
phosphate and FGF23 levels in CKD is rooted in our current understanding of the underlying 
biology.  However, detailed human physiologic studies investigating the joint effects of these 
agents on blood and urine levels of mineral metabolites are not available in health or in CKD.  
Animal data consistently demonstrate that nicotinamide blocks small bowel Pi absorption by 
decreasing protein levels of NaPi2b.20,21 Some studies also suggest that nicotinamide may block 
phosphate reabsorption at the renal proximal tubule,30 but this has not been studied in detail in 
healthy volunteers or CKD patients.  Finally, the effects of nicotinamide on FGF23, PTH, 
calcitriol, and other parameters of mineral metabolism are unexplored in humans.  Therefore, 
our proposed study will fill critical gaps that are needed to advance this novel therapeutic 
approach into future clinical trials.  
 
We propose to study healthy volunteers because detailed data on the effects on mineral 
metabolism of nicotinamide alone or in combination with binders in this population are not 
available.  In the future, we will also extend the proposed studies to patients with CKD.  
 
Given that 24-hr urinary phosphate excretion declines and fractional phosphate excretion rises 
with progressive CKD, an additional justification for the study of healthy volunteers is the ability 
to easily detect changes following proposed interventions in both 24-hour and fractional urinary 
phosphate excretion.  
  
For this detailed physiologic study, we chose to use the 2x2 factorial study design because we 
are specifically interested in investigating the effects of the combined interventions as compared 
to the effects of the placebo and to each monotherapy group.   
 
We chose plasma phosphate, 24-hour urine phosphate, fractional urinary excretion of 
phosphate (FEPI), FGF23 and PTH as end-points because we are interested in the effects of 
the interventions on phosphate handling and mineral metabolism (See Table).  Additional end-
points will include markers of bone turnover, including N terminal propeptide of Type 1 
procollagen (P1NP) and C terminal cross-linked peptide (CTX) to assess the influence of the 
interventions on bone metabolism.  
Summary of End Points 
End-Point 
Prima
ry 
Secondar
y 
Justification 
Plasma Phosphate 
X 
 
Marker of phosphate handling 
24-hr Urine Phosphate 
X 
 
Marker of phosphate handling 
FePI 
X 
 
Marker of phosphate handling 
PTH 
 
X 
Hormonal regulator of mineral metabolism 
FGF23 
 
X 
Hormonal regulator of mineral metabolism 
P1NP 
 
X 
Bone formation marker 
CTX 
 
X 
Bone resorption marker 
 


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2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 To determine the short-term effects of lanthanum carbonate and 
nicotinamide, alone and in combination, on phosphate handling, as 
measured by plasma phosphate, 24-hour urinary phosphate and 
fractional excretion of phosphate in healthy volunteers 
2.2 
Secondary Objectives  
2.2.1 To determine the short-term effects of lanthanum carbonate and 
nicotinamide, alone and in combination, on hormonal regulators of mineral 
metabolism: FGF23 and PTH 
 
2.2.2 To determine the short-term effects of lanthanum carbonate and 
nicotinamide, alone and in combination, on markers of bone turnover: 
P1NP and CTX 
2.3 
Endpoints 
  
Summary of End Points 
End-Point 
Primary Secondary 
Justification 
Plasma Phosphate 
X 
 
Marker of phosphate handling 
24-hr Urine 
Phosphate 
X 
 
Marker of phosphate handling 
FePI 
X 
 
Marker of phosphate handling 
PTH 
 
X 
Hormonal regulator of mineral metabolism 
FGF23 
 
X 
Hormonal regulator of mineral metabolism 
P1NP 
 
X 
Bone formation marker 
CTX 
 
X 
Bone resorption marker 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be registered to the 
study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
3.1.1 Healthy volunteers 
 
3.1.2 Age ≥ 18 years, at the time of screening 
 
3.1.3 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 
 
3.1.4 Adequate organ and marrow function at screening as defined below: 
- HCT 
 
 
≥ 30% 
- platelets                          ≥ 125,000/mm3 


STU00090161 
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- total bilirubin 
 
within normal institutional limits 
 
- AST(SGOT)/ALT(SPGT) 
≤ 2.5 X institutional upper limit  
- 25-hydroxyvitamin D 
 
≥ 10mg/dL 
 
 
3.1.5 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.  
 
3.1.6 Ability to understand and the willingness to sign a written informed 
consent. 
3.2 
Exclusion Criteria 
3.2.1 History of allergic reaction to nicotinamide, niacin (excluding flushing), and/or 
multivitamin preparations 
3.2.2 Liver disease, defined as known cirrhosis by imaging or physician diagnosis, 
documented alcohol use > 14 drinks/week, or 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.  
3.2.3 Creatine kinase (CK) concentrations > 2 times the upper limit of the local 
laboratory reference range at screening 
3.2.4 Major hemorrhagic event within the past six months from screening requiring in-
patient admission 
3.2.5 Blood or platelet transfusion within the past six months from screening 
3.2.6 History of primary hyperparathyroidism  
3.2.7 Current, clinically significant malabsorption 
3.2.8 Anemia (screening HCT < 30%) at screening 
3.2.9 Plasma albumin < 2.5 mg/dl at screening 
3.2.10 25-hydroxyvitamin D <10mg/dL at screening 
3.2.11 Inability or unwillingness to travel to study visits, as described in the protocol 
3.2.12 Inability or unwillingness to provide consent 
3.2.13 Current or recent treatment (within the last 14 days from screening) with 
niacin/nicotinamide > 100 mg/day 
3.2.14 Current or recent use of MVI containing niacin/nicotinamide > 100 mg/day 
3.2.15 Current use of Tums (or calcium carbonate taken for indigestion) at a dose of 
>1000 mg daily   
3.2.16 Current participation in another clinical trial or other interventional research 
 
3.3 
WOMEN OF CHILD-BEARING POTENTIAL 
3.3.1 Should a woman become pregnant or suspect she is pregnant while participating  
in this study, she should inform her treating physician immediately. A female of child-
bearing potential is any woman (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) who meets the following criteria: 
 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive months 
(i.e., has had menses at any time in the preceding 12 consecutive months). 


STU00090161 
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• 
Pregnancy or planning to become pregnant or currently breast-feeding.  
Women of childbearing potential (pre-menopausal and not surgically 
sterilized) will have pregnancy test before enrollment  
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 Overview: 
Eligible participants will be randomized to one of the following 4 groups:  
• 
Lanthanum carbonate + nicotinamide  
• 
Lanthanum carbonate + nicotinamide placebo 
• 
Lanthanum carbonate placebo + nicotinamide  
• 
Lanthanum carbonate placebo + nicotinamide placebo 
 
4.1.2 Regimen description is presented in the table below.  
 
 
Agent 
 
Dose 
 
Route 
 
Schedule 
 
Cycle Length  
Nicotinamide 750 mg twice 
daily 
By mouth 
Daily for 
2 weeks 
2 weeks 
(14 days) 
 
Lanthanum 
carbonate 
1000 mg three 
times daily 
with meals 
By mouth 
Daily for 
2 weeks  
 
Lanthanum carbonate is a chewable tablet. Lanthanum carbonate binds ingested 
phosphorus in the gut and therefore only works when taken with meals. Participants who 
do not eat regular meals will be instructed to take full doses with larger meals and half 
with snacks.  Nicotinamide can be taken together with lanthanum carbonate at breakfast 
and at dinner.  
4.2 
Toxicities and Dosing Delays/Dose Modifications 
 
Lanthanum carbonate may lower blood phosphate levels and can be associated with 
gastrointestinal side effects including nausea, vomiting, constipation and diarrhea.   
 
Nicotinamide may lower blood phosphate levels and may be associated with other laboratory 
abnormalities including thrombocytopenia, abnormalities in liver function tests and CK.  
Gastrointestinal side effects, such as diarrhea and heartburn may also occur.  
 
The following laboratory results are expected study adverse events:  
• 
Hypophosphatemia:  Plasma phosphate level <1.5 mg/dl 
• 
Thrombocytopenia: Platelet count <100,000 
• 
Liver function test abnormalities:  AST, ALT, total bilirubin, alkaline phosphatase> 4 
times the upper limit of the core lab (fill in precise numbers when the lab is named) 
• 
Elevated Creatine Kinase: Creatine Kinase > 4 times upper limit of normal 
 


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The following symptoms are expected study adverse events: 
• 
Bruising   
• 
Bleeding   
• 
Severe diarrhea 
• 
Severe nausea 
• 
Flushing  
• 
Hives 
 
Each patient will be assessed for the development of toxicity at each study visit (see section 
5.4). 
4.3 
Concomitant Medications/Treatments 
Calcium carbonate tablets taken for indigestion, such as Tums, are allowed if taken once per 
day or less, at least 2 hours away from meals and at a maximum dose of 1000 mg daily.  
However, participants who report using Tums often will be encouraged to try over-the counter 
Pepcid (famotidine), Tagamet (cimetidine), or Zantac (ranitidine). 
Non-study source of vitamin B3 (niacin or nicotinamide) as a stand- alone medication or in a 
multivitamin that contains less than 100 mg/day of nicotinamide is allowed.  Larger doses are to 
be avoided.    
4.4 
Other Modalities or Procedures 
N/A 
4.5 
Duration of Therapy 
The intervention will last for 2 weeks. 
4.6 
Duration of Follow Up 
Follow up will last for 2 weeks.  
4.7 
Removal of Participants from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 
5.6 apply.  
4.8 
Participant Replacement 
N/A 
5.0 
STUDY PROCEDURES 
 
There are 8 expected visits for the entire study. Study visits baseline 1 and follow-up 5 will take 
place at the NUCATS Clinical Research Center (CRU). The remaining visits will be completed at 
the Center for Translation Metabolism and Health (CTMH). 
 
 
5.1 Recruitment 
 
Subjects will be recruited using the NUCATS registry, Women’s Health Research 
Institute registry, Illinois Men’s Health Registry, ResearchMatch registry, newspaper and 
online advertisements, and an IRB-approved flyer. Potential participants from the 
registries will be sent an IRB-approved recruitment letter, recruitment e-mail, and 
contacted via telephone. Individuals solicited via Women’s Health Registry and Men’s 


STU00090161 
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9 
Health Registry will be sent recruitment letters specific to the registry. Newspaper and 
online advertisements will use IRB-approved advertisement. 
 
5.2 
Screening Procedures 
Assessments performed exclusively to determine eligibility for this study will be 
done only after obtaining informed consent.  
 
The screening procedures include: 
5.2.1 Informed Consent 
          Consent form will be reviewed in full with each subject. 
5.2.2 Medical history and Physical Exam 
Complete medical and surgical history will be obtained from each subject, 
and a physical exam will be performed on each subject. 
5.2.3 Demographics 
Subject will be queried on age, gender, race, and ethnicity 
5.2.4 Review subject eligibility criteria 
           Study personnel will review inclusion/exclusion criteria with every subject  
           to determine eligibility. 
5.2.5 Review previous and concomitant medications, including 
multivitamins 
5.2.6 Vital signs, height and weight 
Blood pressure, height, and weight will be obtained on each subject. 
5.2.7 Hematology 
CBC  
5.2.8 
Plasma chemistries and Serum 25-Hydroxyvitamin D 
To include: albumin, alkaline phosphatase, ALT/SGPT, AST/SGOT, 
BUN, creatinine, electrolytes (sodium, potassium, chloride, bicarbonate), 
glucose, and total bilirubin; phosphorus; calcium; CK; and 25-
hydroxyvitamin D 
5.2.9 
Random urine 
To include: creatinine and albumin 
5.2.10 Supplies for 24-hr urine collection 
5.2.11 Rapid Urine Pregnancy test (for females of child bearing potential) 
See section 3.1.6.1 for definition. 
5.3 
Baseline Procedures 
During this period, we will get baseline assessments of parameters of interest.  


STU00090161 
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10 
5.3.1 
Baseline Visit 1 
• Return 24-hour urine collection to measure phosphorus, creatinine, 
calcium, and urea in the urine 
• Random urine sample to measure phosphorus, creatinine, and calcium 
in the urine 
• 8-hour CRU stay for 8–hour timed urine collection to measure 
phosphorus, creatinine, calcium and urea in the urine 
• Plasma chemistries (creatinine, phosphate, calcium) 
• Blood draw for correlative studies (PTH, FGF23, P1NP, CTX) 
• Blood draw for optional study elements (PTH, FGF23, P1NP, CTX) 
• Distribute supplies for 24-hr urine collection 
5.4 
Procedures During Treatment 
During this period, participants will be randomized to the intervention arms (Baseline 2/ 
Follow up visit 0), have two 8-hour visits (Baseline visits 1 and Follow up visit 5) and will 
make visits to the CTMH every 3 days (Follow up visits 1 – 4).  
 
5.4.1 
Baseline 2/Follow-up Visit 0 (F0) 
• Return 24-hour urine collection to measure phosphorus, creatinine, 
calcium, and urea in the urine 
• Random urine sample to measure phosphorus, creatinine, and calcium 
in the urine 
• Plasma chemistries (NA, K, Cl, HCO3, BUN, Cr, glucose, phosphate, 
calcium)  
• Blood draw for correlative studies (PTH, FGF23) 
• Randomization to interventions 
• Distribute study drug/placebo 
• Distribute supplies for next 24-hr urine collection 
5.4.2 
Follow-up Visits 1 – 4 (F1-F4) 
• Return 24-hour urine collection to measure phosphorus, creatinine, 
calcium, and urea in the urine 
• Plasma chemistries(NA, K, Cl, HCO3, BUN, Cr, glucose, calcium)  
• Blood draw for correlative studies (PTH, FGF23) 
• Random urine sample to measure phosphorus, creatinine, and calcium 
in the urine 
• Distribute supplies for next 24-hr urine collection 
• Bring in pill bottles for pill counts  
• Safety assessments (phosphate, CK, CBC, LFTs, GI Questionnaire)  
5.4.3 
Follow-up Visit 5 (F5) 
• Return 24-hour urine collection to measure phosphorus, creatinine, 
calcium, and urea in the urine 
• Random urine sample to measure phosphorus, creatinine, and calcium 
in the urine 
• 8-hour CRU stay for 8–hour timed urine collection to measure 
phosphorus, creatinine, calcium and urea in the urine 


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• Plasma chemistries (NA, K, Cl, HCO3, BUN, Cr, glucose, calcium) 
• Safety assessments (phosphate, CK, CBC, LFTs, GI Questionnaire) 
• Blood draw for correlative studies (PTH, FGF23, P1NP, CTX) 
• Blood draw for optional study elements (PTH, FGF23, P1NP, CTX) 
• Bring in pill bottles for pill counts  
5.5 
Time and Events Table 
 
Periods 
SCREENING 
BASELINE  
 
Follow UP 
Visits 
S1 
B1 
B2/F0 
F1 
F2 
F3 
F4 
F5 
Days 
-15 
-5 
-2 
0 
3 
6 
9 
12 
Pregnancy testing 
X 
 
 
 
 
 
 
 
RANDOMIZATION 
 
 
X 
 
 
 
 
 
Distribute drug/placebo  
(X=21 day supply) 
 
 
X 
 
 
 
 
 
Demographics, medical history, physical 
exam 
X 
 
 
 
 
 
 
 
Vital signs (blood pressure, height, 
weight) 
X 
 
 
 
 
 
 
 
Co-Primary end-points 
FePI/ Spot Urine phosphate, calcium, and 
creatinine 
 
X 
X 
X 
X 
X 
X 
X 
24-hr urine phosphate, creatinine, calcium, 
and urea 
 
X 
X 
X 
X 
X 
X 
X 
8 hr urine phosphate, creatinine, calcium, 
and urea 
 
X 
 
 
 
 
 
X 
Spot Urine (creatinine, albumin) 
X 
 
 
 
 
 
 
 
Other mineral metabolites 
PTH 
 
X 
X 
X 
X 
X 
X 
X 
FGF23 
 
X 
X 
X 
X 
X 
X 
X 
P1NP  (bone metabolism marker) 
 
X 
 
 
 
 
 
X 
CTX     (bone metabolism marker) 
 
X 
 
 
 
 
 
X 
25 hydroxyvitamin D 
X 
 
 
 
 
 
 
 
Plasma Phosphate 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma Calcium 
X 
X 
X 
X 
X 
X 
X 
X 
Renal parameters 
Chem 7 (Na, K, Cl, HCo3, BUN, Cr, 
glucose) 
X 
 
X 
X 
X 
X 
X 
X 
Plasma Creatinine 
 
X 
 
 
 
 
 
 
Stored blood samples (optional) 
 
X 
 
 
 
 
 
X 
Stored urine samples (optional) 
 
X 
 
 
 
 
 
X 
CBC, LFTs, CK 
X 
 
 
X 
X 
X 
X 
X 
Adverse events assessment (labs and GI 
questionnaire)  
 
 
 
X 
X 
X 
X 
X 
Pill Count 
 
 
 
X 
X 
X 
X 
X 
 
5.6 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for 
safety, behavioral or administrative reasons. The reason(s) for discontinuation 
will be documented. 


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6.0        Response Criteria 
Plasma Phosphate levels, CBC, LFTs, CK will be monitored as safety 
labs through the intervention period.  
 
6.1   Safety/tolerability 
 
Analyses of safety will be performed for all patients having received at 
least one dose of study drug.  
7.0        ADVERSE EVENTS 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to 
allow for optimal monitoring of patient safety and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study 
drug/device, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the 
changes observed; or 
 death. 
7.2 
Definitions 
7.2.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  
7.2.2 Severity of Adverse Events 
The severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status. 


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Life-threatening (grade 4): the patient was at risk of death at the time of 
the event. 
Fatal (grade 5): the event caused death. 
7.2.3 
Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any 
untoward medical occurrence that: 
7.2.3.1 
Results in death. 
If death results from (progression of) the disease, the disease 
should be reported as event (SAE) itself. 
7.2.3.2 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused 
death if it were more severe). 
7.2.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
7.2.3.4 
Results in persistent or significant disability or incapacity. 
7.2.3.5 
Is a congenital anomaly/birth defect 
7.2.3.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event 
may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; convulsions that 
may not result in hospitalization; development of drug abuse or 
drug dependency. 
7.3 
Steps to Determine If an Adverse Event Requires 
Expedited Reporting 
Step 1: Identify the type of adverse event   
 
Step 2: Grade the adverse event  
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 


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14 
Note: This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the last dose 
of treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity 
of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section 
of this protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
7.4 
Reporting Requirements for Adverse Events 
7.4.1 
Expedited Reporting 
• 
The Principal Investigator must be notified within 24 hours of learning 
of any serious adverse events, regardless of attribution, occurring 
during the study or within 30 days of the last administration of the 
study drug.  
• 
The IRB must be notified within 10 business days of “any 
unanticipated problems involving risk to subjects or others” 
(UPR/UPIRSO).  
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other 
problems), which in the opinion of the Principal Investigator was 
unanticipated, involved risk to subjects or others, and was 
possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-
approved protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, 
updated sponsor safety report), interim result or other finding that 
indicates an unexpected change to the risk/benefit ratio for the 
research. 
5. Any breach in confidentiality that may involve risk to the subject 
or others. 
6. Any complaint of a subject that indicates an unanticipated risk or 
that cannot be resolved by the Principal Investigator. 


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7.4.2 
Routine Reporting 
• 
All other adverse events- such as those that are expected, or are 
unlikely or definitely not related to the study participation- are to be 
reported annually as part of regular data submission. 
7.5 
Unblinding Procedures 
When a participant stops his or her blinded nicotinamide and lanthanum carbonate and 
appropriate clinical management of the participant is dependent on knowledge of whether the 
participant had been taking active nicotinamide or active lanthanum carbonate, the research 
pharmacist will unblind the investigator to the necessary arm.   
7.6 
Stopping Rules  
7.6.1 
Hypophosphatemia 
If a study participant has a plasma phosphate level lower than 1.5 mg/dl, an extra visit will be 
held immediately so the test can be repeated.  If the second lab test confirms a plasma 
phosphate level under 1.5 mg/dl, then both study medications should be stopped. 
7.6.1 
Other side effects  
If a study participant develops any of the following expected study adverse events, study 
interventions will be stopped:   
• 
Thrombocytopenia: Platelet count <100,000 
• 
Liver function test abnormalities:  AST, ALT, total bilirubin, alkaline phosphatase> 
4 times the upper limit of the core lab (fill in precise numbers when the lab is 
named) 
• 
Elevated Creatine Kinase: Creatine Kinase > 4 times upper limit of normal 
• 
Severe bleeding   
• 
Severe diarrhea 
• 
Severe nausea 
• 
Severe Flushing  
• 
Hives   
8.0 
DRUG/DEVICE INFORMATION 
8.1 
Lanthanum Carbonate 
• 
Fosrenol 
 
• 
Classification – phosphate binder 
 
• 
Mode of action: binds intestinal phosphate  
 
• 
Storage and stability: stable at room temperature; protect from moisture 
 
• 
Protocol dose: 1000 mg by mouth three times daily with meals 
 
• 
Preparation: chewable tablet 
 
• 
Route of administration for this study: by mouth 
 


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16 
• 
Incompatibilities: N/A 
 
• 
Availability: provided free of charge by manufacturer 
 
• 
Side effects: hypophosphatemia, nausea, vomiting, diarrhea, abdominal 
discomfort 
 
• 
Nursing implications: none 
8.2 
Nicotinamide 
• 
Niacinamide 
 
• 
Classification – vitamin  
 
• 
Mode of action: blocks phosphate absorption through gut sodium phosphate 
channel 
 
• 
Storage and stability: stable at room temperature; protect from moisture 
 
• 
Protocol dose: 750 mg by mouth twice daily 
 
• 
Preparation: tablet, oral 
 
• 
Route of administration for this study: by mouth 
 
• 
Incompatibilities: N/A 
 
• 
Availability: provided free of charge by manufacturer 
 
• 
Side effects: hypophosphatemia, nausea, vomiting, diarrhea, abdominal 
discomfort 
 
• 
Nursing implications: none 
 
8.2.1 
Return and Retention of Study Drug/Device 
The research pharmacist at NMH will assist with disposal of drugs.  
 
8.1.2 We will use pill counts to document compliance with drugs.   
9.0 
CORRELATIVES/SPECIAL STUDIES 
 
The goal of the planned laboratory correlative studies is to understand how changes in 
phosphate homeostasis affect endocrine regulators of bone and mineral metabolism and 
markers of bone turnover.  Additional stored samples will be archived for future analyses 
of newly discovered biomarkers related to bone and mineral homeostasis and its 
regulation. Submission of samples for correlative studies is mandatory. The consent 
form will have a statement that will inform participants about the planned use of archived 
samples. Participants who chose not to have their samples archived may opt out.  


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9.1 
Sample Collection Guidelines 
We will collect blood (serum and plasma) and urine samples. Samples will be 
labeled with the subject’s de-identified study number and collection date and 
delivered for storage to the team’s freezers. Samples will be processed at the 
NUCATS CRU laboratory.  
Samples will be collected at the intervals indicated in section 5.5.   
 
9.2 
Assay Methodology 
Specialized assays include: FGF23 ELISA (Immutopics, CA); N terminal propeptide 
of Type 1 procollagen (P1NP) ELISA (USCN Life Science, Houston, TX); and C 
terminal cross-linked peptide (CTX) ELISA (Immunodiagnostic Systems, Scottsdale, 
AZ).   All measurements of specialized assays will be performed at specialized labs at 
Feinberg School of Medicine once the study has ended.   
 
Standard assays (plasma and urinary calcium, phosphate and creatinine, LFTs, CBC, 
PTH) will be performed at NMH clinical labs.    
9.3 
Specimen Banking 
Patient samples collected for this study will be retained in the study freezers 
located at CTMH at 633 N. St. Clair, Suite 18-098,Chicago, IL, 60611 and/or in 
the Freezer Farm at the Tarry Research Building at 300 East Superior Street 
Chicago, IL 60611. Specimens will be stored indefinitely or until they are used 
up. If future use is denied or withdrawn by the patient, best efforts will be made to 
stop any additional studies and to destroy the specimens. 
 
Dr. Tamara Isakova will be responsible for reviewing and approving requests for 
clinical specimen from potential research collaborators outside of NU. 
Collaborators will be required to complete an agreement (a Material Transfer 
Agreement or recharge agreement) that states specimens will only be released 
for use in disclosed research. Any data obtained from the use of clinical 
specimen will be the property of NU for publication and any licensing agreement 
will be strictly adhered to.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or 
commercial value. The Informed Consent form contains this information and 
informs the subject that there is the potential for financial gain by NU, the 
investigator or a collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be 
provided to research collaborators when specimens are made available:  
• 
Collection time in relation to study treatment 
• 
Demographic data 
• 
De-identified stored samples 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
This is a 2-week, randomized, double-blinded, 2x2 factorial design study of 80 healthy 
volunteers (20 in each of the four treatment groups) investigating the effects of the 


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18 
interventions on changes in plasma and urinary phosphate.  Participants will be 
randomized to one of the four groups: 1) lanthanum carbonate + nicotinamide; 2) 
lanthanum carbonate + nicotinamide placebo; 3) lanthanum carbonate placebo + 
nicotinamide; 4) lanthanum carbonate placebo + nicotinamide placebo. 
The end-points are listed in the table below:  
 
Summary of End Points 
End-Point 
Primary Secondary 
Justification 
Plasma Phosphate 
X 
 
Marker of phosphate handling 
24-hr Urine 
Phosphate 
X 
 
Marker of phosphate handling 
FePI 
X 
 
Marker of phosphate handling 
PTH 
 
X 
Hormonal regulator of mineral metabolism 
FGF23 
 
X 
Hormonal regulator of mineral metabolism 
P1NP 
 
X 
Bone formation marker 
CTX 
 
X 
Bone resorption marker 
 
10.2 
Sample Size and Accrual 
Assumptions based on prior studies:  
• 
Data on effects of nicotinamide on blood or urine phosphate in healthy volunteers are 
not available.  
• 
Similiarly, data on the combined use of the nicotinamide and lanthum carbonate are 
lacking.  
• 
Therefore, we relied on published data of the effects on lanthanum carbonate on 24-
hour urine phosphate.  In previous short-term studies of healthy volunteers, 
lanthanum carbonate at the dose that we will use in our study decreased 24-hour 
urine phosphate by 236 to 468 mg/day.29 The within group standard deviation of 
change in 24-hour urine phosphate ranged from 168 to 294 mg/day.29  
 
Derivation of the sample size for this study:  
Using the PS Power and Sample Size calculator (independent t test), we estimated that 
a sample size of 20 participants per group will yield 80% power to detect a difference of 
273 mg/dl in urine phosphate, at α=0.05, assuming a within group SD of the change in 
24-hour urine phosphate of 300 mg/day.  Assuming a conservative within group SD of 
the change in plasma phosphate of 0.55 mg/dl, the sample size of 20 volunteers per 
group will allow us to detect a difference as small as 0.50 mg/dl in plasma phosphate.   
Importantly, we based our power calculations on t-tests that compare pre to post 
intervention changes across two groups.  Because the repeated measures analyses we 
will employ using linear mixed models will reduce within-subject variability, we expect to 
have more power than is tabulated above and view the presented power calculations as 
conservative estimates.  Additionally, power for main effects analyses (effects of 
lanthanum carbonate alone and nicotinamide alone; 40 participants per groups; margin 
comparison) will be greater than the presented power for comparisons of dual treatment 
to placebo (20 participants per group; individual cell comparison).  


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10.3 
Data Analyses Plans 
• 
We will study changes over time in absolute levels of the primary and secondary 
end-points.   
• 
We will use mixed-model, repeated-measures analyses to assess the changes. 
• 
Model terms will include:  
o fixed-effects treatment terms (treatment group); 
o the interaction between each treatment and time (nicotinamide x time and 
lanthanum carbonate x time);  
o the interaction between treatments (nicotinamide x lanthanum carbonate); 
o the interaction between treatments and time (nicotinamide x lanthanum 
carbonate x time); 
o random-effects terms, connoting individual participants. 
• 
If the interaction term between treatments and time (nicotinamide x lanthanum 
carbonate x time) is significant, we will compare the response in the dual 
intervention group to the placebo group.   
• 
If the interaction term between treatments and time (nicotinamide x lanthanum 
carbonate x time) is not significant, we will examine the main effects of each 
intervention.   
• 
We will use natural log transformation for end points with skewed distribution.  
• 
If there are significant differences (p<0.05) in age, gender and baseline eGFR 
across randomized treatment groups, we will adjust for these covariates. 
• 
Standard descriptive analyses will be used for safety evaluations. 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, 
etc.) must have the conflict reviewed by the Feinberg School of Medicine.  All 
investigators will follow the University conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
 


STU00090161 
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20 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
11.3 
Registration Procedures 
 
N/A 
 
11.4 
Subject Compensation 
Subjects will receive compensation per study consent form. Study compensates $50.00, 
in the form of a check, for each of the 8 study visits. Total compensation, excluding 
reimbursement for travel expenses, is $400.00. Subjects will be required to submit proof 
of travel expenses (i.e., receipts) to study staff in order to be reimbursed for travel 
expenses. Travel expenses will be paid out in the form of a check as well. 
11.5 
Data Management and Monitoring/Auditing 
The PI and Co-I will monitor data safety monitoring/management. 
11.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.  
11.6.1 
Emergency Modifications 
Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior 
IRB approval.  
 
For any such emergency modification implemented, a IRB modification 
form must be completed within five (5) business days of making the 
change.  
11.6.2 
Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by 
the Principal Investigator and the IRB. According to the IRB, a protocol 
deviation is any unplanned variance from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research 
plan or the value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 


STU00090161 
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21 
• 
Results from willful or knowing misconduct on the part of the 
investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
Protocol Deviations: Deviations should be summarized and reported to 
the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within one 
(1) week of the investigator becoming aware of the event using the same 
IRB online mechanism used to report Unanticipated Problems.  
11.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator. It should also be noted 
that when an amendment to the protocol substantially alters the study design or 
the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent 
to the IRB for approval prior to implementation.  
11.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator 
must retain all study documentation pertaining to the conduct of a clinical trial. In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of 
marketing application in an International Conference on Harmonization (ICH) 
region. In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
11.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 


STU00090161 
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22 
 
The Principal Investigator at each institution or site will be responsible for 
assuring that all the required data will be collected and entered onto the Case 
Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification of 
proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
 
 


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12.0 
REFERENCES 
1. 
Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United 
States. JAMA 2007;298:2038-47. 
2. 
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C-y. Chronic kidney disease and the 
risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-305. 
3. 
Honeycutt AA, Segel JE, Zhuo X, Hoerger TJ, Imai K, Williams D. Medical Costs of 
CKD in the Medicare Population. J Am Soc Nephrol 2013. 
4. 
Sarnak MJ. Cardiovascular complications in chronic kidney disease. Am J Kidney Dis 
2003;41:11-7. 
5. 
Appel LJ, Wright JT, Greene T, et al. Intensive blood-pressure control in hypertensive 
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6. 
de Boer IH, Rue TC, Hall YN, Heagerty PJ, Weiss NS, Himmelfarb J. Temporal trends in 
the prevalence of diabetic kidney disease in the United States. JAMA 2011;305:2532-9. 
7. 
de Boer IH, Sun W, Cleary PA, et al. Intensive diabetes therapy and glomerular filtration 
rate in type 1 diabetes. N Engl J Med 2011;365:2366-76. 
8. 
Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with 
simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal 
Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92. 
9. 
Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int 
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10. 
Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before 
parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011;79:1370-8. 
11. 
Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and 
end-stage renal disease in patients with chronic kidney disease. JAMA 2011;305:2432-9. 
12. 
Scialla JJ, Xie H, Rahman M, et al. Fibroblast Growth Factor 23 and Cardiovascular 
Events in Chronic Kidney Disease. J Am Soc Nephrol 2013, In Press. 
13. 
Scialla JJ, Astor BC, Isakova T, Xie H, Appel LJ, Wolf M. Mineral metabolites and CKD 
progression in African Americans. J Am Soc Nephrol 2013;24:125-35. 
14. 
Scialla JJ, Lau WL, Reilly MP, et al. Fibroblast growth factor 23 is not associated with 
and does not induce arterial calcification. Kidney Int 2013;83:1159-68. 
15. 
Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin 
Invest 2011;121:4393-408. 
16. 
Ferrari SL, Bonjour J-P, Rizzoli R. Fibroblast growth factor-23 relationship to dietary 
phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab 
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17. 
Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast 
growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 2006;91:3144-9. 
18. 
Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. 
Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone 
Miner Res 2006;21:1187-96. 
19. 
Isakova T, Barchi-Chung A, Enfield G, et al. Effects of Dietary Phosphate Restriction 
and Phosphate Binders on FGF23 Levels in CKD. Clin J Am Soc Nephrol 2013;8:1009-18. 
20. 
Schiavi SC, Tang W, Bracken C, et al. Npt2b deletion attenuates hyperphosphatemia 
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13.0 
APPENDICES 
Appendix A. 
Letter of IND exemption from the FDA