Conditions: Chronic Kidney Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 205
Healthy volunteers: no

Brief summary:
The COMBINE clinical trial is a pilot study evaluating the effects of nicotinamide and lanthanum carbonate on serum phosphate and fibroblast growth factor 23 (FGF23) in patients with Chronic Kidney Disease (CKD) stages 3-4.

Detailed description:

Arms:
arm 1: One nicotinamide 750 mg capsule by mouth twice daily (1500 mg) for 12 months. Two lanthanum carbonate 500 mg capsules by mouth with each meal (3000 mg) for 12 months. arm 2: Two lanthanum carbonate 500 mg capsules by mouth with each meal (3000 mg) for 12 months. One Placebo (for nicotinamide) 750 mg capsule by mouth twice daily (1500 mg) for 12 months. arm 3: One nicotinamide 750 mg capsule by mouth twice daily (1500 mg) for 12 months. Two Placebo (for lanthanum carbonate) 500 mg capsules by mouth with each meal (3000 mg) for 12 months. arm 4: One Placebo (for nicotinamide) 750 mg capsule by mouth twice daily (1500 mg) for 12 months. Two Placebo (for lanthanum carbonate) 500 mg capsules by mouth with each meal (3000 mg) for 12 months.

Interventions: intervention 1: Nicotinamide intervention 2: Lanthanum Carbonate intervention 3: Placebo (for Nicotinamide) intervention 4: Placebo (for lanthanum carbonate)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Sugar pill manufactured to mimic Nicotinamide 750 mg capsule intervention 4: Sugar pill manufactured to mimic Lanthanum Carbonate 500 mg capsule

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Pilot Clinical Trials in CKD 
 
EFFECTS OF NICOTINAMIDE AND LANTHANUM 
CARBONATE ON SERUM PHOSPHATE AND FGF23 LEVELS 
IN PATIENTS WITH STAGE 3-4 CHRONIC KIDNEY DISEASE 
 
The CKD Optimal Management with BInders and NicotinamidE: 
COMBINE STUDY 
 
COMBINE Protocol Version 1.2  
June 22, 2015 
 
 
 
 
 


COMBINE PROTOCOL Version 1.2 – 06/22/2015 
Page 1 of 25 
 
EFFECTS OF NICOTINAMIDE AND LANTHANUM CARBONATE ON SERUM PHOSPHATE 
AND FGF23 LEVELS IN PATIENTS WITH STAGE 3-4 CHRONIC KIDNEY DISEASE 
Pilot Clinical Trials in CKD.......................................................................................................... 1 
EFFECTS OF NICOTINAMIDE AND LANTHANUM CARBONATE ON SERUM PHOSPHATE 
AND FGF23 LEVELS IN PATIENTS WITH STAGE 3-4 CHRONIC KIDNEY DISEASE ............. 1 
1 
INTRODUCTION ................................................................................................................ 3 
1.1 
Executive Summary ..................................................................................................... 3 
1.2 
Background.................................................................................................................. 4 
1.3 
Goals/Aims/Hypotheses ............................................................................................... 4 
1.4 
Description of the treatments being tested ................................................................... 5 
1.5 
Design of this Pilot Clinical Trial ................................................................................... 5 
1.6 
Sample Size for this Pilot Clinical Trial ......................................................................... 6 
1.7 
Timeline for this Pilot Clinical Trial ............................................................................... 7 
1.8 
Patient Timeline (Key events of Screening, Baseline, Randomization, Follow-up) – 
Table 1 ................................................................................................................................... 8 
2 
PATIENT SELECTION .......................................................................................................10 
2.1 
Introduction .................................................................................................................10 
2.2 
Inclusion and Exclusion Criteria ..................................................................................10 
2.3 
Identification of participants for screening ...................................................................11 
2.4 
Informed Consent Procedures ....................................................................................11 
2.4 
Informed Consent Procedures ....................................................................................11 
2.5 
Privacy and security ....................................................................................................12 
3 
BASELINE PERIOD EVALUATION ...................................................................................12 
3.1 
Introduction .................................................................................................................12 
3.2 
Baseline collection of concurrent meds at study entry .................................................12 
3.3 
Comorbidity assessment .............................................................................................12 
3.4 
Description of run in ....................................................................................................13 
3.5 
Compliance assessment .............................................................................................14 
3.6 
Maximum time allowed in baseline ..............................................................................14 
3.7 
Collecting reasons for baseline drop out .....................................................................14 
3.8 
Assessment of readiness for randomization ................................................................14 
4 
RANDOMIZATION AND RECRUITMENT MONITORING ..................................................14 
4.1 
Randomization in an intent-to-treat clinical trial ...........................................................14 
4.2 
Logistics of randomization ...........................................................................................14 
4.3 
How recruitment will be monitored ..............................................................................15 
5 
TREATMENT ARMS ..........................................................................................................15 
5.1 
Initiation of treatment ..................................................................................................15 
5.2 
Dose adjustments and treatment stops related to serum phosphate levels .................16 
5.2.1 
Dose adjustment due to hypophosphatemia ........................................................16 
5.2.2 
Treatment safety medication stop due to hyperphosphatemia .............................16 
5.2.3 
Dose adjustments due to intolerable GI or other side effects ...............................17 
5.3 
Management of dose adjustments of study drugs in the presence of other medications
 
17 
5.4 
Supply of treatment .....................................................................................................17 
5.5 
Resupply of treatment .................................................................................................17 
5.6 
Maintaining blinding ....................................................................................................17 
5.7 
Unblinding ...................................................................................................................17 
6 
FOLLOW-UP PERIOD EVALUATION ................................................................................17 
6.1 
Follow-up visit schedule and schedule of tests done during follow-up .........................17 
6.1.1 
Overview ..............................................................................................................17 
6.1.2 
Description of procedures during in-person visits .................................................17 


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6.2 
Monitoring compliance to treatment ............................................................................18 
6.3 
Procedures for patients who start dialysis or undergo kidney transplantation ..............18 
6.4 
Procedures for patients who become pregnant ...........................................................18 
7 
CHARACTERIZATION OF THE MEASUREMENTS AND PROCEDURES DURING 
SCREENING, BASELINE, AND FOLLOW-UP AND METHODS OF MEASUREMENT TO BE 
USED ........................................................................................................................................18 
7.1 
GFR Calculation .........................................................................................................18 
7.2 
List of laboratory measurements .................................................................................19 
8 
ADVERSE EVENTS, ADVERSE EVENT REPORTING .....................................................19 
8.1 
Introduction .................................................................................................................19 
8.2 
Expected Study Adverse Events .................................................................................19 
8.2.1 
Types of AEs that may be treatment or procedure side effects ............................19 
8.2.2 
How AEs will be reported .....................................................................................20 
8.2.3 
Follow-up of AEs ..................................................................................................20 
8.3 
SAE, Hospitalization, and Death reporting ..................................................................20 
8.3.1 
Local Categorization of SAEs as Unanticipated, Related .....................................20 
8.3.2 
Event Committee Review of SAEs .......................................................................20 
9 
STOPPING RANDOMIZED TREATMENT .........................................................................21 
9.1 
Stopping randomized treatment for Adverse Events ...................................................21 
9.2 
Stopping randomized treatment for Adverse Events ...................................................21 
9.3 
Discontinuation of study medications due to patient preference/non-compliance ........21 
9.4 
The role of Study Committees in review of lab data and adverse events .....................21 
10 
DSMB .............................................................................................................................21 
11 
ANALYSIS PLAN ...........................................................................................................21 
11.1 
Primary analysis .........................................................................................................21 
11.2 
Secondary Analyses ...................................................................................................22 
11.3 
Analyses of other follow-up data .................................................................................22 
11.4 
Safety analyses ..........................................................................................................22 
11.5 
Planned analyses of feasibility/logistics including rates of missing data, missing forms,  
missing visits, and of non-compliance....................................................................................23 
11.6 
What will it take to say that this pilot study is feasible? ................................................23 
11.7 
Test run of the analysis plan for the full scale study ....................................................23 
12 
PLANS FOR THE STUDY DESIGN OF THE FULL SCALE TRIAL ................................23 
12.1 
Current Plans for Primary Outcome of the Full Scale Trial ..........................................23 
13 
ACKNOWLEDGEMENTS ...............................................................................................23 
14 
REFERENCES ...............................................................................................................23 
 
 
 
 


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1 
INTRODUCTION 
1.1 
Executive Summary   
Chronic kidney disease (CKD) is a major public health problem1 that impairs functional status, shortens 
lifespan and consumes healthcare resources.  CKD is complicated by disordered mineral metabolism, 
characterized by abnormalities in calcium and phosphate homeostasis, calcitriol deficiency and increased 
parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels.2,3  Observational studies 
report strong associations between disordered mineral metabolism and risks of end-stage renal disease 
(ESRD), cardiovascular disease (CVD), fractures, and death.4-6  Experimental data suggest that arterial 
stiffness and left ventricular hypertrophy (LVH) may serve as useful intermediate endpoints for CVD 
outcomes in CKD patients.  Phosphate excess promotes vascular calcification leading to arterial 
stiffness,7,8 and FGF23 excess exerts hypertrophic effects on the myocardium, contributing to LVH.9,10  
Thus, interventions that lower phosphate and FGF23 may reduce risks of morbidity and mortality in 
CKD.   
Prior to embarking on a large randomized controlled trial to test the impact of phosphate and FGF23 
reduction on hard clinical endpoints in CKD, additional data are needed on the effects of proposed 
interventions on serum phosphate and FGF23 levels.  In this pilot study, a 12-month, randomized, double-
blinded, four arm parallel study in 200 CKD patients with eGFR between 20 and 45 ml/min/1.73m2 will 
be conducted.  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 Specific Aims for this protocol are:  
Specific Aim 1: Determine the efficacy of nicotinamide and lanthanum carbonate on serum phosphate 
and FGF23 levels in CKD stage 3-4:   
Primary hypothesis: Compared to placebo, monotherapy with nicotinamide, monotherapy with lanthanum 
carbonate, and combined nicotinamide and lanthanum carbonate therapy will lower serum phosphate and 
FGF23 levels.  
Secondary hypothesis: Combined active therapy with nicotinamide and lanthanum carbonate will lower 
serum phosphate and FGF23 levels more than nicotinamide alone or lanthanum carbonate alone. 
Specific Aim 2: Determine the safety and tolerability of nicotinamide and lanthanum carbonate in CKD 
stage 3-4:   
Hypothesis: Combined treatment with nicotinamide and lanthanum carbonate will be safe, well-tolerated, 
and acceptable to CKD participants, demonstrating feasibility of long-term compliance in a subsequent 
phase 3 clinical trial. 
The secondary objectives of this pilot clinical trial are to evaluate the following: 
1. The effects of active therapy with nicotinamide and lanthanum carbonate compared to placebo on 
bone and mineral metabolism markers in patients with Stage 3-4 CKD, as assessed by changes in 
PTH, calcitriol, klotho, N terminal propeptide of Type 1 procollagen (P1NP)  and tartrate-resistant 
acid phosphatase (TRAP) 5b levels over 12 months. 
2. The effects of active therapy with nicotinamide and lanthanum carbonate compared to placebo on 
surrogate measures of CVD risk in patients with Stage 3-4 CKD, as assessed by gadolinium-free 
Cardiac Magnetic Resonance Imaging (MRI)-measured changes in left ventricular (LV) mass index, 
LV end diastolic volume, left atrial volume, and levels of brain natriuretic peptide (BNP), troponin T, 
cholesterol, and asymmetric dimethylarginine (ADMA) over 12 months. 
3. The effects of active therapy with nicotinamide and lanthanum carbonate compared to placebo on 
surrogate measures of CKD progression and inflammation with Stage 3-4 CKD, as assessed by 
changes in intra-renal oxygenation and fibrosis as measured by gadolinium-free blood oxygenation 


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level dependent (BOLD) MRI and diffusion-weighted MRI and changes in GFR, albuminuria and 
CRP and IL-6 over 12 months. 
1.2 
Background  
Disordered mineral metabolism is a near-universal complication of CKD2,3 and is strongly linked to risks 
of ESRD, CVD, fractures, and death.4-6  Phosphate excess induces arterial calcification,7 which is an 
important phenotype of CVD in CKD.  Elevated FGF23 maintains serum phosphate in the normal range 
in CKD, but FGF23 excess contributes mechanistically to LVH.9  Both phosphate and FGF23 excess are 
associated with CVD and CKD progression,6 and data in laboratory animals suggest causal links.7,9  
Therefore, our over-arching hypothesis is that interventions targeting phosphate and FGF23 excess in 
CKD stages 3–4 will reduce risks of ESRD, CVD, fractures, and death.   
Small studies suggest that phosphate binders and dietary phosphate modification may lower FGF23 and 
phosphate, and improve other indices of mineral metabolism and vascular biology in CKD.11   
Nicotinamide (vitamin B3, also called niacinamide) lowers serum phosphate levels in animals12 and in 
patients with ESRD.13-16  Rather than binding dietary phosphate, nicotinamide reduces expression of 
NPT2b,12 the major sodium-phosphate co-transporter in the small bowel.  Animal studies demonstrate that 
NPT2b is upregulated when dietary phosphate intake is decreased or when phosphate binders are 
administered.12,17  As a result, attempts to reduce dietary phosphate absorption using phosphate binders 
alone may be limited by upregulation of sodium-phosphate transporters and resultant increases in dietary 
phosphate absorption at times when phosphate binders are not present in the intestinal lumen.  Therefore, 
we hypothesize that use of nicotinamide combined with phosphate binders will provide the most effective 
method to reduce phosphate and FGF23 levels and related risks of ESRD, CVD, fractures, and death in 
CKD patients. 
1.3 
Goals/Aims/Hypotheses 
Our long-term goal is to conduct a placebo-controlled, randomized trial to target phosphate and FGF23 
excess.  Hard end-points will include a combination (to be determined) of ESRD, CVD events, fractures 
and death.  The purpose of this pilot study is to determine whether intervention with both nicotinamide 
and phosphate binders, in either isolation or in combination will provide an efficacious, safe, well 
tolerated and feasible strategy to advance into the large outcomes trial.     
A 12-month, randomized, double-blinded, four-arm parallel study in 200 CKD stage 3–4 patients will be 
conducted.  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 following hypotheses will be tested: 
1.  Compared to placebo, monotherapy with nicotinamide, monotherapy with lanthanum carbonate, and 
 
combined nicotinamide and lanthanum carbonate therapy will lower serum phosphate and FGF23 
 
levels. 
2.  Combined treatment with nicotinamide and lanthanum carbonate will be safe, well-tolerated, and 
 
acceptable to CKD participants, demonstrating feasibility of long-term compliance in a subsequent 
 
phase 3 clinical trial. 
Secondary hypotheses:  
1) Combined active therapy with nicotinamide and lanthanum carbonate will lower serum phosphate 
and FGF23 levels more than nicotinamide alone or lanthanum carbonate alone. 
2) Compared with placebo, active therapy with nicotinamide and lanthanum carbonate will blunt the 
slope of PTH rise, attenuate the decline of calcitriol and klotho levels, and improve bone turnover 
markers, P1NP and Trap-5b. 


COMBINE PROTOCOL Version 1.2 – 06/22/2015 
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3) Compared with placebo, active therapy with nicotinamide and lanthanum carbonate will reduce 
or blunt the increase in LV mass index; attenuate LV diastolic dysfunction, indicated by increased 
LV end diastolic volume and decreased left atrial volume (all measures assessed by gadolinium-
free Cardiac MRI); and reduce levels of biomarkers that are associated with CVD: BNP, troponin 
T, cholesterol, and ADMA. 
4) Compared with placebo, active therapy with nicotinamide and lanthanum carbonate  will blunt 
the slope of decline in GFR and the rise in proteinuria and the inflammatory markers, CRP and 
IL-6, improve intra-renal oxygenation and stabilize or reduce progression of renal fibrosis, as 
assessed by gadolinium-free renal BOLD MRI.  
1.4 
Description of the treatments being tested 
Nicotinamide: Animal studies12 and pilot studies in humans show that nicotinamide substantially lowers 
serum phosphate levels, and can do so with only 1-2 pills/day.13-16  Nicotinamide reduces serum 
phosphate levels by blocking intestinal phosphate absorption through down-regulation of NPT2b.12  The 
lipid drug niacin contains both nicotinamide and nicotinic acid,  and it has been shown that it lowers 
serum phosphate in CKD patients.18  However, nicotinamide alone may have advantages over niacin.  
Unlike niacin, nicotinamide does not cause flushing and is thought to be less likely to cause liver test 
abnormalities, hyperuricemia, or insulin resistance.  Nicotinamide has considerable long-term safety data 
in the general population and is available over the counter as a dietary supplement in the US.  The use of 
nicotinamide at a dose of 750 mg once daily during the first month following randomization, followed by 
up-titration to 750 mg twice daily thereafter is proposed.   
Phosphate binders: Several studies suggest that calcium-based binders do not lower FGF23.19,20  
Therefore, active therapy will consist of fixed doses of lanthanum carbonate (3000 mg/day), which will 
be off patent by 2017.  Use lanthanum carbonate at a dose of 500 mg three times daily with meals during 
the first month following randomization and a 1000 mg three times daily with meals thereafter is 
proposed.  This fixed dose was chosen because it has been demonstrated that this dose safely reduced 
urinary phosphate, signifying effective phosphate binding, in CKD stages 34.20,21  Importantly, 
lanthanum carbonate has been used in the hemodialysis population, with 6-year long safety data 
demonstrating a good safety profile.22  Participants who do not eat regular meals will be instructed to take 
full doses with larger meals and half with snacks.   
An IND exemption from the FDA has been applied and received for the use of both of these agents alone 
and in combination for this trial.   
Dietary phosphate restriction: In all study arms, during the run-in phase, dietary information will be 
provided to participants to reduce dietary phosphate intake.  The study coordinator will provide this 
information, which will include: a) instructions on how to read food labels in order to avoid foods with 
phosphate additives23; b) advice to reduce serving sizes of animal protein; c) encouragement of 
consumption of vegetarian sources of protein instead of animal protein; d) advice to reduce consumption 
of dairy, and e) encouragement of consumption of egg whites instead of egg yolks.  Prior proof-of-
concept data demonstrated feasibility of this approach and the importance of this adjunctive intervention 
to potentiate the efficacy of phosphate binders in lowering serum phosphate and FGF23 levels.11       
1.5 
Design of this Pilot Clinical Trial  
This is a 12-month, randomized, double-blinded, four arm parallel study in 200 CKD stage 3–4 patients 
(50 in each of the four treatment groups) investigating the effects of the interventions on changes in serum 
phosphate and FGF23 levels.  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 COMBINE Study is a multi-center clinical trial being carried out by the NIDDK-funded Pilot 
Clinical Trials in CKD Consortium.  Participants will be enrolled at each of the core clinical centers 


COMBINE PROTOCOL Version 1.2 – 06/22/2015 
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(George Washington University; Northwestern University; University of California San Diego/Denver 
Nephrology; University of Utah). 
1.6 
Sample Size for this Pilot Clinical Trial  
Assumptions based on prior studies:  
 
In our pilot trial in CKD,18 niacin lowered serum phosphate by 0.42 mg/dL relative to placebo.  This 
magnitude of effect occurred within 2 months and was stable for the remainder of the 6-month 
study.18  Thus, it is anticipated that a similar magnitude of effect in the proposed study despite the 
longer follow-up time proposed in this study.  The within group standard deviation of change in 
serum phosphate over 6 months was 0.55 mg/dL 
 
In our prior unpublished data, the within group standard deviation for the change in FGF23 levels in 
untreated individuals over 2 years was 18.65 pg/ml. 
Power justification:  
This pilot study is powered to demonstrate both a decrease in serum phosphate and a decrease in FGF23 
levels.  Specifically, the primary hypotheses for these two primary end points will compare each of the 
three treatment groups to placebo.  To control for three comparisons and two primary end points, 
Bonferroni correction is applied by dividing the standard α of 0.05 by 6 to yield a two-sided α of 0.0083.  
Using this conservative method for correction of multiple testing, an estimated sample size of 43 
participants per group will yield 80% power to detect a difference of 0.42 mg/dl in serum phosphate, at 
α=0.0083, assuming a within group SD of the change in serum phosphate over time of 0.55 mg/dL.  The 
same sample size of 43 participants per group will allow detection of a difference of 14.3 pg/ml in 
FGF23, with 80% power, at α=0.0083, assuming a SD of the change of 18.65 pg/ml. 
Fifty participants per arm will be enrolled to provide a reasonable buffer from drop-outs (~14% drop out 
rate).   Importantly, our power calculations are based on t-tests that compare pre to post intervention 
changes across two groups.  Because the repeated measures analyses employed using linear mixed models 
will reduce within-subject variability, there will be greater power than is tabulated above and the 
presented power calculations are conservative estimates. 
Sample size for the secondary objectives:  
To maximize power for the secondary objectives analyses, change over time in the outcome measures in 
all actively treated vs. placebo-treated participants (3:1) will be compared.  With this approach, we 
anticipate having sufficient power for all end points proposed under secondary objectives.  
In a previous study of CKD patients with comparable GFR,19 PTH levels declined by 35.5%, from 107 
pg/ml to 69 pg/ml by 6 weeks among the 21 participants treated with sevelamer hydrochloride.  In our 
previous study, the within group standard deviation (SD) for % change in PTH over 3 months was 42%.  
With our planned analysis being the comparison of all actively treated vs. placebo-treated participants 
(3:1), assuming a conservative SD of the change of 45%, 150 actively-treated and 50 placebo-treated 
individuals will allow us to detect a difference in % change in PTH as small as 21% in response to active 
treatment with 80% power at a two-sided α=5%.  Keeping all assumptions the same but changing the SD 
to 50% yields a minimum detectable difference of 23%, which will decrease to 22.2% for a possible 14% 
drop out rate.  Importantly, our power calculations are based on t-tests that compare pre to post 
intervention changes across two groups.  Because the repeated measures analyses employed using linear 
mixed models will reduce within-subject variability, there will be greater power than is tabulated above 
and view the presented power calculations as conservative estimates. 
It is anticipated that the sample size for the MRI studies will be approximately 70% of the total sample 
size (n=140) because of contraindications (pacemakers, metal fragments, and claustrophobia) and 
participant refusal.  It is believed that this estimate is conservative, given that > 70% of enrolled 
participants in the NHLBI-sponsored Multi-Ethnic Study of Atherosclerosis successfully completed the 
MRI measurements.24  A 2-sided t-test to calculate the power to detect a significant difference from 


COMBINE PROTOCOL Version 1.2 – 06/22/2015 
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baseline to end of study in change in LVMI between 105 actively-treated and 35 placebo-treated 
participants was used.  For our estimate of the within-subject SD for change in LVMI over time, data on 
repeated measures of LVMI by MRI from the PRIMO study was used, which was a randomized trial of 
paricalcitol in patients with a similar range of eGFR as in the COMBINE study.  In the 91 placebo-treated 
PRIMO participants, the SD for the change in LVMI over 48 weeks was 2.4 g/m2.7.25  Assuming a SD of 
the change of 2.4 g/m2.7, 105 actively-treated and 35 placebo-treated individuals will allow us to detect a 
difference in change in LVMI as small as 1.3 g/m2.7 in response to active treatment with 80% power at a 
two-sided α=5%.  Eighty percent power for change in LVMI if 124 participants (93 active-treated and 31 
placebo) are enrolled and provide at least one baseline and one follow-up MRI examination will be 
maintained.  Keeping all assumptions the same but allowing for a more conservative SD of 3.0 g/m2.7 will 
enable us to detect a difference in change in LVMI as small as 1.7 g/m2.7.  A difference of ~3.0 g/m2.7 is 
considered to be a clinically meaningful between-group difference in LVMI and corresponds to a mean 
between-group difference of ~10 g in LVM.25,26  The study will have >90% power to detect a difference 
of this magnitude, assuming a SD of the change of 2.4 – 3.0 g/m2.7.     
Since there are no studies with repeated measures of BOLD MRI in CKD, we relied on collaborators’ 
cross-sectional data to calculate the power for our proposed analyses in Aim 3.  Assuming a common SD 
of 10 s-1, a conservative correlation of repeated R2* measures of 0.5, and a two-sided α of 5%, 105 
participants in the actively-treated arm and 35 participants in the placebo arm will allow us to detect a 
difference between the groups in R2* as small as 4.5 s-1 with 80% power.  Keeping all assumptions the 
same, but changing the SD to 15 s-1 yields a minimal detectable difference of 6.4 s-1. 
1.7 
Timeline for this Pilot Clinical Trial 
The study will include the following 3 phases:  
1. Screening Period  
2. Baseline and Run-in Period  
3. Follow-up Period 
A 2-week run-in will be included in the 3-week long Baseline Period.  During the run in, compliance with 
the nicotinamide placebo and lanthanum carbonate placebo, visits, and procedures will be assessed.  
During the run-in, a first visit will occur to dispense placebo pills, followed by 2 visits one week apart.  
After participants meet all inclusion criteria, screening requirements and MRI safety criteria, pre-
randomization cardiac and BOLD renal MRI will be obtained. These baseline imaging studies should be 
performed anytime between Baseline Visit 0 (B0) and prior to Baseline Visit 2 (B2).  The optimal timing 
of the baseline MRI scans is prior to B2, but the studies may occur up to two calendar months after B2. 
Thereafter, follow-up visits will take on the following schedule:  
o monthly visits for the first 3 months (months 1-3) 
o visits every 3 months from month 3 (months 3-12), with an extra visit at month 11 
A timeline of the key events in the study is shown in Table 1 below.  
 


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1.8 
Patient Timeline (Key events of Screening, Baseline, Randomization, Follow-up) – Table 1 
 
Periods 
SCREENING 
BASELINE/RUN-IN 
FOLLOW-UP 
Visits 
 S0 
B0 
B1 
B2/F0 
F1 
F2 
F3 
F6 
F9 
F11 
F12 
Months (unless otherwise specified) 
-3 weeks 
-2 weeks 
-1 weeks 
0 weeks 
1 
2 
3 
6 
9 
11 
12 
Pregnancy testing 
X 
 
 
 
 
 
 
 
 
 
 
Distribute placebos for run in and measure 
height 
 
X 
 
 
 
 
 
 
 
 
 
Distribute drug/placebo (X = 30 day supply) 
 
 
 
X 
X 
X 
XXX 
XXX 
XX 
X 
 
Demographics, medical history 
X 
 
 
 
 
 
 
 
 
 
 
BP, pulse, weight 
X 
 
X 
X 
 
 
X 
X 
X 
 
X 
Dietary information and adherence 
reinforcement 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PTH 
X 
 
X 
X 
 
 
X 
X 
X 
 
X 
Serum calcium 
 
 
X 
X 
 
 
X 
X 
X 
 
X 
Spot urine phosphate, calcium, creatinine, and 
albumin 
 
 
X 
X 
 
 
X 
X 
 
 
X 
24-hr urine phosphate, calcium, creatinine,  and 
urea nitrogen 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 
Renal parameters 
Chem 7 (Na, K, Cl, HCO3, BUN, Cr, glucose)  
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum uric acid 
 
 
X 
 
 
 
 
X 
 
 
X 
Whole blood HbA1c 
 
 
X 
 
 
 
 
 
 
 
 
Blood samples for FGF23 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Biorepository blood samples 
 
 
X 
X 
 
 
X 
X 
 
 
X 
Biorepository urine samples 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 
Safety assessments 
Serum phosphate 
X 
 
 
 
X 
X 
X 
X 
X 
 
X 
Hemoglobin, Platelets, LFTs, CK (Local)1 
X 
 
 
 
 
 
 
CBC, LFTs, CK (Central) 
 
 
 
 
X 
X 
X 
X 
X 
 
X 
Adverse events assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance questions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill Counts 
 
 
X 
X 
X 
X 
X 
 
 
 
X 
GI symptoms questionnaire 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac and BOLD renal MRI 
 
 
X 
 
 
 
 
  
 
 
X 
Bone and mineral metabolism markers2 
 
 
X 
 
 
 
 
X 
 
 
X 
CVD biomarkers3 
 
 
X 
 
 
 
 
X 
 
 
X 
Inflammation biomarkers4 
 
 
X 
 
 
 
 
X 
 
 
X 


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Notes for Table 1: 
S0: screening visit 
B: baseline visit; baseline visits are 1-2 weeks apart 
F: follow-up visits 
X: This evaluation/procedure applies at this visit 
 
1With the exception of screening tests, which will be performed locally, all other tests will be performed at a central lab. 
FGF23, serum phosphate, PTH, CBC, serum calcium, 24-hr and spot urinary phosphate, serum creatinine, UACR, 24-hr urine creatinine and urea, 
uric acid, and HbA1c will be performed centrally as received or in batches.  
 
2Bone and mineral metabolism markers include calcitriol, klotho, P1NP and Trap-5b (performed centrally in batches). 
 
3CVD biomarkers include BNP, troponin T, cholesterol, and ADMA (performed centrally in batches). 
 
4Inflammation markers include CRP and IL-6 (performed centrally in batches). 
 
Please see appendix for volumes of blood drawn at each visit.  


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2 
PATIENT SELECTION 
2.1 
Introduction 
CKD stage 3b–4 patients will be recruited.   All inclusion and exclusion criteria will be based on 
measurements and questionnaires obtained at the screening visit.  Labs will be run in the local lab to 
allow final determination of eligibility with rapid turn-around time. 
2.2 
Inclusion and Exclusion Criteria 
Inclusion criteria:  
1.  
Patients with eGFR 20-45 ml/min/1.73m2  
2.  
Age >18 years 
3.  
Serum phosphate ≥ 2.8 mg/dL 
4.  
Platelet count ≥ 125,000/mm3 
5.  
Able to provide consent 
6.  
Able to travel to study visits  
7.   
Able to eat at least two meals a day 
8.       In the opinion of the site investigator, willing and able to follow the study treatment regimen and  
 
 
comply with the site investigator’s recommendations. 
 
Exclusion criteria:  
1. 
History of allergic reaction to nicotinamide, niacin (excluding flushing), multivitamin 
preparations, or lanthanum carbonate 
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), 
alkaline phosphatase, or total bilirubin concentrations > 2 times the upper limit of the local 
laboratory reference range 
3. 
Creatine kinase (CK) concentrations > 2 times the upper limit of the local laboratory reference 
range 
4. 
Major hemorrhagic event within the past six months requiring in-patient admission 
5. 
Blood or platelet transfusion within the past six months 
6. 
Secondary hyperparathyroidism (PTH > 5 times the upper limit of normal range for the 
laboratory) or currently taking cinacalcet (Sensipar) 
7. 
Current, clinically significant malabsorption, as determined at the discretion of the site 
investigator 
8. 
Anemia (screening Hg < 9.0 g/dl) 
9. 
Serum albumin < 2.5 mg/dl  
10. 
Anticipated initiation of dialysis or kidney transplantation within 12 months as assessed by and at 
the discretion of the site investigator. 
11. 
Use of immunosuppressive medications.  (This criterion excludes anyone who has received a 
solid organ transplant. Stable oral steroids ≤ 10 mg of prednisone/day or inhaled steroids are 
exempted.)  
12. 
In the opinion of the site investigator, active abuse of alcohol or drugs 
13. 
Recent (within the last 14 days) initiation or change in dose of treatment with 1,25 (OH)2 vitamin 
D or active vitamin D analogues (paricalcitol or hectorol).  Patients on stable doses of these 
agents initiated more than 14 days prior to screening are eligible to participate.  
14. 
Current or recent treatment (within the last 14 days) with phosphate binder or niacin/nicotinamide 
> 100 mg/day 
15. 
Current participation in another clinical trial or other interventional research 
16. 
Currently taking investigational drugs 
17. 
Institutionalized individuals, including prisoners and nursing home residents 
18. 
Malignancy requiring therapy within 2 years (basal or squamous cell skin carcinoma and 
localized prostate cancer are exempted) 


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19. 
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. 
20. 
Life expectancy < 12 months as determined by the site investigator. 
21. 
Hospitalization within the past 30 days prior to Screening visit (24 hour observation admissions 
are exempted) 
22. 
Plans to leave the immediate area within 12 months 
23. 
Eat less than 2 meals a day 
24. 
Routinely leaves town for multiple weeks each year such that protocol visits would be missed 
In addition to the inclusion/exclusion criteria, at the Screening Visit participants will also be asked 
questions listed on the MRI safety screening form.  These questions will also be reviewed immediately 
before MRI scanning on the days of the MRI visits.  Participants who meet all of the inclusion criteria and 
none of the exclusion criteria and who have a contraindication for the MRI will not undergo the imaging 
studies but will proceed with all other study procedures. 
2.3 
Identification of participants for screening 
Sites may use some or all of the following recruitment strategies: clinic-based recruitment; referrals from 
providers; community-based recruitment campaigns.  Brief descriptions of steps taken with each method 
are listed below.  
Clinic-based recruitment:  
 
After HIPAA waivers and waivers of Informed Consent are obtained, if required by local Institutional 
Review Boards, electronic medical records will be reviewed to identify potential patients who are 
eligible for participation.   
 
Study staff will approach patients during their clinic sessions and invite them to learn more about the 
study. Recruitment letters may also be used instead of verbal contact during the course of providing 
medical care. Following introduction, study staff will communicate with interested individuals and set 
up a screening visit.  
Referral from providers: 
Providers will be introduced to the study and will be provided with list of inclusion and exclusion criteria. 
The primary providers will be encouraged to discuss the study with potentially eligible participants, and 
to either provide the participant with contact information for the study, or alternative ask if study 
personnel may contact the participant to discuss the study in more detail. Study staff will initiate contact 
with interested and potentially eligible patients and describe the study to them. Recruitment letters may 
also be used instead of phone contact. Following introduction, study staff will set up screening visits with 
interested individuals. 
Community-based recruitment:     
The site investigators will initiate contact with community leaders and introduce them to the study. 
Community leaders will suggest possible ways to disseminate information regarding the study to potential 
participants in the community. Study staff will respond to contact initiated by interested individuals and 
briefly describe the study to them. Following introduction, study staff will communicate with interested 
individuals and set up a screening visit. Additional strategies, including targeted mailings, advertisements 
within healthcare settings and external promotions will also be considered.   
2.4 
Informed Consent Procedures 
2.4   Informed Consent Procedures 
All participants will provide informed consent.  Participants will be given ample time to review the 
consent and ask questions and will be told that participation in the study is entirely voluntary.  They will 
also be told that if they choose not to participate in the study their care will in no way be affected.   
 


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Consent discussions:  
Discussions regarding consent will occur in either a private exam room or in private research offices.  In 
either case, these discussions will occur behind closed doors for both privacy and to allow the participant 
time to focus on the consent without distractions.  Participants will be asked to describe what they 
understand about the study protocol after their review to assure accurate understanding, and will be given 
the opportunity to take the consent home to read and/or discuss with family members or other health care 
providers before consenting, if they so choose. 
 
Consent and Withdrawal of Consent for the NIDDK Biosample Repository: 
Participants may consent or withdraw consent for the repository at any time during the COMBINE Study.  
If a participant consents to the NIDDK biosample repository, his or her samples will stored at the NIDDK 
biosample repository indefinitely. A participant may withdraw consent for the repository during the study 
by notifying the COMBINE physician at his site.  This physician will notify the DCC staff of this request 
in writing.  The DCC will then notify the repository.  The repository will first obtain approval from 
NIDDK to destroy the samples and then discard the samples with its biological and laboratory waste. The 
DCC will follow through to make sure the samples have been destroyed.  After the COMBINE study 
ends, participants may no longer withdraw consent for the biosample repository, as there will no longer a 
way to link any individual with any stored specimen. 
2.5 
Privacy and security 
Local clinical sites will store patient information in a secure manner, and HIPAA privacy rules will be 
followed.   For purposes of this study, patients will be identified only by an assigned identification 
number and a randomly generated alphanumeric code.  The study database will be password protected, 
and clinical site personnel will be restricted from seeing data for patients from centers other than their 
own.  The study database will reside on a password-protected computer at the Data Coordinating Center 
(DCC).  No individual identifiers (patient name, SSN, or device serial number) will be stored. Data will 
be entered with strong encryption and a Thawte, Inc., system will be used for secure transmission of data 
from the clinical sites to the Data Coordinating Center. The DCC ensures accuracy and reliability of 
computer systems used for this study with detailed edit checks and tests of data interface screens, reports, 
and procedures before implementation.  Computer-generated, time-stamped audit trails are kept. The 
database is incrementally backed up daily, with full back ups performed weekly.  Backups are stored at a 
secure location separate from the site of the database server. 
In those instances where a patient document (such as a hospital discharge summary or death certificate) is 
sent to the DCC, the site study coordinator will de-identify this prior to providing it to the DCC.  The 
DCC will store these de-identified patient documents in locked file cabinets. 
Clinical site and DCC staff members will be required to change their passwords every 75 days, and staff 
who are no longer active in the study will be blocked from database access.  
3 
BASELINE PERIOD EVALUATION 
3.1 
Introduction 
Participants who successfully complete the screening visit and are deemed eligible will proceed to the 
Baseline Period.  The Baseline Period will consist of a 2-week run in period with 3 weekly visits (B0, B1 
and B2, Table 1).  
3.2 
Baseline collection of concurrent meds at study entry  
Participants will be asked to bring their medications, including all current prescription medications, over-
the-counter medicines, with them to the study visit.  Study staff will record all concomitant medications 
that the participant is taking.  
3.3 
Comorbidity assessment 
Study staff will record medical history, including history of tobacco and alcohol use. 


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3.4 
Description of run in  
The study will include a 2-week run-in, during which compliance with the two placebos and adherence to 
requirements for visits and procedures will be assessed.   Placebo treatment will consist of one 
nicotinamide 750 mg placebo daily and three lanthanum 500 mg placebos daily (one taken with each 
meal) reflecting similar dosing from the F0 to F1 period. During this run-in, 2 weekly visits will take 
place.   
The following adjustments in lanthanum carbonate placebo will be made during run-in for participants 
who eat fewer than 3 meals per day:  
 
Participants who eat only 2 meals a day and no snacks will take one 500 mg lanthanum carbonate 
placebo with each meal 
 
Participants who eat 2 meals a day and one snack will take one 500 mg lanthanum carbonate placebo 
with each meal and one with a snack 
For calculation of compliance, all participants will be assumed to be taking two lanthanum carbonate 
placebo per day. 
Patients will bring 24-hour urine collections to B1 and B2 visits.   Study staff will record the 24-hour 
urine volume and participants will be asked whether all urine was collected.  Aliquots of the 24-hour 
urine will be collected and submitted to the core lab.   
At each visit, participants will receive education from the trained coordinators regarding efforts to 
reducing dietary phosphate intake.  The information will include a) instructions on how to read food 
labels in order to avoid foods with phosphate additives23; b) advice to reduce serving sizes of animal 
protein; c) encouragement of consumption of vegetarian sources of protein instead of animal protein; d) 
advice to reduce consumption of dairy, and e) encouragement of consumption of egg whites instead of 
egg yolks.   
At each baseline study visit, blood samples will be collected. Whenever blood is drawn, time of day will 
be recorded. When two core lab measures of serum phosphate, FGF23 level, and mineral metabolites are 
obtained during the baseline period, the mean of these two will be used as the baseline values in the 
analyses. 
Height will be measured at screening or at the baseline 0 visit. 
Prior studies have shown that assessment of the effects of dietary phosphate restriction on serum 
phosphate levels were masked if serum phosphate measurements were done in the early morning.27 In 
contrast, assessments in the mid-afternoon allowed for detection a change in serum phosphate levels 
following interventions.27   Because of this, it is recommended that the trial’s two baseline serum 
collections are both conducted between noon and 6:00 pm.  It is also recommended that subsequent clinic 
appointments be held in the afternoon to maximize detection of the effect of the intervention on serum 
phosphate levels and minimize influence of circadian changes.  Ability to come in for afternoon 
appointments is not an absolute requirement for study participation.  Participants who conduct both of 
their baseline visits in the morning due to necessity will be categorized as morning participants.  Study 
coordinators will schedule their follow-up visits at about the same time as their baseline visits were held 
to minimize effects of circadian rhythm on longitudinal changes in phosphate and FGF23. 
After participants meet all inclusion criteria and screening requirements, pre-randomization cardiac and 
BOLD renal MRI scans will be obtained.  These imaging studies could occur anytime between Baseline 
Visit 0 (B0) and prior to Baseline Visit 2 (B2).  The optimal timing for the baseline MRI scans is prior to 
B2, but the studies may occur up to two weeks after B2.  Participants who have a contraindication to the 
MRI (i.e. pacemaker) will not undergo MRI studies but will continue to undergo all other study 
procedures.  


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Each participating clinical center will be provided with a detailed imaging protocol and will be required to 
submit qualifying studies for certification by the MRI Cores prior to enrolling participants.  All cardiac 
and BOLD renal MRI results will be captured according to pre-specified protocols, sent to and stored at 
the Cardiac MRI Core at Northwestern University.  All cardiac MRI Core results will be read by the 
Cardiac MRI Core at Northwestern University.  All BOLD renal MRI results will read by the Renal MRI 
Core at NorthShore.  
3.5 
Compliance assessment 
Compliance with study procedures will be defined as attendance at Baseline visits 0 and 1 and pill count 
results showing > 80% adherence to baseline placebo medications during Baseline, as assessed at least 
once (either B1 or B2).   
3.6 
Maximum time allowed in baseline 
The maximum time between the screening and the B0 visits will be 1 month.  Baseline officially begins 
when the patient is given his or her study medications at the B0 visit.  It is expected that patients will be 
randomized within 3 weeks of the B0 visit.  If necessary, patients can be randomized up to 6 weeks (42 
days) after B0.  If more than 42 days pass, the patient is excluded but may restart baseline, repeating 
screening and baseline measures to assure that the participant still meets all inclusion and exclusion 
criteria.. 
3.7 
Collecting reasons for baseline drop out  
Study staff will document reasons for baseline exclusion or drop out.  
3.8 
Assessment of readiness for randomization  
Study staff will run the “Ready to Randomize Report” checklist for each participant to check that the 
participant meets criteria. 
4 
RANDOMIZATION AND RECRUITMENT MONITORING  
4.1 
Randomization in an intent-to-treat clinical trial 
The study site Principal Investigator or a designated site investigator will review the screening and 
baseline materials and sign off on randomization before randomization is completed.   Randomization 
marks the participant's official and irrevocable entry into the Follow-up period. Once a participant has 
been randomized, efforts will be made to conduct all evaluations irrespective of whether the participant 
starts the study treatment regimen, how long the participant continues on the study treatment regimen or 
not, and how well the participant complies with the study treatment regimen.  
Routine data collection will end when a patient begins dialysis, dies, is deemed lost to follow-up or 
withdraws consent. Otherwise, all efforts will be made to continue data collection through the end of 
follow-up even if a participant’s medication never begins, the participant is not compliant, or the 
participant must stop randomized medications for any reason.  The primary analysis of outcome will be 
analyzed as intent-to-treat, by randomized treatment group. 
4.2 
Logistics of randomization 
The DCC will prepare randomization schedules prior to the start of recruitment. Randomization will be 
stratified by participating site. Randomly permuted blocks of random sizes will be used to help balance 
numbers of participants assigned to each treatment regimen.  This method guarantees that at no time 
during randomization will the number of participants in any arm be grossly imbalanced and ensures that 
the sites will be unable to predict assignments of future patients based on knowledge of assignments of 
past patients. All randomization schedules will remain confidential and known only by members of the 
DCC staff. 
Baseline data that have been categorized as essential must be in the database and support eligibility in 
order for a subject to be randomized. The study coordinator can run the Ready to Randomize Report at 
any time during baseline to check the patient’s status with respect to meeting eligibility requirements. 


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When the site investigator signs off that a participant should be randomized and the participant’s Ready to 
Randomize Report shows eligibility criteria have been met, the Study Coordinator will use his or her 
current database password to access an on-line interactive randomization program. The program will 
verify eligibility and Baseline criteria to confirm that the participant is eligible and ready to be 
randomized and a randomized treatment assignment will be recorded for that participant, based upon his 
or her stratum. The study is blinded, so treatment assignment will not be displayed. The computer will 
display the participant’s initial bottle numbers for the Nicotinamide/Placebo and for the 
Lanthanum/Placebo.  Confirmation of randomization will be displayed on the screen and emailed to the 
Participating Clinical Center.  The treatment assignment will be used to assign the patient with his or her 
coded packages of study drug.   
4.3 
How recruitment will be monitored 
The DCC will email study-wide weekly recruitment reports showing study-wide weekly and cumulative 
enrollment in baseline and randomization. The reports will also include each site’s current baseline goal, 
achievement of baseline goal, randomization goal, and achievement of randomization goal.  Clinical site 
investigators will meet regularly with their study teams to discuss progress on weekly goals, identify 
barriers and problems, and revise recruitment plans as necessary. The Investigators from multiple sites 
will meet by conference call at regular scheduled intervals to review each site’s recruitment progress, 
share problems and successes, and revise recruitment plans as necessary. 
5 
TREATMENT ARMS 
5.1 
Initiation of treatment 
Participants meeting eligibility criteria, having given their informed consent and successfully collected 
required run in data and completed the run-in period will be eligible for randomization.  Baseline cardiac 
and BOLD renal MRI studies should preferably take place prior to randomization. However, the studies 
may occur up to two weeks after B2.  As soon as Baseline data, including cardiac and BOLD renal MRI, 
if available, have been collected and required data show that the patient has met criteria for eligibility for 
randomization, the study coordinator will randomize the patient.  The patient should receive the first 
bottles of blinded study medication as soon as possible post-randomization. 
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 
 
During the first month following randomization (F0 to F1), randomized treatments will be started at lower 
doses. All participants will take one 750-mg nicotinamide or matched placebo daily.   
Lanthanum carbonate or its placebo will be prescribed as follows: 
Participants who eat 3 meals a day will take one 500 mg lanthanum carbonate or matched placebo with 
each meal (1500 mg). 
Those who eat fewer than 3 meals a day will receive adjusted doses: 
 
Participants who eat 2 meals a day with no snacks will take one 500 mg lanthanum carbonate or 
matched placebo with each meal (1000 mg). 
 
Participants who eat 2 meals a day and one or more snacks will take one 500 mg lanthanum carbonate 
or matched placebo with each meal and one 500 mg lanthanum carbonate or matched placebo with a 
snack (1500 mg). 
For the remainder of the study (F1 through F12), randomized treatments will be taken at full doses.  All 
participants will take nicotinamide 750 mg or matched placebo twice daily (1500 mg). 


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Participants who eat 3 meals a day will take two 500-mg lanthanum carbonate or matched placebo with 
each meal (3000 mg). 
Those who eat fewer than 3 meals a day will receive adjusted doses: 
 
Participants who eat 2 meals a day with no snacks will take two 500-mg lanthanum carbonate or 
matched placebo with each meal (2000 mg). 
 
Participants who eat 2 meals a day and one snack will take two 500-mg lanthanum carbonate or 
matched placebo with each meal and one 500 mg lanthanum carbonate or matched placebo with the 
snack (2500 mg). 
 
Participants who eat 2 meals a day and two or more snacks will take two 500-mg lanthanum 
carbonate or matched placebo with each meal and one 500-mg lanthanum carbonate or matched 
placebo with 2 snacks (3000 mg). 
5.2 
Dose adjustments and treatment stops related to serum phosphate levels 
5.2.1 Dose adjustment due to hypophosphatemia  
If a study participant has a core lab serum phosphate level lower than 2.8 mg/dl at any visit, an extra visit 
should be held as soon as possible so the serum phosphate test can be repeated.  This repeat lab will be the 
"action lab" for dose adjustments, regardless of the core lab serum phosphate level.  The local action lab 
should be obtained as soon as possible, but must be obtained within 15 days of the core lab blood draw.  
In the event that the local action lab cannot be obtained, or is not available within 15 days, then the 
available core lab serum phosphate level becomes the action lab for dose adjustments. 
If the action lab test demonstrates a serum phosphate level of 2.8 mg/dL or higher, the participant should 
continue on full dose medications until the next protocol visit.  If the serum phosphate level on the action 
lab test is between 1.5 and 2.7mg/L, both study medications should be prescribed at half dose until the 
next protocol visit.  If the serum phosphate level is ≤ 1.4 mg/dL on the action lab test, both study 
medications should be stopped until the next protocol visit.   
Participants with an action lab test of 1.5 md/dL or higher can enter into the same algorithm summarized 
above at any subsequent protocol visit.  In contrast, participants with an action lab test of 1.4 mg/dL or 
lower require special consideration through the remainder of the trial.  In such an individual, if a core lab 
serum phosphate is 2.8 mg/dL or higher at a subsequent protocol visit, both study medications should be 
restarted at half dose, and the doses of these medications should not be titrated above half dose throughout 
the remainder of the trial.  If the serum phosphate level on a subsequent protocol visit core lab is 2.7 
mg/dL or lower, the participant should return for a local action lab draw within 15 days, as summarized 
above.  If the action lab is 2.7 mg/dL or lower, the participant should remain off both study medications 
until such time as their serum phosphate is 2.8 mg/dL or higher at a subsequent core lab measurement.  
Last, if a participant has previously had an action lab test ≤ 1.4 mg/dL resulting in the need to hold their 
study medications at any point during the trial, and has a subsequent action lab test ≤ 1.4 mg/dL again at 
any point during the remainder of the trial, this individual should be maintained off both study 
medications for the remainder of the trial.   In such an individual, even if subsequent core or local action 
lab tests return to levels of 2.8 mg/dL at future visits, the study medications should not be restarted.  
Additional recommendations for managing COMBINE participants with hypophosphatemia are included 
in the Manual of Operations (MOP). 
5.2.2 Treatment safety medication stop due to hyperphosphatemia 
If a study participant has a central serum phosphate level of 5.9 or greater, an extra visit should be held as 
soon as possible so the test can be repeated locally.  If the local test confirms a serum phosphate level 
over 5.9 mg/dl, this is a treatment safety medication stop for both study medications.  All visits and 
measurements will continue.   If the patient has a primary nephrologist or primary care physician, it is 
recommended that he or she be notified about the hyperphosphatemia and management will be deferred to 
these providers.   


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5.2.3 Dose adjustments due to intolerable GI or other side effects 
Calcium carbonate tablets such as Tums, may be taken for indigestion if used once per day or less.  
However, patients who report using Tums (calcium carbonate) often will be encouraged to try over-the 
counter Pepcid (famotidine), Tagamet (cimetidine), or Zantac (ranitidine). 
If a participant develops GI or other side effects that he or she considers to be intolerable or that are 
considered intolerable by the site investigators, dose adjustment will be at the discretion of the site 
investigator.  Appropriate actions may include reduction of the dose of lanthanum carbonate or its placebo 
and/or reduction of the dose of nicotinamide or its placebo, as described in detail in the MOP. 
5.3 
Management of dose adjustments of study drugs in the presence of other medications 
Use of any 1,25(OH)2 vitamin D preparations and active vitamin D analogues is strongly discouraged 
during the study.  Use of 1,25(OH)2 vitamin D and/or active vitamin D analogues   will be recorded. 
5.4 
Supply of treatment  
The COMBINE Study Drug Distribution Center will send COMBINE participating sites kit boxes of 
either bottles of blinded lanthanum and lanthanum placebo or bottles of nicotinamide and nicotinamide 
placebo.    
 
5.5 
Resupply of treatment 
Treatment bottles will be sufficient to supply 30 days of study agents plus 10 days of extra medication to 
account for variability in dates of scheduling for follow-up visits (80 tablets per bottle for nicotinamide 
and its placebo, and 240 tablets per bottle for lanthanum carbonate and its placebo).  For follow-up visits 
separated by multiple months, participants will receive the appropriate number of treatment kits to 
provide sufficient drug/placebo (e.g., 3 kits for a 3 month interval between visits).  Dose reductions 
procedures are described in detail in the MOP.  
5.6 
Maintaining blinding  
Throughout the Follow-up Period, all efforts will be made to keep study coordinators, investigators and 
participants blinded to treatment group.  Coordinator and investigator blinding will be assessed quarterly; 
patient blinding will be assessed at the end of the study. 
5.7 
Unblinding 
In the situations previously described, a participant will stop his or her blinded nicotinamide and 
lanthanum carbonate.  In this situation where appropriate clinical management of the patient is dependent 
on knowledge of whether the patient had been taking active nicotinamide or active lanthanum carbonate, 
the site investigator will explain the necessity to the study Executive Committee, and the Executive 
Committee will unblind the site physician to the necessary arm.   
6 
FOLLOW-UP PERIOD EVALUATION   
6.1 
Follow-up visit schedule and schedule of tests done during follow-up  
6.1.1 
Overview 
In person follow-up visits will occur monthly for first 3 months after Randomization and every 3 months 
from month 3 until month 9.  There will be a two month interval between month 9 and 11, and finally a 1 
month interval between month 11 and 12 (Table 1).  Additional visits will be held as needed at the 
discretion of the site investigator and study team members.  All visits will be documented in the study 
database. 
6.1.2 
Description of procedures during in-person visits 
At in-person visits, patient compliance to study drugs will be assessed either by questionnaire or pill 
count depending upon the visit (Table 1).  The study coordinator will reinforce instructions on dietary 
phosphate restriction.  Concomitant medication therapy will be reviewed and updated at baseline, F3 and 
every 3 months thereafter.  Information on adverse events (serious and non-serious) will be collected.  
The schedule of laboratory tests to be obtained during the in-person visits is listed in Table 1.  Additional 
blood samples will be collected and stored for future measurements. A GI symptoms form will be 


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completed by questionnaire at each protocol visit.  Blood pressure will be measured by trained personnel 
at all follow-up visits.  Twenty-four hour urine specimens will be collected at some visits (Table 1) and 
will be measured phosphate, calcium, urea, and creatinine.  The 24 hour urine phosphate will be used as 
an indicator of dietary phosphate absorption and the 24 hour urea will be used as an indicator of dietary 
protein intake. 
At each follow-up visits, participants will be counseled that they must not take any phosphate binders or 
multivitamins containing vitamin B3 in the form of niacin or nicotinamide in quantities greater than 100 
mg/day.  If a participant is taking a standard multi-vitamin tablet with < 100 mg/day of nicotinamide, the 
dose of the multivitamin may not be changed during the study period. 
Between F11 and F12 or upon withdrawal from study (for dialysis initiation or preemptive transplantation), 
participants will undergo cardiac and BOLD renal MRI. The cardiac and BOLD renal MRI may occur 
anytime between F11 and 2 weeks after F12 or at the time of early discontinuation prior to initiation of 
renal replacement therapy.  If a participant withdraws from the study within 6 weeks of their baseline 
MRI studies, discontinuation MRI studies will not be performed.  MRIs should not be obtained in 
participants who have started dialysis or have been transplanted.  Participants who have a 
contraindication to the MRI (i.e. pacemaker) will not undergo MRI studies but will continue to undergo 
all other study procedures.     
6.2 
Monitoring compliance to treatment   
In order to document compliance with the treatment regimen, participants will be instructed to return all 
drug containers (even if empty) to study staff at all visits.  Pill counts will be done at B1, B2, F1, F2, F3, 
and F12. To decrease the chance of a participant forgetting to bring pills at pill-count visits, participants 
will be asked to bring remaining pills and empty containers to each visit during the study. 
Study staff will record the number of each type of pill returned, and the study database will calculate 
percent of medications taken. Participants will also be asked a semi-quantitative question for each 
medication: whether or not they are taking each medication regularly (in every intended instance or 
almost every intended instance), irregularly, or not at all.  
Compliance with each study drugs will be defined as use of ≥80% of expected drugs based on pill count 
data. Data from the semi-quantitative questions will be used to enhance adherence and to provide a 
secondary measure of adherence. 
6.3 
Procedures for patients who start dialysis or undergo kidney transplantation  
Participants will be withdrawn from the study if they initiate renal replacement therapy or undergo kidney 
transplantation.  MRIs should be obtained in these participants prior to their first renal replacement 
therapy. 
6.4 
Procedures for patients who become pregnant 
Participants will be withdrawn from the study if they become pregnant. 
 
7 
CHARACTERIZATION OF THE MEASUREMENTS AND PROCEDURES DURING SCREENING, 
BASELINE, AND FOLLOW-UP AND METHODS OF MEASUREMENT TO BE USED 
7.1 
GFR Calculation 
GFR will be estimated from Core Biochemistry Lab serum creatinine values using the CKD-
Epidemiology Collaboration equation.27 
 
 


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7.2 
List of laboratory measurements 
The following lab tests will be performed at the COMBINE Primary Core Lab at Spectra: 
 
Serum Tests 
sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, glucose, calcium, phosphate, 
aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, 
creatine kinase, uric acid, and PTH 
Whole Blood Tests 
hemoglobin A1c, white blood cell count, hemoglobin, hematocrit, and platelets. 
Urine Tests 
calcium, creatinine, phosphorus, and urea nitrogen 
The following lab tests will be performed at a central FGF23 laboratory: 
 
Serum Tests 
FGF23  
Levels of calcitriol, klotho, P1NP, Trap-5b, BNP, troponin T, cholesterol, ADMA, CRP and IL-6 
will also be measured at the central FGF23 laboratory (performed in batches, in either plasma or 
serum). 
8 
ADVERSE EVENTS, ADVERSE EVENT REPORTING 
8.1 
Introduction 
Adverse events include any untoward medical occurrence in a participant administered the study drugs 
and which does not necessarily have a causal relationship with the study drugs.  AEs can include 
abnormal laboratory findings, symptoms, or disease temporally associated with the use of study drugs, 
whether or not the event is considered causally related to the use of the study drugs.  AEs can result from 
use of the study drugs as stipulated in the protocol, and from accidental or intentional overdose, drug 
abuse, or drug discontinuation.  An AE may meet the criteria for a serious adverse event (SAE). 
8.2 
Expected Study Adverse Events 
8.2.1 
Types of AEs that may be treatment or procedure side effects 
Lanthanum carbonate may lower serum phosphate levels and is associated with gastrointestinal side 
effects including nausea, vomiting, constipation and diarrhea.   
Nicotinamide may lower serum phosphate levels and may be associated with other laboratory 
abnormalities including thrombocytopenia, abnormalities in serum liver function tests and CK.  
Gastrointestinal side effects, such as diarrhea and heartburn may also occur.  
The following laboratory results will be flagged as expected study adverse events in this trial: 
 
Hypophosphatemia:  Serum phosphate level <1.5 mg/dl 
 
Hyperphosphatemia: Serum phosphate >5.9 mg/dl  
 
Thrombocytopenia: Platelet count <100,000 
 
Liver function test abnormalities:  AST, ALT, total bilirubin, alkaline phosphatase > 4 times 
the upper limit of normal  
Elevated Creatine Kinase: Creatinine kinase > 4 times upper limit of normal.  
 
The following symptoms will be flagged as expected study adverse events in this trial.  
 
Bruising   
 
Bleeding   
 
Severe diarrhea 
 
Severe nausea 


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 
Flushing  
 
Hives 
 
Heartburn.  
The following are expected adverse events related to the MRI scans: 
 
Risks related to undetected metal 
 
Distress from incidental findings that may necessitate additional work up  
 
Risks from furosemide administration in participants with unknown or unrecorded allergy 
to furosemide.  
8.2.2 
How AEs will be reported 
Laboratory tests will be performed periodically to monitor safety, as indicated in Table 1.  Laboratory 
measurement based AEs will be detected.  Other adverse effects will be assessed at each follow-up visit 
during symptom questionnaire discussions.  Adverse events related to MRI scans will be recorded after 
each MRI visit and summary reports will be made available to the DSMB.  
8.2.3 
Follow-up of AEs 
Hypo- and hyperphosphatemia will be treated as described in the MOP. 
GI side effects will be treated as described in the MOP. 
Some AEs, if confirmed, lead to discontinuation of one or both blinded study medications.  Details are 
provided in Protocol Section 9.1 
8.3 
SAE, Hospitalization, and Death reporting 
Standard SAEs listed as follows will be reported in detail and reviewed by the Event Review Committee. 
 
Death 
 
Life-threatening event   
 
Hospitalization 
 
Prolongation of hospitalization  
 
Congenital anomaly   
 
Persistent or significant disability/incapacity 
 
Important medical event requiring medical or surgical intervention to prevent serious outcome 
 
Spontaneous abortion 
8.3.1 
Local Categorization of SAEs as Unanticipated, Related 
When an SAE is documented, the local Clinical Center’s Investigator will report on the SAE Detail Form 
whether the SAE was unanticipated.  An unanticipated SAE, as defined by DHHS 45 CFR part 46, meets 
following three criteria: 1) unexpected, in terms of nature, severity, or frequency, given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the study population; 2) related or 
possibly related to participation in the research (in this guidance document, possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research);  and 3) suggests that the research places participants or others at a 
greater risk of harm (including physical, psychological, economic, or social harm) than was previously 
known or recognized will determine use the following definitions to assess the relationship of the adverse 
event to the use of study treatment.   
The site investigator will also classify the SAE as not related, probably not related, possibly related, 
probably related, or related to study procedures and treatments. 
8.3.2 
Event Committee Review of SAEs 
The COMBINE Study Event Committee will review the first 10 SAEs occurring at each site in the 
COMBINE Study.  After that, the Event Committee will review all deaths, all SAEs that the site 
investigators categorized as possibly related, probably related, or related and a 10% QC subset of the 


COMBINE PROTOCOL Version 1.2 – 06/22/2015 
Page 21 of 25 
 
SAEs that the site investigator categorized as unrelated.  The primary Event Committee reviewer for each 
reviewed SAE will be chosen from members of the Event Committee who are from sites other than the 
site where the SAE occurred. When SAE data are presented to the study’s DSMB for safety review, both 
the local site and Event Committee categorization will be presented. 
9 
STOPPING RANDOMIZED TREATMENT   
9.1 
Stopping randomized treatment for Adverse Events  
Participants will stop treatment with both nicotinamide and lanthanum carbonate due to either hypo- or 
hyperphosphatemia. Data collection will continue as usual. 
Participants will stop treatment with nicotinamide, but continue on the blinded lanthanum carbonate, if 
the following occur: 
 
On two consecutive measures, participant is found to have liver function test (AST, ALT, total 
bilirubin, or alkaline phosphatase) or CK levels > 4 times the upper limit of normal without other 
identifiable cause. 
 
On two consecutive measures, participant is found to have a platelet count <100,000 with clinical 
signs of platelet dysfunction (bruising or bleeding noted at a study visit and documented on the 
symptom form) or <75,000 without clinical signs 
9.2 
Stopping randomized treatment for Adverse Events  
Participants will stop treatment with nicotinamide and/or lanthanum carbonate, but data collection will 
continue as usual, if the site investigator and the Event Committee agree that an SAE was possibly, 
probably, or definitely related to treatment and that it is unsafe for the patient to continue on the specified 
treatment (nicotinamide and/or lanthanum carbonate). 
Procedures for dose adjustment in the case of gastrointestinal side effects are described in the MOP. 
9.3 
Discontinuation of study medications due to patient preference/non-compliance  
Participants who wish to discontinue study medications will be encouraged by the Site PI and study 
coordinator to continue with visits, lab tests, and data collection so data will be available for intent to treat 
analysis of the trial. The site PI will encourage passive data collection such as hospitalization 
documentation for participants who no longer want to attend visits.  
9.4 
The role of Study Committees in review of lab data and adverse events  
Lab data from the Core Lab will be reported to each site investigator and the site team as soon as the 
results are available to the study database.  The Quality Control Committee will review lab data.  The 
Event Review committee will review SAEs and any events that the clinical centers categorize as requiring 
treatment discontinuation for safety reasons. 
10 
DSMB 
NIDDK will name a DSMB for this clinical trial.  The DSMB will include clinicians, statisticians, and 
other experts as needed, and will include experts on research and clinical expertise in CKD-mineral bone 
disorders.   Acting as a protocol review committee, the DSMB will review and approve the study 
protocol.   As the study progresses, NIDDK will schedule routine meetings and conference calls of the 
DSMB.  At these meetings, the DSMB will review reports of study progress in the areas of recruitment, 
retention, quality control, and safety related to study medications and to MRI scans.  The DSMB can ask 
for additional reports or additional meetings at their discretion.   
11 
ANALYSIS PLAN 
11.1 Primary analysis 
Specific Aim 1 of this clinical trial will evaluate changes over time in absolute levels of serum phosphate 
and FGF23 levels, with each active treatment group compared to the double placebo group.  Based on 
prior data, both serum phosphate and FGF23 levels are expected to decline from baseline within the first 
three months and then to be stable thereafter.   


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Because the distribution of FGF23 is expected to be skewed, FGF23 values will be log transformed. A 
piecewise mixed-model, repeated-measures analysis will be performed to assess separately changes in 
two primary endpoints within the first 3 months and in the period thereafter (months 3 – 12).  The 
analysis will be stratified by clinical center. Covariates included in the model will include baseline eGFR 
and gender. 
When two measures of serum phosphate and FGF 23 are available, the average of these two baseline 
values of serum phosphate (for models evaluating phosphate as the outcome variable) and FGF23 (for 
models evaluating FGF23 as the outcome variable) levels will be used as the baseline value for analyses 
of treatment comparison (Table 1).    
Specific Aim 2 will address tolerability and safety evaluations in the intention to treat population.   
Tolerability: The primary measure of tolerability will be the percentage of persons who come off study 
drug across treatment.  The percentages will be summarized by treatment group and differences will be 
evaluated using the Fisher's exact test.  Compliance by pill count and questionnaire will be evaluated as 
secondary outcomes. 
Safety: The number and percentage of the participants who report at least one adverse event will be 
summarized by treatment group and overall.  The treatment group difference in the percentages will be 
evaluated using Fisher's exact test. Adverse events will also be summarized descriptively with counts and 
percentages. 
11.2 Secondary Analyses 
A secondary objective is to determine whether or not combined treatment with lanthanum carbonate and 
nicotinamide lowers serum phosphate or FGF23 more so than either nicotinamide alone or lanthanum 
alone.   If no significant interaction between nicotinamide and lanthanum carbonate is seen, the main 
effects of each active treatment as in a factorial design study will be evaluated.  As in analysis for the 
primary outcome, we will stratify for clinical center and use averages of baseline serum phosphate (in 
models evaluating phosphate as the outcome variable) and averages of baseline FGF23 (for models 
evaluating FGF23 as the outcome variables) as the baseline values in the analyses.   Models will be 
adjusted for eGFR and gender, as in the primary analysis. 
To address expected cross-over from on-protocol to off-protocol management due to hypo- and 
hyperphosphatemia and off-protocol binder use, “as-treated” exploratory analyses will be included.  
For analyses of the secondary objectives, linear mixed models to analyze effects of all active-treatment 
groups combined vs. placebo group will be used.  In pre-specified secondary analyses, differences 
between the four treatment groups, perform as treated analyses and test the association between the 
magnitude of reduction in phosphate and FGF23 and changes in the secondary objective end points will 
be used.   
11.3 Analyses of other follow-up data  
Mixed-model, repeated-measures analyses will be used for comparisons of changes of PTH, calcium, 
eGFR, and urine ACR.  When analyses of 24-hour urine are performed, the only collections that will be 
used will be those in which the measured 24-hour urine creatinine excretion is within 30% of estimated 
creatinine excretion using the CKD-EPI creatinine excretion rate estimation equation.24 
11.4 Safety analyses 
Standard analyses will be used for safety evaluations conducted in the intention-to-treat population. As-
treated analyses will be performed if there are treatment crossovers due to non-compliance or if study 
medications are stopped due to adverse or other events. 


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11.5 Planned analyses of feasibility/logistics including rates of missing data, missing forms, 
 missing visits, and of non-compliance. 
This 12-month study will provide important feasibility data on long-term tolerability, safety, and 
adherence.  Standard analyses of recruitment, retention, and compliance will be used for feasibility 
evaluations   
11.6 What will it take to say that this pilot study is feasible?  
The COMBINE Study will be judged to be feasible if 1) any of the primary efficacy analyses on serum 
phosphorus or FGF23 is significant at the .05/6 level and 2) the intervention(s) associated with the 
outcome(s) met the following criterion for compliance and tolerability: The majority of randomized 
patients are able to complete 12 months of follow-up without having to discontinue either the lanthanum 
arm or the nicotinamide arm. 
11.7 Test run of the analysis plan for the full scale study 
Although this pilot study is not powered to detect changes in CKD progression, longitudinal data on 
serum creatinine and spot urinary albumin-creatinine ratio (UACR) will be considered.  At the end of the 
study, changes in eGFR over time and rates of ESRD, CVD events, fractures and death by randomized 
treatment group will be done. 
12 
PLANS FOR THE STUDY DESIGN OF THE FULL SCALE TRIAL 
12.1 Current Plans for Primary Outcome of the Full Scale Trial 
Our long-term goal is to conduct a placebo-controlled, randomized trial to target hard clinical endpoints 
hypothesized as down-stream consequences of phosphate and FGF23 excess.  Hard end-points will 
include a combination (to be determined) of ESRD, CVD events, fractures and death. 
13 
ACKNOWLEDGEMENTS 
If using CTSA/GCRCs, they will be acknowledged here by grant number.   
 
Nicotinamide and Nicotinamide placebo were donated by Endurance.  Lanthanum Carbonate and 
Lanthanum Carbonate placebo were donated by Shire. 
 
14 
REFERENCES    
1. 
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS. 
Prevalence of chronic kidney disease in the United States. JAMA 2007; 298:2038-47. 
2. 
Isakova T, Wahl P, Vargas GS, Gutierrez OM, Scialla J, Xie H, Appleby D, Nessel L, Bellovich 
K, Chen J, Hamm L, Gadegbeku C, Horwitz E, Townsend RR, Anderson CA, Lash JP, Hsu CY, 
Leonard MB, Wolf M. Fibroblast growth factor 23 is elevated before parathyroid hormone and 
phosphate in chronic kidney disease. Kidney Int 2011; 79:1370-8. 
3. 
Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL. Prevalence of 
abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney 
disease: results of the study to evaluate early kidney disease. Kidney Int 2007; 71:31-8. 
4. 
Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutierrez OM, Steigerwalt 
S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, 
Feldman HI, Wolf M. Fibroblast growth factor 23 and risks of mortality and end-stage renal 
disease in patients with chronic kidney disease. JAMA 2011; 305:2432-9. 
5. 
Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, Strippoli GF. Serum levels of 
phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in 
individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 2011; 
305:1119-27. 
6. 
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. 
7. 
Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, Morii H, Giachelli CM. 
Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000; 87:e10-7. 


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8. 
Scialla JJ, Lau WL, Reilly MP, Isakova T, Yang HY, Crouthamel MH, Chavkin NW, Rahman M, 
Wahl P, Amaral AP, Hamano T, Master SR, Nessel L, Chai B, Xie D, Kallem RR, Chen J, Lash 
JP, Kusek JW, Budoff MJ, Giachelli CM, Wolf M. Fibroblast growth factor 23 is not associated 
with and does not induce arterial calcification. Kidney Int 2013; 83:1159-68. 
9. 
Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutierrez OM, Aguillon-Prada R, 
Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, 
Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di 
Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro OM, Kusek JW, 
Keane MG, Wolf M. FGF23 induces left ventricular hypertrophy. J Clin Invest 2011; 121:4393-
408. 
10. 
Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann 
U, Coglianese E, Christenson R, Wang TJ, deFilippi C, Wolf M. Fibroblast growth factor 23 and 
left ventricular hypertrophy in chronic kidney disease. Circulation 2009; 119:2545-52. 
11. 
Isakova T, Barchi-Chung A, Enfield G, Smith K, Vargas G, Houston J, Xie H, Wahl P, 
Schiavenato E, Dosch A, Gutierrez OM, Diego J, Lenz O, Contreras G, Mendez A, Weiner RB, 
Wolf M. Effects of Dietary Phosphate Restriction and Phosphate Binders on FGF23 Levels in 
CKD. Clin J Am Soc Nephrol 2013; 8:1009-18. 
12. 
Sabbagh Y, O'Brien SP, Song W, Boulanger JH, Stockmann A, Arbeeny C, Schiavi SC. Intestinal 
npt2b plays a major role in phosphate absorption and homeostasis. J Am Soc Nephrol 2009; 
20:2348-58. 
13. 
Cheng SC, Young DO, Huang Y, Delmez JA, Coyne DW. A randomized, double-blind, placebo-
controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients. Clin J Am 
Soc Nephrol 2008; 3:1131-8. 
14. 
Shahbazian H, Zafar Mohtashami A, Ghorbani A, Abbaspour MR, Belladi Musavi SS, Hayati F, 
Lashkarara GR. Oral nicotinamide reduces serum phosphorus, increases HDL, and induces 
thrombocytopenia in hemodialysis patients: a double-blind randomized clinical trial. Nefrologia 
2011; 31:58-65. 
15. 
Takahashi Y, Tanaka A, Nakamura T, Fukuwatari T, Shibata K, Shimada N, Ebihara I, Koide H. 
Nicotinamide suppresses hyperphosphatemia in hemodialysis patients. Kidney Int 2004; 65:1099-
104. 
16. 
Young DO, Cheng SC, Delmez JA, Coyne DW. The effect of oral niacinamide on plasma 
phosphorus levels in peritoneal dialysis patients. Perit Dial Int 2009; 29:562-7. 
17. 
Schiavi SC, Tang W, Bracken C, O'Brien SP, Song W, Boulanger J, Ryan S, Phillips L, Liu S, 
Arbeeny C, Ledbetter S, Sabbagh Y. Npt2b Deletion Attenuates Hyperphosphatemia Associated 
with CKD. J Am Soc Nephrol 2012; 23:1691-700. 
18. 
Ix JH, Ganjoo P, Tipping D, Tershakovec AM, Bostom AG. Sustained hypophosphatemic effect 
of once-daily niacin/laropiprant in dyslipidemic CKD stage 3 patients. Am J Kidney Dis 2011; 
57:963-5. 
19. 
Oliveira RB, Cancela AL, Graciolli FG, Dos Reis LM, Draibe SA, Cuppari L, Carvalho AB, 
Jorgetti V, Canziani ME, Moyses RM. Early control of PTH and FGF23 in normophosphatemic 
CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol 2010; 5:286-91. 
20. 
Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler M, Spiegel DM, Allison MA, 
Asplin J, Smits G, Hoofnagle AN, Kooienga L, Thadhani R, Mannstadt M, Wolf M, Chertow 
GM. Effects of Phosphate Binders in Moderate CKD. J Am Soc Nephrol 2012; 23:1407-15. 
21. 
Isakova T, Gutierrez OM, Smith K, Epstein M, Keating LK, Juppner H, Wolf M. Pilot study of 
dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in 
patients with chronic kidney disease. Nephrol Dial Transplant 2011; 26:584-91. 
22. 
Hutchison AJ, Barnett ME, Krause R, Kwan JT, Siami GA. Long-term efficacy and safety profile 
of lanthanum carbonate: results for up to 6 years of treatment. Nephron Clin Pract 2008; 110:c15-
23. 


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23. 
Sullivan C, Sayre SS, Leon JB, Machekano R, Love TE, Porter D, Marbury M, Sehgal AR. Effect 
of Food Additives on Hyperphosphatemia Among Patients With End-stage Renal Disease: A 
Randomized Controlled Trial. JAMA 2009; 301:629-35. 
24. 
Ix JH, Katz R, Peralta CA, de Boer IH, Allison MA, Bluemke DA, Siscovick DS, Lima JA, 
Criqui MH. A high ankle brachial index is associated with greater left ventricular mass MESA 
(Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2010; 55:342-9. 
25. 
Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, 
Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Packham 
D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD. Vitamin D therapy and 
cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized 
controlled trial. JAMA 2012; 307:674-84. 
26. 
Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B, Kleiman J, Krause S, Burns 
D, Williams GH. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with 
essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. 
Circulation 2003; 108:1831-8. 
27. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T, Coresh J. A new equation to estimate glomerular filtration rate. Ann 
Intern Med 2009; 150:604-12. 
 
 

ICF_001.pdf: 
Version Date: 12/07/2015 
 
 
 
  
 
 
 
Page 1 of 19 
 
 
 
 
 
 
 
Northwestern University 
Consent Form and HIPAA Authorization for Research 
 
PROTOCOL TITLE:  EFFECTS OF NICOTINAMIDE AND LANTHANUM 
CARBONATE ON SERUM PHOSPHORUS AND FGF23 LEVELS IN PATIENTS WITH 
STAGE 3-4 CHRONIC KIDNEY DISEASE 
 
PRINCIPAL INVESTIGATOR:  Myles Wolf, MD, MMSc 
 
CO-INVESTIGATOR:   Tamara Isakova, MD, MMSc 
 
SUPPORTED BY:  The National Institutes of Health (NIH) 
 
Introduction  
You are being asked to take part in a research study. This document has important information 
about the reason for the study, what you will do if you choose to be in this research study, and 
the way we would like to use information about you and your health.   
 
Conflict of interest disclosure 
The following disclosure is made to give you an opportunity to decide if this relationship will 
affect your willingness to participate in this research study: 
 
If your doctor is also the person responsible for this research study, please note that he/she is 
interested in both your clinical care and the conduct of this research study.  You have the right to 
discuss this study with another person who is not part of the research team before making your 
decision whether or not to be in the study.  
 
What is the reason for doing this study? 
Myles Wolf, MD, MMSc, is conducting a research study sponsored by the National Institutes of 
Health to determine new methods to lower serum phosphorus levels and levels of the hormone 
"FGF23"(Fibroblast Growth Factor 23) in chronic kidney disease patients.  
 
You are being asked to participate in this research study because you have chronic kidney 
disease, a condition in which your kidneys do not filter substances from the blood as well as 
healthy kidneys.  
 
Phosphorus is a mineral found in many foods.  It works with calcium and vitamin D to keep 
bones healthy.  Healthy kidneys keep the right balance of phosphorus in the body.  FGF23 is a 
hormone that helps the kidneys to control the blood levels of phosphorus.  Hormones are natural 
substances, made by the body and measured in the blood, that affect various bodily functions. 
FGF23 “tells” the kidneys how much phosphorus to get rid of in the urine.   
 
In people with chronic kidney disease, kidneys struggle to get rid of enough phosphorus, so 
FGF23 levels increase in the blood to help get rid of extra phosphorus. Over time, with 
progressive loss of kidney function, both phosphorus and FGF23 can build up in the blood 
simultaneously.  Researchers believe that too much phosphorus and FGF23 in the blood may 


Version Date: 12/07/2015 
 
 
 
  
 
 
 
Page 2 of 19 
 
 
 
 
 
 
 
lead to weak bones that break easily, increase the risk of heart problems, and accelerate 
progression of kidney disease.  However, the best way to control phosphorus and FGF23 levels 
in the blood in patients with chronic kidney disease is not known.   
 
The purpose of this research study is to:  
• 
test the effectiveness of the study drugs, nicotinamide and lanthanum carbonate, either 
individually or in combination, to lower blood levels of phosphorus and FGF23; 
• 
determine the tolerability and safety of the study drugs, nicotinamide and lanthanum 
carbonate, either individually or in combination over 12 months in patients with chronic 
kidney disease; 
• 
test the effects of the study drugs on bone, heart and kidney health.  
 
This is a research study to test two drugs being used for investigational purposes.  Each study 
drug is described in more detail below. 
 
Nicotinamide (also called niacinamide or Vitamin B3) is a water soluble vitamin that is 
essential to health at low doses for all individuals.  Nicotinamide is not regulated by the United 
States Food and Drug Administration (FDA), but is marketed and distributed as a dietary 
supplement in the United States.  Studies in animals show that nicotinamide at higher doses 
limits the amount of phosphorus absorbed by the intestine from food into the blood.  
Nicotinamide has also been tested in small studies of dialysis patients (patients with complete 
loss of kidney function), and was associated with substantial reductions in blood phosphorus 
levels.  Prior large-scale studies have tested high doses of nicotinamide in healthy individuals 
who took the medicine for up to 5 years.  In these studies, nicotinamide was found to be safe and 
well tolerated.  The rate of side effects in participants who took nicotinamide was comparable to 
the rate in participants that received placebo.  (A placebo is an inactive substance that is made to 
look like the study drug.) 
 
Lanthanum carbonate (also called Fosrenol) is a phosphorus binding medication that is used 
in patients on dialysis to reduce the amount of phosphorus that the body is able to absorb from 
the diet.  These tablets are used when blood levels of phosphorus are too high.  Fosrenol is 
approved by the FDA to treat high phosphorus levels in the blood of patients on dialysis, but has 
not been approved by the FDA for people with chronic kidney disease not severe enough to 
require dialysis. 
 
This study also uses a placebo.  A placebo looks like the study drug, but contains no active 
medication.  Placebos are used in research studies to learn if helpful or harmful effects seen in 
research participants are truly from the study drug.  If you take part in this study, you will have a 
1 in 2 (50%) chance of getting placebo, and a 1 out of 2 (50%) chance of receiving the active 
drug for each of the two medications used.   
 
Because this is a research study, the nicotinamide and lanthanum carbonate will be given to you 
only during this study and not after the study is over. 
 


Version Date: 12/07/2015 
 
 
 
  
 
 
 
Page 3 of 19 
 
 
 
 
 
 
 
We will obtain Magnetic Resonance Imaging (MRI) scans (no injection of dye (contrast)) of 
heart and kidneys to answer our research questions.  There are no known radiation risks 
associated with MRI, and the images we will obtain in this study do not require contrast.   
 
Cardiac MRI uses structural MRI to look at the heart.  Cardiac MRI is a type of scan that uses 
magnetic fields and radio waves to make a picture of the size of the chambers of the heart. 
 
Renal MRI uses blood oxygenation level dependent (BOLD) functional MRI to look at the 
kidneys.  BOLD MRI is a type of scan that uses magnetic fields and radio waves to make a 
picture of kidney function. 
 
Additional information regarding these procedures will be provided below.  If you decide not to 
have the MRI scans or if we determine that you should not have them, you can proceed with the 
other study procedures.    
 
If we determine that it is safe for you to receive MRI scans and if you choose to have them, then 
the following procedures will take place during your MRI scans. 
 
The MRI scans will take place at the Olson Pavilion, 710 North Fairbanks, Basement, Chicago, 
IL.  Each MRI study visit will take about 1.5 hours.  On the days of the MRI visits, you will 
come after fasting for at least 4 hours. Fasting refers to food and drinks only; you should take 
your medications without interruption.  If you take insulin, your study doctor /staff will tell you 
what to do about taking it on the day of the MRI.   
 
At these visits we will: 
- 
Take a cardiac MRI scan (no contrast) to check size of the chambers of your heart; 
- 
Take a renal MRI scan (no contrast) to check the function of your kidneys. 
 
You will have one cardiac and one renal MRI scan (no contrast) when you start the study.  These 
will be repeated 12 months later.   
 
How many people will take part in this study?   
The study investigators hope to enroll 50 subjects at Northwestern University and 200 
nationwide. The study sites are Northwestern University, North Shore University Health System, 
George Washington University, University of California San Diego, Denver Nephrology and 
University of Utah. 
 
What will you do if you choose to be in this study?  
If you consent to participate, your participation in this study will last approximately 12 months 
and include 11 study visits. The study visits will take place at the Center for Translational 
Metabolism and Health located at633 N. St. Clair, , 18th floor.. The following tests and 
procedures will be performed to determine if you qualify to take part in this study during the 
screening visit:   
 
 
 


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Screening Visit  
This study visit will last approximately 1 hour.  During this visit you will meet with a member of 
the research team who will explain the study in detail to you.  You will be asked to read this 
consent form carefully.  If you would like to participate, we will ask you to sign the consent 
form.  You will get a signed copy to keep for your records.   
 
After you sign the consent form, we will do some tests and procedures to see if you qualify to 
take part in this research study.  A member of the research team will review the results of these 
tests and procedures.  If you don’t qualify, we will tell you why.  The following procedures will 
be done: 
• 
We will measure your blood pressure, heart rate, height and weight.  
• 
We will ask you questions about your medical history and current medications.  
• 
We will ask you additional questions to find out if it is safe for you to have the MRI scans.  
• 
About 3 tablespoons (45 mL) of blood will be drawn.  We will measure your electrolytes, 
BUN/creatinine (a measure of kidney function), parathyroid hormone, serum phosphorus, 
serum glucose, total blood count, LFT (liver function test), and CK (creatine kinase, a muscle 
function test).   
• 
We will do a urine pregnancy test if you are a woman under 50 years old.   
 
You will not be able to participate in the study if we find that your: 
• 
blood count is too low 
• 
platelet count is too low (platelets help to control blood clotting) 
• 
albumin level is too low (albumin is a protein in the blood) 
• 
liver function tests are high 
• 
levels of parathyroid hormone in your blood are too high (parathyroid hormone controls how 
calcium is used in the body) 
• 
levels of phosphorus in your blood are too low 
• 
levels of CK in your blood are too high (Creatine Kinase (CK) is a muscle enzyme) 
• 
urine pregnancy test is positive or if you are breastfeeding a child 
• 
you eat less than 2 meals per day 
 
If you qualify for the study, you will proceed into the Baseline Period, described below.  
 
Baseline Period (Baseline Visits 0, 1 and 2) 
The Baseline Period will include a run-in (time on study before you receive the study treatment) 
that will last 3 weeks and will consist of three visits.  During this time the research team will 
evaluate how well you do with the study procedures.  You will be asked to collect all of your 
urine over 24 hours at home on two separate occasions and to return these samples to the study 
personnel.  You will also receive information about how to keep a low phosphorus diet.  During 
this time, you will also receive an MRI scan (no contrast) of your heart and kidneys.  Your MRI 
scan (no contrast) visit could coincide with one of the Baseline visits, or it could take place on a 
different day.  
 
Baseline Visit 0 will take approximately 30 minutes to complete.  At this visit, the following 
procedures will be performed:  
 


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• 
We will give you a container for 24-hour urine collection and instructions. We will ask you 
to return the 24 hour urine specimen at your next study visit.  
• 
We will ask you to complete a questionnaire about gastrointestinal (stomach) symptoms you 
may be having. This questionnaire should take less than 5 minutes to complete.  
• 
We will give you study medications, which you will be asked to start taking according to 
instructions.  To help us count how many tablets you have taken, we will ask you to bring the 
study pill bottle back with you to your next visit. 
 
Baseline Visit 1 will take approximately 1 hour to complete.  At this visit, the following 
procedures will be performed:  
• 
You will be asked to deliver your first 24-hour urine collection to study personnel. This 
sample will be used to measure 24-hour urine phosphorus, calcium, and to determine your 
kidney function, creatinine and urea nitrogen (BUN).  
 We will check your blood pressure, heart rate, and weight. 
• 
About 4 tablespoons (60 mL) of blood will be drawn to measure FGF23, uric acid, 
hemoglobin A1c (a marker of glucose control/diabetes), electrolytes, BUN, creatinine, 
glucose, albumin, parathyroid hormone, calcium, and phosphorus levels.   
• 
If you agree, we will draw blood samples (30 mL, 2 tablespoons) and save urine samples to 
store for future studies (refer to the Optional Study Elements section at the end of this 
form). 
• 
We will ask you for a urine sample. This sample will be used to test urine phosphorus, 
calcium, albumin, and creatinine. This sample will not require a timed collection, but will be 
a "spot" specimen provided at the time of your visit. 
• 
We will give you a container for your second 24-hour urine collection and instructions.  We 
will ask you to return the 24-hour urine specimen at your next study visit. 
• 
You will be asked to bring in your study medication pill bottle with you, so we can count 
how many tablets you have taken. 
• 
A member of the research team will review with you information about keeping a low 
phosphorus diet and will instruct you on how to avoid food items high in phosphorus.  
• 
We will give you a questionnaire to fill out about any gastrointestinal (stomach) symptoms 
you may have, about your ability to take the study drugs, and to assess for any potential side 
effects of the study drugs.  
 
Baseline Visit 2 will take approximately 1 hour to complete.  At this visit, the following 
procedures will be performed:   
• 
You will be asked to deliver your second 24-hour urine collection to study personnel.  This 
sample will be used to measure 24-hour urine phosphorus, creatinine, calcium, and urea 
nitrogen. 
• 
We will check your blood pressure, heart rate, and weight. 
• 
We will draw a blood sample of approximately 3 tablespoons (45 mL) to measure your 
FGF23, serum phosphorus, electrolytes, BUN/creatinine (a measure of kidney function), 
glucose, parathyroid hormone,  and calcium levels.  
• 
If you agree, we will draw blood samples (30 mL, 2 tablespoons) and save urine samples to 
store for future studies (refer to the Optional Study Elements section at the end of this 
form). 


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• 
We will ask you for a "spot" urine sample. This sample will be used to test the urine for 
phosphorus, calcium, albumin, and creatinine. 
• 
A member of the research team will review with you information about keeping a low 
phosphorus diet and will instruct you on how to avoid food items high in phosphorus. 
• 
You will be asked to bring in your study medication pill bottle so we can count how many 
tablets you have taken. 
• 
We will give you a questionnaire to fill out about any gastrointestinal (stomach) symptoms 
that you may have, about your ability to take the study drugs, and to assess for any potential 
side effects of the study drugs. 
• 
You will be randomized into 1 of 4 groups (see Randomization to Study Groups section 
below). 
• 
You will receive a 30-day supply of study drugs based on the study group you are 
randomized to.  
 
Cardiac MRI procedures 
For the cardiac MRI Scan (no contrast), we will: 
• 
We will ask you to complete an MRI safety questionnaire before you receive your MRI. 
• 
We will ask you to change into a hospital gown and remove any jewelry/bra/metal objects. 
• 
We will ask you to lie very still on the scanning table. 
• 
We will attach ECG (electrocardiogram) electrodes to you, as the pictures are taken in time 
with your heartbeat. 
• 
We will place a lightweight pad with a scanning device (radio antenna) over your chest.  
• 
We will give you a squeeze ball that you can squeeze to stop the MRI scan if you feel you 
need to.   
• 
We will place you inside the MRI scanner with a set of headphones or ear plugs.   
• 
You will remain in communication with the MRI technician when in the MRI scanner.  
• 
You may hear a loud knocking sound during the MRI scan, which indicates that a picture is 
being taken.  During this time you should breathe quietly and remain still.  For some scans 
you may be asked to hold your breath for up to 20 seconds. 
 
The scan will take about 30 minutes. 
 
Renal MRI procedures 
For the renal MRI Scan (no contrast): 
• 
We will reposition the scanning device (radio antenna) over the abdomen.   
• 
We will give you a squeeze ball that you can squeeze to stop the MRI scan if you feel you 
need to.   
• 
We will place you inside the MRI scanner with a set of headphones or earplugs.   
• 
You will remain in communication with the MRI technician when in the MRI scanner.  
• 
You may hear a loud knocking sound during the MRI scan, which indicates that a picture is 
being taken.  During this time you should breathe quietly and remain still.  For some scans 
you may be asked to hold your breath for up to 20 seconds. 
• 
We will put in an intravenous line (“IV”) in your arm.  An IV is a thin, flexible plastic tube 
that is threaded into a vein using a needle.   It allows us to inject medications into your vein 
• 
We will inject 20 mg of Furosemide (Lasix, a drug used to get excess water out of the body 
and increase urine; "water pill") into your vein, and we will take more pictures.   


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The scan will take about 30 minutes. 
 
The total duration of the MRI study visits will be approximately 1.5 hours.   
 
Randomization to Study Groups 
This is a randomized, double-blinded study, which means that neither you or the study doctor or 
the study staff will know which treatment you are receiving.  However, in an emergency, study 
doctors can get this information. Randomization means you will be randomly assigned to a 
treatment based on chance, like a flip of a coin. Neither you nor the researcher chooses your 
assigned group. You will have an equal chance of being in any one of the four groups. 
 
At the end of Baseline Visit 2, we will review your results from Baseline Visit 1 and determine if 
you still qualify for the study.  If you don’t qualify, we will tell you why.   
 
If you remain eligible for the study, you will be randomly assigned to 1 of 4 groups: 
 
• 
First group:  Will receive both nicotinamide and lanthanum carbonate, 
• 
Second group:  Will receive lanthanum carbonate and nicotinamide placebo,  
• 
Third group:  Will receive lanthanum carbonate placebo and nicotinamide, 
• 
Fourth group:  Will receive lanthanum carbonate placebo and nicotinamide placebo. 
 
Taking the Study Drugs 
At every follow up visit, we will give you a supply of study drugs to take home with you.   
 
You will chew one 500 mg lanthanum carbonate (or placebo) tablet three times a day with meals 
for the first month on the study.  Thereafter, from months 2 through 12, you will chew two 500 
mg lanthanum carbonate (or placebo) tablets three times a day with meals, unless instructed 
otherwise by study staff.    
 
You will take one 750 mg nicotinamide tablet (or placebo) by mouth once per day for the first 
month on the study.  Thereafter, from months 2 through 12, you will take one 750 mg 
nicotinamide tablet (or placebo) by mouth twice a day, unless instructed otherwise by study staff.   
 
It is important for you to follow our instructions about how to take the study drugs.  Bring any 
unused study drugs or your empty pill bottles with you to your next study visit.  
 
Doses or frequency of your study medications may need to be adjusted during the study and 
members of the study team will give you detailed instructions on any changes.  
 
 
Follow up Period (Follow up Visits 1-12) 
During this period, you will make 7 additional visits, which will be a month apart during the first 
3 months and thereafter the visits will be 3 months apart for 2 additional visits, and then at a 2 
month and 1 month follow-up interval during the last 3 months of the study.  The visit names 
correspond to the month of the follow up period.  For example, follow up visit 6 corresponds to 


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Page 8 of 19 
 
 
 
 
 
 
 
the 6th month of follow up.  At the end of the follow up period, you will have your final cardiac 
and renal MRI scans (no contrast).   
 
During Follow up Visits 1-9 and 12, the following procedures will be done:    
• 
We will ask you questions about your current health and medications you are taking. 
• 
We will draw blood samples (about 4 tablespoons (60 mL)) to measure your FGF23, 
phosphorus, electrolytes, glucose, and BUN/creatinine (a measure of kidney function). 
• 
We will measure PTH and calcium levels during Follow up Visits 3, 6, 9 and 12. 
• 
We will measure uric acid and HbA1C (an average measure of blood sugar) levels during 
Follow up Visits 6 and 12. 
• 
We will also draw lab tests, including CBC (blood count), LFT (liver function test) and 
CK/creatinine kinase (muscle function test), to monitor your treatments for safety.  In the 
event that these show abnormalities, they may trigger additional visits.  
• 
A member of the research team will review with you information about a low phosphorus 
diet and will instruct you on how to avoid food items high in phosphorus. 
• 
You will be asked to bring in your study medication pill bottles with you at each study visit 
so that we can count how many tablets you have taken. 
• 
We will give you a questionnaire to fill out about any gastrointestinal (stomach) symptoms 
that you may have, about your ability to take the study drugs, and about any side effects from 
the study drug.  
 
During Follow up Visits 3, 6 and 12, if you agree, we will draw blood samples (30 mL, 2 
tablespoons) and save urine samples to store for future studies (refer to the Optional Study 
Elements section at the end of this form).   
 
During Follow up Visits 2, 3 and 11, the following additional procedures will be done:    
• 
We will give you a container for your 24-hour urine collection and instructions so we can 
measure the amount of phosphorus, calcium, creatinine, and urea nitrogen you are excreting 
in your urine.   
•   You will be asked to return your 24-hour urine collections at Follow up Visits 3, 6 and 12. 
This sample will be used to measure 24-hour urine phosphorus, creatinine, calcium, and urea 
nitrogen tests.  
 
During Follow up Visit 9, the following additional procedures will be done: 
 We will check your blood pressure, heart rate, and weight. 
 
During Follow up Visits 3, 6, and 12, the following additional procedures will be done:  
• 
We will check your blood pressure, heart rate, and weight. 
•     We will ask you for a "spot" (untimed) urine sample. This sample will be used to conduct 
spot urine phosphorus, calcium, albumin, and creatinine measurements. 
At the end of the follow up period, you will have your final cardiac and renal MRI scans (no 
contrast).   The procedures for these tests will be the same as during the Baseline Period.  If you 
leave the study early, we may ask you to do these scans in advance of the 12th month.  
 
 
 


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Unscheduled visits 
In addition to the follow up visits described above, you may be asked to come back for additional 
unscheduled visits during which the following procedure will be done.  
• 
If the study physician thinks you need additional blood testing, we will draw a blood sample 
to monitor your treatments for safety. 
• 
You will bring in your study medication pill bottles with you; so that we can count how 
many tablets you have taken. 
• 
We will give you a questionnaire to fill out about any gastrointestinal symptoms that you 
may have, about your ability to take the study drugs, and about any side effects from the 
study drugs.  
• 
The doses or frequency of your study medications may be adjusted.  
 
Telephone calls 
In addition to the scheduled follow up visits and unscheduled visits, a member of the study team 
may contact you by phone between your visits to determine how you are feeling and whether or 
not doses or frequency of your study medications need to be adjusted.  You may also be asked if 
you are having any trouble taking any of your study medications, and if you have been started on 
any new medications since the last visit.  Information obtained during the telephone calls may 
trigger an unscheduled visit to ensure your safety while taking the study medications.  
 
Taking Other Medications During the Study 
During the 12 months duration of the study, you will be asked not to take any non-study 
medicine that binds phosphorus. These include Tums©, calcium carbonate, sevelamer carbonate 
or Renvela©, calcium acetate or Phoslo©. You will be asked not to take over the counter forms 
of nicotinamide, though a standard multi-vitamin can be taken.  If your non-study doctor feels 
that these medications are necessary, you will be taken off of the study drugs but we will ask you 
to continue to make follow up visits until study completion. You will be asked not to take 
activated forms of vitamin D such as calcitriol, paracalcitol or Zemplar©, doxercalciferol or 
Hecterol©.    
 
After You Complete the Study 
After you complete the study, we will refer you back to your own doctor for your ongoing 
medical care.  
 
All procedures conducted for this study are for research purposes only. 
 
What are some of the possible risks and discomforts?  
Risks of hypophosphatemia (low phosphorus levels in the blood). 
Severe hypophosphatemia (very low phosphorus levels in the blood) can cause muscle weakness, 
muscle cramps and shortness of breath.  Other very rare (less than 0.01% chance) side effects of 
severe hypophosphatemia include: irritability, paresthesias (feeling of pins and needles), 
confusion, seizures, coma, heart failure, muscle breakdown, low platelet count, which leads to 
bleeding and rarely anemia and reduced function of white blood cells that fight infection.  Prior 
studies using lanthanum carbonate and nicotinamide individually in persons with chronic kidney 
disease produced only very mild decreases in blood phosphorus levels.  We do not expect your 
phosphorus levels to decrease to dangerous levels.  A small decrease will not cause any 


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symptoms, and researchers believe that small decreases may be beneficial to health.  Your 
phosphorus levels will be checked repeatedly throughout the study when blood and urine 
samples are collected.  If the phosphorus levels are found to be too low you will be notified by 
the study team and asked to return for an unscheduled visit for repeat blood draw to verify the 
blood phosphorus level.  If low levels are confirmed, we will decrease the dose of lanthanum 
carbonate by half and reduce the frequency of nicotinamide from twice a day to once a day and 
repeat the lab tests.  If the level of phosphorus remains too low, we will stop both study drugs 
and repeat the lab tests.  Once the low phosphorus level is resolved, study drugs will be 
reintroduced at reduced doses and safety assessments will be done during follow up visits.  
 
You may have side effects from the specific study medications, as described below. 
 
Lanthanum carbonate 
Lanthanum carbonate may cause nausea, vomiting, diarrhea, or abdominal pain.  It must be taken 
with meals to reduce the likelihood (1-10% chance) of developing these side effects.  You will 
be asked about these side effects during your study visits.  You can also contact us at any time if 
you experience any of these symptoms.  If you develop any of these side effects we will decrease 
the dose of lanthanum carbonate by half.  If you still cannot tolerate the medicine on the lower 
dose, we will stop the study drug. 
 
Nicotinamide  
In patients receiving dialysis, nicotinamide has rarely been associated with low blood platelet 
counts.  Blood platelets help stop bleeding, and low levels may predispose to bruising and 
bleeding risk.  In these studies, the platelet counts returned to normal quickly after holding the 
study drug.  This is not a recognized side effect of nicotinamide use in other settings, and based 
on the body's handling of nicotinamide in people with less severe kidney disease, we do not 
anticipate low platelet counts or bleeding in this trial (less than 1% chance).  Nonetheless, we 
will monitor closely for this possibility with frequent blood tests.  For safety, the study 
medication will be held if your blood platelet count drops below a safety threshold. 
 
Nicotinamide has some similarities to the cholesterol lowering medicine niacin.   Niacin 
commonly causes flushing, often experienced as an intense hot flash shortly after consumption.   
Niacin has also been known to increase the risk for gout, cause muscle injury, and worsen 
glucose control (less than 5% chance).  Prior studies suggest that these effects are largely due to 
the non-nicotinamide components within niacin.  Nonetheless, we will monitor you with serial 
blood tests for uric acid (a marker for gout risk), muscle injury, and glucose control.  For safety, 
the study medication will be held if your markers of muscle injury increase above a safety 
threshold. 
 
Niacin and nicotinamide may also alter liver function tests.  Liver injury is reported to be rare 
with nicotinamide, but we do not know if it is more common in people with kidney disease.  We 
will monitor you with serial blood tests for liver function.  We will also ask you to report to us 
and your doctor the following symptoms that may be related to liver disease: nausea, vomiting, 
abdominal pain, yellowing of the skin, and itching.  For safety, the study medication will be 
stopped if your liver blood tests increase above a safety threshold. 
 


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Nicotinamide may cause dyspepsia (upset stomach), heartburn, and bloating in some cases (1-
10% chance).  We will monitor for these symptoms using questionnaires at each visit. 
 
In dialysis patients, high dose nicotinamide has been associated with diarrhea in some cases (less 
than 5% chance).  We will monitor these symptoms using questionnaires at each visit. 
 
You will be asked about these side effects during your study visits.  You can also contact us at 
any time if you experience any of these symptoms.  If you develop any of these side effects we 
will decrease the frequency dosing of nicotinamide.  If you still cannot tolerate the medicine with 
the lower frequency, we will stop the study drug. 
 
Risks of the study procedures: 
Blood Draws 
Blood drawing may cause a small amount of pain. In addition, a temporary bruise or “black and 
blue mark” may develop.  Rarely, people faint after having blood drawn.  Very rarely, the vein 
may become inflamed (swollen, sore) or infected at the place where blood was drawn, which can 
be treated. 
 
24 hour-urine collection 
The collection of all urine for 24 hours of urine may be cumbersome. 
 
Study questionnaires 
Participating in this research may involve providing details that you consider confidential or 
private. Some of the questions may make you upset or uncomfortable. You have the right to 
refuse to answer any of the questions.  
 
MRI scans 
MRIs use powerful magnets to make images. There are no known radiation risks associated with 
MRI, and the images we will obtain in this study do not require contrast. Some people cannot 
have an MRI because they have some type of metal in their body.  For instance, if you have a 
heart pacemaker, artificial heart valves, metal implants such as metal ear implants, bullet pieces, 
chemotherapy or insulin pumps or any other metal such as metal clips or rings, you should not 
have an MRI. During this test, you will lie in a small closed area inside a large magnetic tube. 
Some people are scared or anxious in small places (claustrophobic).  The MRI scanner makes 
loud banging noises while taking a measurement, so either ear plugs or specially designed 
headphones will be used to reduce the noise. The MRI can be stopped at any time at your 
request.   
 
We are doing the MRI in this study to answer research questions and not for medical care 
purposes. The information created by this study will not become part of your hospital record.  
These MRI scans are not the same as the ones that your own doctor would order.  It may or may 
not show problems that would be found in standard MRIs.  If we do see something that looks 
like a medical problem, we will ask a radiologist (a doctor who specializes in reading these kinds 
of scans) to look at the results.  If the radiologist thinks there might be a problem, we will tell 


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you and help you get follow-up care.  If the radiologist thinks that you might have a medical 
problem, but it turns out that you don’t, we may have caused you to worry for no reason. 
 
IV placement 
An IV may cause a bruise and/or bleeding at the needle site. Depending on the length of time the 
IV is in place, a bruise may last for a day or so. Occasionally a person feels faint when blood is 
drawn. Rarely an infection may develop. If infection does occur, it can be treated.    
 
 
 
Furosemide (Lasix)   
Furosemide may increase your urine production and lower your potassium levels and blood 
pressure. Other very rare side effects of furosemide include upset stomach, dizziness, rash, 
sensitivity to light, and ringing or buzzing noises in the ears. You will receive a single dose of 
furosemide. At this dose, your potassium levels and blood pressure will most likely stay the 
same. The other side effects are also extremely rare after a single dose of furosemide.            
 
Fasting for 4 hours prior to MRI 
We will ask you to fast at least 4 hours prior to the MRI visits. There is a risk for low blood 
sugar when you fast. If you are taking insulin, we will ask you to take one half of your morning 
dose of insulin. We will also remind you to eat a snack after completing the MRI test. This will 
help prevent a risk of a hypoglycemic event. 
 
Unknown Risks 
There may be other side effects, in addition to those described here, that are not known at this 
time. We will give you any new information that we learn during the course of the study.  This 
new information might affect your willingness to be in or stay in the study. If you notice any side 
effects during the study, you should tell us right away. 
 
Unforeseeable risks  
Because this is an investigational study there may be some unknown risks that are currently 
unforeseeable. You will be informed if the researchers learn of any change in the amount of risk 
to you. 
 
What do I need to know about reproductive health/sexual activity if I am in this study?  
The effect of the study drug on pregnancy and breast feeding is uncertain. Therefore, women 
who are pregnant, may become pregnant, or are breastfeeding, will be excluded from this study. 
If you become pregnant, or think you may be pregnant during the study, you should notify 
the study staff immediately. 
 
If sexually active, women should use an effective method of birth control while taking the study 
drug. Barrier contraceptives (condoms or diaphragm) with spermicide, intrauterine devices 
(IUD’s), hormonal contraceptives, oral contraceptive pills, surgical sterilization, and complete 
abstinence are examples of effective methods.  
 


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If you are considered to be postmenopausal, you are not required to use contraception while in 
this study.  Rarely, women considered to be postmenopausal become pregnant.  If you suspect 
that you become pregnant while taking the study drug, it is important that you tell the study 
nurse/doctor immediately. 
 
What are the possible benefits for me or others? 
You are not likely to have any direct benefit from being in this research study. Results from this 
study may benefit other people with kidney disease in the future.  
 
What other procedures or courses of treatment might be available to me?    
You do not have to be in this study to receive treatment for your kidney disease.   
This research study is for research purposes only. The only alternative is to not participate in this 
study.  High phosphorus levels are uncommon in patients with chronic kidney disease who are 
not yet on dialysis.  Use of phosphorus binders in this population when serum phosphorus levels 
are within the normal range is not recommended.   For these reasons, most likely you would not 
receive any treatment outside this study for your phosphorus levels.  However, if you have 
additional questions, you should discuss participation in this study with your doctors.    
 
Are there any financial costs to being in this study? 
There will be no costs to you for being in this study. There will be no costs to you or your 
insurance for any procedures or testing done only as part of this research study.  If you receive a 
bill for services that you think could be related to your participation in this study, you should 
contact the study physician. 
 
Travel Expenses:   
You will be given reimbursement for expenses related to parking, bus or train fare. You will 
need to provide receipts for travel expenses.   
 
Will I receive payment for participation in this study?     
You will receive $50 payment for participating in the screening visit. If you are deemed eligible 
to participate, you will receive $50 for each completed study visit. The protocol contains 11 
study visits. If you complete all study visits your total compensation will be $550. If you 
participate in the MRI component of the study, for each MRI visit you will receive an additional 
$225 for a total of an additional $450. Therefore, if you complete all the study visits and receive 
the MRI scans at the beginning and end of study, you will receive $1000.  You will be paid by 
check from the accounting services at Northwestern University following each study visit.  If 
you withdraw from the study, you will be paid for the portions that you completed.  You will not 
receive any payment for any unscheduled visits (however, transportation to the clinic will be 
reimbursed).  
 
The Accounting Services at Northwestern University will be given your name, address, and 
Social Security Number in order to issue a check for your study participation. Study payments 
are considered taxable income and reportable to the IRS. A Form 1099 will be sent to you if your 
total payments are $600 or more in a calendar year. 
 


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What should I do if I am injured as a result of being in this study?  
If you become ill or get an injury or illness as a result of study (medications, devices or 
procedures), you should seek medical treatment through your doctor or treatment center of 
choice. You should promptly tell the study doctor about any illness or injury.   
 
The Northwestern University researchers will not pay for medical care required because of a bad 
outcome resulting from your participation in this research study. This does not keep you from 
seeking to be paid back for care required because of a bad outcome. 
  
 If I have questions or concerns about this research study, whom can I call? 
You can call us with your questions or concerns.  
 
If you have any illness or injury during your time on this study, you should call us promptly.  
Dr. Myles Wolf and Dr. Tamara Isakova are the researchers in charge of this study. You can call 
them at 312-503-6921 during office hours Monday through Friday from 8am to 5pm.   
 
You can also call study coordinators Michelle Bradley at 312-503-1909, Gina Schwartz at 312-
503-3865, Patrick Fox at 312-503-1887, or Carlos Martinez at 312-503-1808 with questions 
about this research study during office hours Monday through Friday from 8am to 5pm. 
 
For problems arising evenings or weekends, you may call the Northwestern Memorial Hospital 
operator at 312-926-2000 and ask to have Dr. Myles Wolf or Dr. Tamara Isakova paged. 
 
What are my rights as a research subject?  
If you choose to be in this study, you have the right to be treated with respect, including respect 
for your decision whether or not you wish to continue or stop being in the study.  You are free to 
choose to stop being in the study at any time.   
 
Choosing not to be in this study or to stop being in this study will not result in any penalty to you 
or loss of benefit to which you are entitled.  Specifically, your choice not to be in this study will 
not negatively affect your right to any present or future medical treatment. 
 
Any new findings developed during the course of this research that may affect your willingness 
to continue in this study will be shared with you.  
 
Your participation in this study may be stopped by the investigator without your consent for the 
following reasons: 
 
 If it appears to be medically harmful to you; 
 If you fail to follow directions for participating in the study; 
 If it is discovered that you do not meet the study requirements; 
 If the study is canceled; or  
 For administrative reasons, including competitive enrollment - the target number of subjects 
has entered the treatment phase. 
 


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If you want to speak with someone who is not directly involved in this research, or have 
questions about your rights as a research subject, please contact the Northwestern University 
Institutional Review Board (IRB) Office. You can call them at 312-503-9338. 
 
What about my confidentiality and privacy rights?   
We are committed to respect your privacy and to keep your personal information confidential.  
When choosing to take part in this study, you are giving us the permission to use your personal 
health information that includes health information in your medical records and information that 
can identify you. For example, personal health information may include your name, address, 
phone number or social security number. Your health information we may collect and use for 
this research includes:  
 All information in a medical record  
 Results of physical examinations 
 Medical history 
 Lab tests, or certain health information indicating or relating to a particular condition as 
well diaries and questionnaires 
 Records about study medication or drugs 
 
Participation in this study requires collecting private data about you including your social 
security number (in order to issue a check for your study participation), contact phone number 
and email and contact information for someone close to you. This personal health information 
will provide a mechanism for us to contact you for safety reasons, for example if we observe an 
unexpected finding on your blood or urine tests that require follow-up or a change in therapy.  
You will be assigned a unique study ID that bears no relation to your personal health 
information.  This is a multi-center study, other patients will be recruited at other institutions 
across the US. Data from all sites will be combined for data analysis. The study has a Data 
Coordinating Center at the Cleveland Clinic. To protect your privacy, when your data are sent to 
the Cleveland Clinic Data Coordinating Center, only your unique study ID will be used. The 
study database at the Cleveland Clinic will not include your name, address, phone number, or 
other personal health information.   
 
Your research records will be labeled with a unique study ID. The list that matches your name 
with the study ID will be kept in a locked file in the research team’s office. Any research records 
that identify you will be kept only as paper records in a secure location, or as files behind a 
secure computer firewall.  
 
Your blood and urine samples will be labeled only with the study ID number, the date of 
collection, and the study visit number.   
 
A final dataset will be developed using your data and data from other participants in this study.  
This dataset will not contain your personal health identifiers, but only your unique study ID 
number.  The de-identified dataset will be maintained for data analysis through December 31, 
2033. 
 
Any presentations or publications from this information will not identify you.  
 


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The following groups of people may give the researchers information about you:   
 All current and previous health care providers, including but not limited to Northwestern 
Medical Group (NMG) and Northwestern Memorial Hospital (NMH).     
 
Once we have the health information listed above, we may share some of this information with 
the following people. Please note that any research information shared with people outside of 
Northwestern University and its clinical partners (or affiliates) will not contain your name, 
address, telephone or social security number or any other direct personal identifier unless 
disclosure of the direct identifier is required by law [except that such information may be viewed 
by the Study sponsor and its partners or contractors at the Principal Investigators office]   
 
 Authorized members of the Northwestern University workforce, who may need to see your 
information, such as administrative staff members from the Office for Research, Office for 
Research Integrity and members of the Institutional Review Board (a committee which is 
responsible for the ethical oversight of the study).  
 
 Clinical affiliates, including but not limited to Northwestern Medical Group (NMG) and 
Northwestern Memorial Hospital (NMH). Your participation in this clinical trial will be 
tracked in an electronic database and may be seen by investigators running other trials 
that you are enrolled in and by your healthcare providers 
 
 Clinical affiliates, including but not limited to Northwestern Medical Group (NMG) and 
Northwestern Memorial Hospital (NMH), for purposes including, but not limited to, the 
affiliate’s provision of care to you and/or the affiliate’s scheduling of appointments 
and/or billing activities.  
 
 Other University research centers and University contractors who are also working on the 
study. 
 
 Study monitors and auditors who make sure that the study is being done properly. 
 
 Government agencies and public health authorities, such as the Food and Drug 
Administration (FDA) and the Department of Health and Human Services (DHHS). 
 
 Registries or other research-related databases: The study data will be submitted to the 
NIDDK Data Repository. The data repository will keep the data de-identified (without your 
personal identifying information) from this NIH study available to future researchers forever. 
Those persons who get your health information may not be required by Federal privacy laws 
(such as the Privacy Rule) to protect it.  Some of those persons may be able to share your 
information with others without your separate permission. 
 
The results of this study may also be used for teaching, publications, or presentations at scientific 
meetings.  Any presentations or publications will not identify you. 
 


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ClinicalTrials.gov  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 
 
 
 
Please note that: 
 You do not have to sign this consent form.  If you do not, it will not affect your treatment by 
health care providers, or the payment or enrollment in any health plans, or affect your 
eligibility for benefits. However, you will not be allowed to take part in this research study.  
 You may change your mind and “take back” (revoke) this consent at any time. Even if you 
revoke this consent, the Principal Investigator may still use or share health information that 
was obtained about you before you revoked your consent as needed for the purpose of this 
study. To revoke your consent for the use of your health information, you must do so in 
writing to:  
PI’s Name: Myles Wolf, MD 
Institution: Northwestern University 
Department: Institute of Public Health and Medicine 
Address: 633 N. St Clair, Suite 18-089 
 Unless you revoke your consent, it will not expire.   
 If you agree to have your sample(s) stored in the Repository, you can change your mind up 
until the end of the COMBINE study. When study researchers receive written instructions 
from  you, they  will destroy your  sample and all information that  identifies you.  After the 
COMBINE study ends, you will not be able to withdraw your sample because the Repository 
will not know which one is yours.  The sample will stay in the Repository indefinitely. 
 
Optional Study Elements: 
 
Future Use of Data: After completion of the trial, a copy of the de-identified data will be 
retained for future research.  The dataset will not contain any data that will identify you, but 
rather only your unique study ID.  De-identified data may be shared with associates of the study 
investigators, pending approval by the institutional review board, and kept in a locked file in the 
research team’s office. Any research records that identify you will be kept only as paper records 
in a secure location, or as files behind the secure computer firewall.  
 
Data linking your personal health identifies with the unique study ID codes in the dataset will be 
retained only by the study physician.  These files will allow linkage with administrative datasets 


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such as Medicare claims data to determine long-term outcomes such as death and dialysis 
initiation.  In all cases, data will be kept in a locked file in the research team’s office.  
 
Blood and urine samples stored for future research     
Allowing for the storage and future testing of your tissue and blood samples will involve no cost 
to you. 
 
The primary purpose of the blood and urine specimens that you will provide is (1) to determine 
the effects of nicotinamide and lanthanum carbonate on your blood phosphorus levels, FGF23 
levels, and associated phosphorus regulatory hormone levels, and (2) to monitor for safety and 
side-effects.  However, we would like to store some of your blood and urine samples and health 
information for future research related to the area of chronic kidney disease, cardiovascular 
disease, and bone disease.  We will label all your samples with a unique study code instead of 
your personal health identifiers to protect your privacy.   
 
Some of your blood and urine specimens will be sent to the National Institute of Diabetes and 
Digestive and Kidney Disease (NIDDK) Repository, a research resource supported by the 
National Institutes of Health. The purpose of this collection is to make samples available for use 
in research for the study of chronic kidney disease, cardiovascular disease, and bone disease after 
the current study is completed. Sending samples to the Repository may give scientists valuable 
research material that can help them to develop new diagnostic tests, new treatments, and new 
ways to prevent diseases.  These specimens will also be labeled by a unique code and without 
your personal health identifiers.  Therefore, the Repository will not be able to give out your 
name, or other information that identifies you to the scientists who receive the samples.    
 
This study will not collect or use any genetic data, now or at any time in the future.  Your sample 
will be used only for research and will not be sold. The research done with your tissue and blood 
sample may lead to the development of new products in the future. No compensation will be 
given to you now or in the future for the use of these samples. 
 
Requests for samples: An appropriate external panel will review all requests to use Repository 
samples.  That panel will include a bioethicist and other individuals with expertise in one or 
more areas including; clinical research, epidemiology, physiology, statistical analysis, and 
molecular genetics research. NIH Program and Review staff are excluded from membership on 
this panel, but can provide appropriate guidance, background information, and technical 
assistance.    
 
Specimens will not be used for genetic research.  
 
Please initial one option below to indicate your preference: 
 
_______  I consent to banking of my blood and urine specimens for future research. 
 
_______  I do not consent to banking of my blood and urine specimens for future research. 
 


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Re-contact: Dr. Wolf and his associates may conduct future studies in patients with kidney 
disease, and may wish to contact you about your interest in participating in future trials.  Please 
initial one option below to indicate your preference: 
 
_______  I consent to re-contact for participation in future studies. 
 
_______  I do not consent to re-contact for participation in future studies. 
 
The following section calls for you to indicate your choice for optional procedures that you do 
not have to agree to in order to participate in the main study. 
 
 
 
Cardiac MRI Scans:  
Please initial your choice:    
 
_______  I consent to having a Cardiac MRI. 
 
_______  I do not consent to having a Cardiac MRI. 
 
Renal MRI Scans:  
Please initial your choice:    
 
_______  I consent to having a Renal MRI. 
 
_______  I do not consent to having a Renal MRI. 
 
Consent Summary:  
I have read this consent form and the research study has been explained to me. I have been given 
time to ask questions, and have been told whom to contact if I have more questions.  I agree to be 
in the research study described above. A copy of the consent form will be provided to me after I 
sign it.   
 
A copy of this signed consent document, information about this study and the results of any test 
or procedure done may be included in my medical record and may be seen by my insurance 
company. 
 
 
_____________________________________________________  
__________ 
Subject’s Name (printed) and Signature 
 
 
 
 
Date 
 
 
_____________________________________________________  
__________ 
Name (printed) and Signature of Person Obtaining Consent                         Date