Evaluation of the Effects of Niacin Therapy on Lipoprotein Composition and Function
Phase: NA
Conditions: Cardiovascular Disease
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

15-H-0042: Niacin and lipoprotein composition/function 
PI:  Marcelo Amar, M.D. 
Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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CLINICAL RESEARCH PROJECT  
 
 
 
Protocol # 15-H-0042 
 
 
 
 
 
 
 
 
 
IND/IDE # none 
 
 
 
 
 
 
 
 
Closed to accrual: July 10, 2019 
 
NHLBI Protocol: 
Evaluation of the effects of Niacin therapy on lipoprotein 
composition and function 
 
Short Title:  
 
Niacin and lipoprotein composition/function 
 
Keywords Words:   
HDL, LDL, VLDL, Cholesterol, Lipoproteins, Niacin  
 
Principal Investigator: 
*Marcelo J. Amar, M.D. (E) 
Translational Vascular Medicine Branch (TVMB) 
Building10, Room 5D03, NHLBI/NIH 
Bethesda, MD  20892 
Phone:  301-402-0521 
Email:  ma90x@nih.gov 
 
 
Non-NIH Collaborators: 
Tomas Vaisar, Ph.D 
Research Associate Professor 
University of Washington Diabetes Institute 
Department of Medicine 
850 Republican St. 
Seattle, WA 98109 
Email: tvaisar@u.washington.edu 
 
 
Subjects in study: 
 
 
Number 
Sex 
Age Range 
200 (goal is 32 
completed studies) 
M/F 
18 
 
 
 
 
 
 
Product Uses Ionizing Radiation:  
 
 
No 
Project Uses IND/IDE: 
 
 
 
 
No 
Project Uses “Durable Power of Attorney”: 
 
No 
 
Off Site: 
 
 
 
 
 
 
No  
Multi-Institutional Project:  
 
 
 
No 
 
 

15-H-0042: Niacin and lipoprotein composition/function 
PI:  Marcelo Amar, M.D. 
Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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Table of Contents 
1. 
Précis ................................................................................................................................. 4 
2. 
Introduction ....................................................................................................................... 4 
3. 
Primary Objectives ............................................................................................................ 5 
4. 
Study Design and Methods ............................................................................................... 6 
4.1 
Study Population and Recruitment ........................................................................ 6 
4.2 
Study Procedures...................................................................................................... 6 
4.3 
Study Visits ............................................................................................................... 6 
5. 
Subject Eligibility ............................................................................................................. 8 
5.1 
Inclusion Criteria ..................................................................................................... 8 
5.2 
Exclusion Criteria .................................................................................................... 8 
6. 
Pharmaceuticals ................................................................................................................ 9 
6.1 
Study Agent Information ......................................................................................... 9 
6.2 
Dosing Instructions ................................................................................................ 10 
6.3 
Study Agent Compliance ....................................................................................... 10 
6.4 
Regulatory Status ................................................................................................... 10 
7. 
Research Laboratory Methods ........................................................................................ 10 
8. 
Listing of tests that may be used on this research ........................................................... 11 
9. 
Sample Collection, Storage, and Data Management ...................................................... 12 
10. 
Monitoring of Subjects and Criteria for Withdrawal of Subjects ................................ 13 
10.1 Stopping Rules for Subjects (off-study criteria) ...................................................... 13 
11. 
Analysis of the Study ................................................................................................... 14 
11.1 Sample Size Determination ...................................................................................... 14 

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Date: July 10, 2019 
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11.2 Statistical Analysis ................................................................................................... 14 
12. 
Human Subject Protection ........................................................................................... 14 
12.1 Rationale for Subject Selection ................................................................................ 14 
12.2 Rationale for the Exclusion of Children ................................................................... 15 
12.3 Rationale for the Exclusion of Pregnant Women ..................................................... 15 
12.4 Inclusion of NIH Staff .............................................................................................. 15 
12.5 Evaluation of Benefits and Risks/Discomforts ........................................................ 15 
12.6 Protocol Consent Processes and Documents ............................................................ 16 
12.6.1 Consent Processes for NIH Employees ............................................................... 17 
12.6.2 Consent Processes for non-English Speaker ........................................................ 17 
13. 
Conflict of Interest ....................................................................................................... 17 
14. 
Adverse Event Management ........................................................................................ 17 
14.1 Reports to the IRB .................................................................................................... 18 
14.2 Reports to the CD ..................................................................................................... 18 
15. 
Data and Safety Monitoring Plan ................................................................................. 18 
16. 
Compensation .............................................................................................................. 18 
17. 
References .................................................................................................................... 19 
18. 
APPENDIX A: NIH INFORMATION SHEET ON STAFF RESEARCH 
PARTICIPATION (April 2016) ............................................................................................. 21 
 
 
 

15-H-0042: Niacin and lipoprotein composition/function 
PI:  Marcelo Amar, M.D. 
Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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1. Précis 
This single center clinical pilot study will investigate the effects of niacin on blood lipids and 
lipoprotein composition in human subjects who are healthy.  Niacin (vitamin B3 or nicotinic 
acid) is a common nutrient found in many foods and is currently sold over the counter as a 
nutritional supplement.  Extended-release versions of niacin are available over the counter 
(e.g., Slo-Niacin®) or by prescription (Niaspan®) and help to alleviate symptoms of flushing 
associated with larger doses of the vitamin.  Studies of the effects of niacin therapy on 
clinical lipid measures consistently indicate a shift toward a healthier lipoprotein profile with 
increased HDL-C and decreases in both triglyceride and LDL-C.  Despite this favorable shift 
in lipid profile, cardiovascular outcome studies on patients receiving niacin alone or in 
combination with statin therapy have resulted in mixed results creating uncertainty of the 
value of niacin therapy. The proposed study will examine in detail the effects of niacin 
therapy on lipoprotein composition and function, while also tracking measures of vascular 
health.     
2. Introduction 
Despite numerous academic and therapeutic advances, CVD remains the leading cause of 
morbidity and mortality in developed countries1.  Clinical strategies for assessment of CVD 
risk involve the measurement of specific lipoprotein associated lipid levels including low 
density lipoprotein associated cholesterol (LDL-C), and is positively correlated with disease, 
and high density lipoprotein associated cholesterol (HDL-C), which is thought to be 
protective.  The statin classes of drugs reduces LDL-C and are the current standard of care 
for reducing CVD risk, but only decrease cardiovascular events by approximately 30-35%2.  
Thus, even after LDL-C lowering is accomplished with statin therapy there remains 
significant amount of residual cardiovascular risk.  One potential avenue for reducing this 
residual risk may be through treatments that increase HDL-C.  HDL has been demonstrated 
to possess a multitude of beneficial functions, which likely contribute to its cardio-protective 
nature.  The most extensively studied of these functions is HDL’s role in the process of 
reverse cholesterol transport (RCT), whereby excess cholesterol is removed from peripheral 
tissues and transported to the liver for excretion.  In addition to RCT, HDL also has various 
antioxidant, anti-inflammatory and vasodilator activities, all of which are thought to 
contribute to the overall cardio-protective role for HDL 3.  These properties make HDL stand 
out as the obvious next target for prevention of cardiovascular disease.            
While the prospect of raising HDL-C to prevent CVD is enticing, recent clinical trials 
involving the raising of HDL-C have been largely disappointing.  Although a few small 
molecule compounds, which effectively raise HDL-C are still under development, such as the 
cholesteryl ester transfer protein (CETP) inhibitors, none of these compounds in early stage 
clinical trials have shown promise.  
The only currently FDA approved drug for raising HDL-C is Niaspan ®. Niacin is a water 
soluble vitamin found in many foods (meat, fish, fruits and vegetables) and has been shown 

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Date: July 10, 2019 
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to have a favorable impact on plasma lipid measures, increasing HDL-C by as much as 15 to 
35%, while at the same time decreasing plasma triglycerides (20-50%) and LDL-C (5-25%).  
Early clinical studies performed by the Coronary Drug Project on the effects of long term 
niacin treatment showed beneficial effects on overall mortality in the niacin treated group 4.  
The HDL-Atherosclerosis Treatment Study (HATS) combined niacin with statin therapy to 
determine if any further clinical advantage could be gained by adding a HDL-C modifying 
agent to the standard of care for LDL-C lowering.  This study pointed strongly to a beneficial 
effect of niacin in combination with Simvastatin.  Patients in the Simvastatin-niacin group 
had a 42% reduction in LDL-C and 26% increase in HDL-C.  Additionally, while stenosis 
progressed by 3.9% in the placebo group, atherosclerotic regression occurred in the 
combination treatment group and clinical endpoints (e.g. myocardial infarction and death) 
were reduced from 24% to 3% (placebo vs. Simvastain-niacin) 5.  These beneficial effects 
were suggested to be a result of a shift in HDL subspecies distribution to include an increase 
in the level of large Į-1 HDL particles, which have been shown to be protective against 
CVD6.  However, two recent large clinical trials of niacin, namely AIM-High and HSP2-
Thrive have failed to show cardiovascular benefit from using niacin on top of a statin 7,8. 
Although these trials have been criticized because of their design 9 they have raised questions 
about the clinical utility of niacin and HDL-C as a therapeutic target.  
Plasma lipoproteins, especially HDL, are highly heterogeneous populations of particles.  
Within the total HDL pool there are subpopulations of particles with varying protein and 
lipid compositions.  These distinct subpopulations have varying functionality, which are 
dependent upon their composition, with some being more protective and some less protective 
against CVD.  In addition to their lipid and protein cargo, HDL has recently been 
demonstrated to carry microRNAs in the plasma and deliver them to specific cell types where 
they can modulate various functions10.  The detailed characterization of lipoprotein 
subpopulations and their functional attributes is still a fairly new area of research and the 
effect of pharmacologic compounds in this area is largely unexplored.  To date, most of the 
drug development efforts based on HDL have used the cholesterol content of HDL (HDL-C) 
as its target.  Although HDL-C is inversely related to cardiovascular disease based on 
epidemiologic studies, other composition or functional attributes of HDL may be more 
closely related to its atheroprotective function and hence a better target for drug 
development.  It may also be that although niacin raises HDL-C, it causes other detrimental 
changes in HDL that ultimately diminish its ability to protect against cardiovascular disease.  
A more thorough understanding of how niacin is affecting the composition and functionality 
of HDL and other lipoproteins would allow us to better predict its clinical utility and may 
lead to new insights in how to develop future HDL modifying agents. 
3. Primary Objectives  
x Determine the effect of oral niacin on lipoprotein composition, including but not 
limited to Lipoprotein Profile (NMR), proteome, lipidome and microRNA cargo. 

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Date: July 10, 2019 
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x Determine the effect of oral niacin on lipoprotein functionality, as measured by 
ability to efflux cholesterol from cultured macrophage cells. 
x Determine the effect of oral niacin therapy on inflammatory status and gene 
expression in white blood cell populations. 
x Correlation of above parameters with vascular health, as assessed by CAVI. 
4. Study Design and Methods  
4.1 Study Population and Recruitment 
This novel pilot study will be carried out at the NIH Clinical Center outpatient clinic 7 in 
healthy volunteers.  We will screen up to 200 subjects, males and females, to obtain at least 
32 completed studies.  Participants will be recruited via flyer, and/or recruitment 
advertisement placed in the NIH Record, the NHLBI Recruitment website, the Clinical 
Center News and by email/listserv.   
4.2 Study Procedures 
Blood Draw:  In addition to Section 8 blood tests listed, subjects will have 4 research blood 
draws of 10 mL each, stored at -80ºC and analyzed when sufficient samples are accumulated.   
Diet & Exercise Assessment:  Subjects will also be asked not to change their routine diet or 
exercise habits, during the study period.  A short physical activity assessment will be 
collected with each visit to review any changes in physical activity.   
Cardio-Ankle Vascular Index (CAVI):  CAVI is a novel indicator of arterial stiffness.  This 
measurement will be obtained to assess initial stiffness of the arteries and changes during the 
treatment phase. The test is not invasive and consists of measurement of BP in the four 
extremities while monitoring ECG by single lead and the heart sound. 
4.3 Study Visits 
There will be up to 5 visits for this study.  The return visits can be delayed up to two weeks, 
if there are scheduling problems.  The first study day will be the screening and baseline 
followed by three additional visits coinciding with study landmarks. The study will be 
discussed in detail with interested subjects.  Any procedures needed to assess eligibility (i.e. 
blood laboratory tests, pregnancy test) will be performed after obtaining informed consent.  
Visit 1:  At the first visit (screening and baseline), the subjects will be consented, and have a 
diet and exercise assessment to determine their nutritional status and a physical examination.  
The subject will have vital signs and Body Mass Index measured, and will undergo a history 
and physical examination.  During this visit, fasting screening and baseline laboratory tests 
and a pregnancy test for female subjects of childbearing potential will be obtained. In 

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Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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addition, 10 mL of blood will be stored for research tests.  At the end of the first visit, if the 
subject is not yet excluded from the study, a Cardio-Ankle Vascular Index (CAVI) test will 
be performed. Once eligibility is confirmed, subjects will receive a 4 week supply of the 
dietary supplement of Extended Release Niacin (purchased by the NIH CC pharmacy 
through its vendors such as Rugby/Watson or Major; 250 mg, 500mg or 1000mg/capsule) 
and will be instructed to take 500 mg/day for the first seven days and then increase to 1000 
mg/day, which may be taken bid and/or with other dosing flexibility) during the following 7 
days. 
Re-screening Visit as applicable:  Repeat laboratory values, including baseline research 
blood, may be needed to reassess eligibility within 40 days of a screening failure.  If a subject 
is found ineligible, during or after the first visit, the 10 mL of research blood will be 
discarded.  
Visit 2:  Two weeks after the first visit (+/- 2 weeks) the subjects participating in the niacin 
supplementation portion of the study will return for their second visit.  The subject will have 
vital signs and Body Mass Index measured and undergo a brief physical examination. Fasting 
blood will be collected for laboratory and pregnancy tests (in female subjects of child bearing 
potential) and 10 mL of blood will be stored for research tests.  At the end of the 2nd visit, the 
subjects will be escalated to 2000 mg/day (which may be taken bid and/or with other dosing 
flexibility) extended release niacin for an additional 14 weeks.    
Visit 3:  The third visit will occur 16 weeks (+/- 2 weeks) after starting niacin 
supplementation.  At this visit, the subject will be given a diet and exercise assessment, a 
repeat CAVI test, and a brief physical examination.  A nurse will take the subject's vital signs 
and Body Mass Index and fasting blood will be collected for laboratory testing, and 10 mL of 
blood will be stored for research. At the end of the 3rd visit, the subjects will be instructed to 
discontinue niacin supplementation. 
Visit 4:  The fourth, and final, visit will occur 4-6 weeks after stopping niacin 
supplementation. A two weeks window extension may be used to accommodate for 
scheduling problems.  At this visit, the subject will be given a final diet and exercise 
assessment.  A nurse will take the subject's vital signs, Body Mass Index measured, and will 
undergo a brief physical examination and fasting blood will be collected for laboratory 
testing, and 10 mL of blood will be stored for research. A repeat CAVI test will be 
performed. 
Subjects will be encouraged to complete the seven day food record prior to the first and third 
study visits, in order to facilitate the nutritional and exercise assessment.  However, if the 
subject does not complete, or only partially completed the seven day food record, the 
nutritional and exercise assessment will still take place and it will determine any changes in 
life-style.   

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Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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Note: The slow increase in niacin dose is standard practice and has been found to minimize 
the incidence and severity of potential adverse events, which usually only occur in the first 
few days of niacin administration.  Should a subject require additional time to adapt to the 
dose schedule, they will be allowed to continue to take the current dose for no greater than 2 
weeks beyond the scheduled dosing period and their return date for next visits will be 
adjusted accordingly and will not be considered a protocol deviation or AE. 
Fig 1.  Study design 
 
5. Subject Eligibility 
5.1
Inclusion Criteria 
x
Males and females who are at least 18 years of age at time of enrollment.
x Subject understands the investigational nature of the study and provides written, 
informed consent. 
 
5.2 Exclusion Criteria 
x Subjects taking any lipid modification therapy, including but not limited to statins, 
fibrates and bile acid sequestrants. 
x Subjects taking fish oil or any other supplements, which in the investigator’s opinion 
may interfere with the study. 
x Subjects with acute liver disease or active peptic ulcer disease. 
x Subjects with elevated uric acid levels (>10mg/dL) or gout  
x Pregnancy or women currently breastfeeding.  

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Date: July 10, 2019 
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x Female subjects taking hormonal contraceptives or hormone replacement therapy 
may be included in this study only if they have been on a stable dose for at least 3 
months. 
x BMI less than 18.5 
x Subjects with weight that varies greater than 20% over the past 3 months. 
x Subjects taking the following medications for at least six weeks, which may interfere 
with the study, will be excluded: BAS, antibiotics, anticoagulants, anticonvulsants, 
antiarrhythmic, Cyclosporine, Mycophenolate and Synthroid.  Subjects with chronic 
diarrhea, gastric bypass or lap band procedures, ostomies, bowel motility problems, 
or other conditions that could affect intestinal fat absorption. 
x Subjects initiating new medications or patients on multiple medications may also be 
excluded. 
x Inability to swallow capsules 
x Patients with a history of type I or type II diabetes or HbA1c > 6.5%. 
x Volunteers may also be excluded, if in the opinion of the study investigators, they 
have some other condition or disorder that may adversely affect the outcome of the 
study or the safety of the volunteer.  
6. Pharmaceuticals 
6.1 Study Agent Information 
Product Name:  Niacin Extended Release 
Supply:  Commercially available 
Product Description:  Extended Release Niacin (purchased by the NIH CC pharmacy 
through its vendors such as Rugby/Watson or Major. 
Storage:  Room temperature (20 to 25°C or 68 to 77°F) 
Route of Administration:  Oral 
 Toxicities:  None known 
Stability:  Each lot is dated to three years expiration 

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Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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Preparation:  Rugby Extended Release Niacin is an oblong, green-clear-yellow capsule 
for oral administration and is available in 250 mg capsules. The capsules also contain the 
inactive ingredients sugar, shellac, gelatin, cornstarch, talc, turmeric, riboflavin and the 
following coloring agents: FD&C green #3 and FD&C yellow #6. Any other substitute 
Niacin Extended release will have similar or comparable inactive ingredients. 
6.2 Dosing Instructions 
The assigned dosing is consistent with earlier clinical trials.  To minimize impact of the 
common side effect of flushing, subjects may be instructed to take niacin with a small snack 
prior to going to sleep.  At each study visit, subjects will be given enough niacin to last them 
until their next visit plus an additional two weeks to allow for continuation of 
supplementation in the event of scheduling issues. 
6.3 Study Agent Compliance 
The subjects will be instructed to return remaining capsules, in original containers, to NIH at 
each applicable study visit for a pill count.  Between visits a member of the clinical trial team 
may contact subjects to monitor compliance and any side effects, and to provide any 
additional study information, answer questions, and motivate participants.   
Participants may receive a Don’t Forget! Instructions and Study Schedule information sheet 
to help keep track of when they should begin taking the study drug, the time and date of 
schedules appointments, and when to complete the seven day food record, which also has 
instructions. 
6.4 Regulatory Status 
Whether an IND is needed for a clinical investigation evaluating a dietary supplement is 
determined by the intent of the clinical investigation.  If the clinical investigation is intended 
only to evaluate the dietary supplement’s effect on the structure or function of the body, an 
IND is not required. 
7. Research Laboratory Methods 
Approximately 40 mL of fasting blood samples will be collected at each visit and used to 
perform the following routine clinical laboratory tests: Electrolytes, Lipid Panel, Lipoprotein 
Profile analysis by NMR, liver function tests (AST, ALT, bilirubin), ApoA-I, ApoB, Thyroid 
Panel, uric acid, creatinine kinase, hs-CRP, HbA1C, and insulin. In addition, we may 
perform tests for leptin (research), adiponectin (research) and other lipid and lipoprotein 
metabolism related markers (research). In addition, approximately 10 ml of research blood 
will be used or stored for future testing related to lipoprotein metabolism.  Routine diagnostic 
tests will be performed in the Department of Laboratory Medicine on the second floor of 
building 10 in the Clinical Center (CC). The following research tests may be done in the 
Lipoprotein Metabolism Section’s laboratory: lipoprotein distribution will be assessed after 

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Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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separation by FPLC and HDL and LDL sub-fraction analysis may be done on a BioAgilent 
Analyzer in the Lipoprotein Metabolism laboratory.  FPLC isolated lipoproteins may be 
analyzed for miRNA content and protein and lipid content by chemical assays and mass 
spectrometry.  In vitro cholesterol efflux experiments may also be performed.  The following 
research tests may be performed by the Center for Human Immunology, Autoimmunity and 
Inflammation on the seventh floor of bldg. 10: RNA expression by microarray, flow-
cytometry phenotyping of white blood cells, and measurement of plasma cytokines.  For any 
future research in stored samples not described above we will request NHLBI IRB approval.  
8. Listing of tests that may be used on this research 
Clinical laboratory tests: 
x Liver function test (ALT, AST, bilirubin) 
x Uric acid 
x Creatinine 
x Creatinine kinase (CK) 
x Insulin 
x Fasting glucose 
x Pregnancy testing 
Clinical lipid and lipoprotein related tests: 
x Lipid Panel (Total cholesterol, LDL-C, HDL-C, Triglyceride) 
x Lipoprotein Profile (NMR) 
x ApoA-I 
x ApoB 
x Hs-CRP 
x HbA1C 
x Alpha-1-antitrypsin 
Other research tests: 
x Leptin  
x Adiponectin  
x Other lipid and lipoprotein metabolism related markers 
x FPLC lipoprotein lipid profiles 
x Proteomics/Lipidomics analyses of lipoprotein subfractions 
x In vitro cholesterol efflux assay 
x RNA expression by microarray 
x Flow cytometry phenotyping of white blood cells 
x Measurement of plasma cytokines 
x Cardio-Ankle Vascular Index (CAVI) 

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Date: July 10, 2019 
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x Endothelial function assay 
 
*Standard of care laboratory tests and procedures not listed above may be requested and will 
not be used for this research but will only be used to evaluate or elucidate the patients’ health 
condition as specified on item 5.2. 
9. Sample Collection, Storage, and Data Management 
INTENDED USE OF THE SAMPLES/SPECIMENS/DATA 
Samples and data collected under this protocol may be used to study changes in lipids, and 
lipoproteins that may help reduce high cholesterol levels in subjects and could be used in 
conjunction with other therapies available.  No DNA genetic testing will be performed. 
HOW SAMPLES/SPECIMENS/DATA WILL BE STORED 
Samples will be stored at -80C freezers on the 2nd floor of building 10 in the Department of 
Laboratory Medicine or at -80C freezer (freezer 2) on the 8th floor of building 10 in the 
Department of Lipoprotein Metabolism Section, following current NIH sample storage 
guidelines.  Access to research samples will be limited, using a locked freezer.  Samples and 
data will be stored, using codes assigned by the investigators or their designee(s).  Data will 
be kept on the NHLBI P: drive, accessible through password-protected computers.  Only the 
members of the research team will have access to the samples and data. 
All human subjects personally identifiable information (PII) as defined in accordance to the 
Health Insurance Portability and Accountability, eligibility and consent verification will  be 
recorded in   and stored in a secured NIH drive.  Primary data obtained during the conduct of 
the protocol will be kept in secure network drives that comply with NIH security standards.  
Primary and final analyzed data will have identifiers so that research data can be attributed to 
an individual participant. 
HOW SAMPLES/SPECIMENS/DATA WILL BE TRACKED 
Research samples will be stored using BSI in accordance with NHLBI DIR Biospecimen 
policy.  
WHAT WILL HAPPEN TO THE SAMPLES/SPECIMENS/DATA AT THE 
COMPLETION OF THE PROTOCOL? 
At the completion of the protocol (termination), samples and data will either be destroyed, or 
after IRB approval, transferred to another existing protocol or a repository. 
WHAT CIRCUMSTANCES WOULD PROMPT THE PI TO REPORT TO THE IRB 
LOSS OR DESTRUCTION OF SAMPLES/SPECIMENS/DATA 

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Date: July 10, 2019 
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The NIH Intramural Protocol Violation definition related to loss of or destruction of samples 
(for example, due to freezer malfunction) will be followed in reporting to the IRB. 
Any loss or unanticipated destruction of samples (for example, due to freezer malfunction) or 
data (for example, misplacing a printout of data with identifiers) will be reported to the IRB.  
Transmission of Data to Outside Investigators: 
Collaborator, Tomas Vaisar, Ph.D., with the University of Washington Diabetes Institute, 
will receive aliquots of human serum collected from subjects taking the lipid altering vitamin 
niacin. High density lipoprotein (HDL) will be isolated from the serum and then used for an 
in vitro assay to determine HDL’s influence on endothelial cell function. The samples will be 
coded and sent to collaborator following a fully executed MTA.  
 
10. Monitoring of Subjects and Criteria for Withdrawal of 
Subjects 
10.1 
Stopping Rules for Subjects (off-study criteria) 
x Ineligibility to start the niacin supplementation portion of the study 
x Pregnancy 
x Development of hyperuricemia (male >8.6 mg/dL, female >5.8 mg/dL) with clinical 
symptoms or an absolute laboratory value >10 mg/dL  
x Development of diabetes (HbA1c > 6.5%)  
x Development of hyperuricemia (men > 7 mg/dL; women > 6 mg/dL). 
x Severe gastrointestinal discomfort 
x Subjects taking less than 2/3 of the niacin pills or not taking the pills for 7 
consecutive days.    
x Any other severe symptoms related to niacin supplementation and as determined by 
contact with the physician. 
x On study onset of any of the exclusion criteria listed above (Section 5.2) 
Routine clinical laboratory data will be reviewed after each study visit and the study will be 
discontinued, if it is observed that niacin is associated with any significant change in liver 
panel (indicated by > 3-fold increase above baseline in ALT or AST), electrolyte profile (at 

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Date: July 10, 2019 
Version: 14.0 (Amendment M) 
 
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discretion of observing physician), or sustained muscle aches (Grade 2, according to CTCAE 
4.03 criteria). 
11. Analysis of the Study 
The primary outcome measurements of this study are changes in protein or lipid composition 
of any lipoprotein fraction and changes in vascular compliance as measured by CAVI. 
11.1 
Sample Size Determination  
With a sample size of n = 32 completed studies, the study will have 80% power to detect a 
15% change in plasma HDL cholesterol levels between the baseline and niacin treatment 
periods, using a normal approximation to the one-sample (paired), two-sided t-test at alpha = 
0.05.  A standard deviation of 15 mg/dL was assumed for the paired differences in plasma 
cholesterol levels between the baseline and final treatment period.  Since up to a 30% subject 
attrition is expected, a minimum of n = 48 subjects will be recruited for the study.  
11.2 
Statistical Analysis 
Descriptive statistics (mean, standard deviation, minimum, maximum, and median) will be 
calculated for all variables.  All response variables will be assessed for conformance to the 
normal distribution and transformed as needed to meet the assumptions of normal 
distribution and homogeneity between periods.  If necessary, non-parametric analyses will be 
performed. 
The analysis of the data will investigate the effects of niacin in the plasma cholesterol levels 
of the pooled genders primarily, but the effect in male and females may also be analyzed 
separately. 
Food records will be analyzed, using the Nutrition Data System for Research (NDSR) 
software developed by the Nutrition Coordinating Center, University of Minnesota, 
Minneapolis, MN11. 
12. Human Subject Protection 
12.1 
Rationale for Subject Selection 
Subjects of both genders will be considered for inclusion in this study.  There will be no 
racial, ethnic, or gender discrimination.  Cognitively impaired and institutionalized 
persons will not participate in this study.  Criteria for exclusion or withdrawal from the 
study are based on the presence of other disease processes that may interfere with the 
interpretation of our results or situations that may be harmful to the health of subjects. 
“Recruitment, enrollment and compensation of NIH employee subjects will be consistent 
with NIH Manual Chapter 23s00-630-3” Leave Policy for NIH Employees”. 

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12.2 
Rationale for the Exclusion of Children 
 Children under 18 years of age will not be considered for inclusion in this study due to 
increased potential for liver toxicity. 
12.3 
Rationale for the Exclusion of Pregnant Women 
Subjects must not be pregnant or actively seeking pregnancy in order to participate in this 
study. Pregnancy may introduce unpredictable effects on lipoprotein metabolism and 
influence the results of the study. The specific effects of pregnancy in this context may be the 
subject of a separate study.  Some form of contraception must be used by subjects while 
enrolled.  Contraception use will be determined by a questionnaire given to the subjects at 
time of enrollment. 
12.4 
Inclusion of NIH Staff 
x NIH staff (employees, NIH contractors, special volunteers, guest researchers, and 
trainees) may voluntarily participate in this protocol. 
 
x Recruitment, enrollment and compensation of NIH employee subjects will be 
consistent with the Guidelines for the Inclusion of Employees in NIH Intramural 
Research Studies (December 2015) (SOP 14F, Appendix A) and NIH Policy Manual 
Chapter 2300-630-3,”Leave Policy for NIH Employees Participating in NIH Medical 
Research Studies” (SOP 14F, Appendix B) 
 
x If the individual requesting to participate in the protocol is a co-worker, the consent 
from the NIH staff member (co-worker) will not be obtained by the staff member’s 
direct supervisor but by another research staff member approved for obtaining 
informed consent and who is also not a co-worker. 
 
x Neither participation nor refusal to participate as a subject in this protocol will have 
an effect, either beneficial or adverse, on the participant’s employment or position at 
NIH. 
 
x The consenting staff member will make the NIH Information Sheet on Employee 
Research Participation available to staff members who are considering enrolling in 
research. (SOP 14F, Appendix C) 
 
x Staff subjects’ privacy and confidentiality will be respected by protocol and 
consenting staff the same as for all subjects participating in research protocols. 
However, all subjects will be made aware that there are limits to these protections. 
12.5 
Evaluation of Benefits and Risks/Discomforts 
 

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As of July 10, 2019, this study is now closed to new subject accrual and continues in data 
analysis only and the level of risk is minimal. 
Benefits: 
There are no direct benefits to the patient, however, increasing HDL-C and decreasing LDL-
C and triglyceride levels in the general population is thought to be beneficial 23.   
Subjects will be provided information from routine clinical laboratory tests. 
Risks/Benefit Analysis: 
Risk (45 CFR 46.406): Research involving greater than minimal risk and no prospect of 
direct benefit to individual subjects, but likely to yield generalizable knowledge about the 
condition or disorder under study.  
Study Agent:  One drawback of niacin supplementation is the common occurrence of side 
effects, such as flushing and itching of the skin.  These are experienced by most patients to 
varying degrees may result in poor adherence to niacin regimens but these side effects have 
not been shown to lead to serious medical problems. To overcome this side effect an 
extended release form of niacin will be employed and extensive guidance will be given to 
each subject on the best times and forms to take the supplement to minimize these side 
effects. Other side effects may include myositis and changes in liver enzymes, which will be 
monitored at each visit.    
Blood Draw: Subjects may feel lightheaded or dizzy after having blood drawn.  There may 
be pain at the blood draw site and a slight risk of bruising.  To minimize this risk, the routine 
blood-drawing protocol will be followed and pressure will be applied to the site.   
The protocol will follow the NIH Clinical Center MAS policy M95-9 guidelines for limits of 
blood drawn for research purpose in the Clinical Center.  For adults, no more than 10.5 
mL/kg or 550 mL, whichever is smaller, will be drawn for research purposes over any 8-
week period. 
Cardio-Ankle Vascular Index (CAVI):  Inflation of blood pressure cuffs may cause transient 
discomfort. Subjects with fragile skin may suffer minor trauma (as per ABIs, related to usual 
BP measurements).  This procedure involves the use of a VaSera VS-1500N system; an FDA 
approved vascular screening system. 
12.6 
Protocol Consent Processes and Documents 
Each subject will receive an oral and written explanation of the goals, procedures, and risks 
of this study. The Principal Investigator and those Associate Investigators who are listed on 
the cover page of the protocol with an asterisk next to their name may obtain informed 
consent from research participants.  Consent will be obtained at the NIH Clinical Center.    

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The original, signed informed consent document will be placed in the medical record, and the 
subject will receive a signed copy of the informed consent document.  A copy will also be 
placed in the shadow chart.  A member of the protocol team will be available to answer 
questions about the study to be performed. 
12.6.1 Consent Processes for NIH Employees 
If the individual requesting to participate in the protocol is a co-worker, the consent from the 
NIH staff member (co-worker) will not be obtained by the research coordinator or the 
employee’s direct supervisor but by another research staff member who is approved for 
obtaining informed consent, and who is also not a coworker. 
12.6.2 Consent Processes for non-English Speaker 
If there is an unexpected enrollment of a non-English speaking research participant for which 
there is no translated extant IRB approved consent document, the principal investigator 
and/or those authorized to obtain informed consent will use the Short Form Oral Consent 
Process as described in MAS Policy M77-2, 45 CFR 46.117 ( b) (2). The summary that will 
be used is the English version of the extant IRB approved consent document.  
We request prospective IRB approval of the use of the short form for up to a maximum of 5 
participants in a given language and will notify the IRB at the time of continuing review of 
the frequency of the use of the Short Form.  Should we reach the threshold of 5, we will 
notify the IRB of the need for an additional use of the Short Form and that we will have that 
consent document translated into the given inherent language. 
13. Conflict of Interest 
None of the investigators have any conflict of interest to report.   
14. Adverse Event Management 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. Adverse events will be attributed (unrelated, unlikely, possibly, 
probably or definitively) to study medication and/ or disease and AEs will be graded by 
severity utilizing CTC version 4.0. A copy of the criteria can be downloaded at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All adverse events occurring during the study, including those observed by or reported to the 
research team, will be recorded.  

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14.1 
Reports to the IRB 
The PI or designee will refer to HRPP Policy 801 “Reporting Research Events” and HRPP 
802 “Non-compliance in Human Subject Research” to determine IRB reporting requirements 
and timelines. 
14.2 
Reports to the CD 
The PI or designee will refer to NHLBI DIR guidelines to determine CD reporting 
requirements and timelines.  
15. Data and Safety Monitoring Plan 
Safety Monitoring 
Principal Investigator:  Accrual and safety data will be monitored by the PI.  The protocol 
will be continuously evaluated for any unusual or unpredicted complications with the aim of 
detecting and preventing unacceptable increase in morbidity and mortality over and above 
that anticipated from niacin. 
NHLBI IRB 
Accrual and safety data will be monitored and reviewed annually by the Institutional Review 
Board (IRB).  Prior to implementation of this study, the protocol and the proposed patient 
informed consent document will be reviewed and approved by the properly constituted IRB 
operating according to the 45 CFR 46 Code of Federal regulations.  This committee must 
approve all amendments to the protocol or informed consent document, and conduct 
continuing annual review so long as the protocol is open to accrual or follow up of subjects. 
16. Compensation 
Compensation will be provided to the subjects for their time and inconvenience of 
participating on this protocol based on the values listed below. Compensation of NIH staff 
participants will be consistent with the NIH Manual Chapter 2300-630-3: Leave Policy for 
NIH staff. 
 
Procedures 
Inconvenience Unit 
$ 
Frequency 
Total $$ 
Outpatient Visit (first hour) 
2 
$20 
Up to 5 
$100 
Outpatient Visit (additional 
hours up to 4 hours) 
1 
$10 
Up to 5 
$200 
Physical Examination 
1 
$10 
5 
$50 
Screening Blood Draw 
1 
$10 
Up to 2 
$20 

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Research Blood Draw 
1 
$10 
4 
$40 
Diet & Exercise Assessment 
1 
$10 
3 
$30 
CAVI 
2 
$20 
3 
$60 
Total potential compensation: 
$500 
Subjects will receive partial compensation (one third payment) if they participate up to at 
least the second outpatient visit but will receive full compensation after only completing the 
entire study.  Subjects that fail to complete the study return for the second outpatient visit for 
reasons independent of their control (i.e. medical reasons, unplanned pregnancy) will also 
receive partial compensation. In cases where screening failure is independent of subject will 
(laboratory values), then compensation will be given to the subject for the tests performed 
and will be calculated based on the table above.  
17. References 
1. 
Fedder DO, Koro CE, L'Italien GJ. New National Cholesterol Education Program III 
guidelines for primary prevention lipid-lowering drug therapy: projected impact on the size, 
sex, and age distribution of the treatment-eligible population. Circulation 2002;105:152-6. 
2. 
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid 
lowering with statins after acute coronary syndromes. The New England journal of medicine 
2004;350:1495-504. 
3. 
Gordon SM, Hofmann S, Askew DS, Davidson WS. High density lipoprotein: it's not 
just about lipid transport anymore. Trends Endocrinol Metab 2011;22:9-15. 
4. 
Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug 
Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-55. 
5. 
Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or 
the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92. 
6. 
Asztalos BF, Batista M, Horvath KV, et al. Change in alpha1 HDL concentration 
predicts progression in coronary artery stenosis. Arterioscler Thromb Vasc Biol 
2003;23:847-52. 
7. 
HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of 
ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for 
stopping study treatment. Eur Heart J 2013;34:1279-91. 
8. 
Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL 
cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67. 

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9. 
Bloomgarden Z, Handelsman Y. Did AIM-HIGH aim too low? J Diabetes 2012;4:1-
2. 
10. 
Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs 
are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat 
Cell Biol 2011;13:423-33. 
11. 
Schakel. Maintaining a nutrient database in a changing marketplace:  Keeping pace 
with changing food products - A research prospective. Journal of Food Composition and 
Analysis 2001;14:315-22. 
 
 

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18. APPENDIX A: NIH INFORMATION SHEET ON STAFF 
RESEARCH PARTICIPATION (April 2016) 
As an NIH employee, contractor, Special Volunteer, Guest Researcher, or trainee, you may 
participate in intramural research studies unless it is prohibited by your Institute or Center 
(IC), or if you are excluded by the criteria of the protocol in which you want to enroll. The 
inclusion of NIH staff in a particular protocol must also be approved by the IRB. You may be 
motivated by altruism, a commitment to research in your own or related fields, or want 
access to clinical trials of potential direct therapeutic benefit. When deciding, you should 
make an informed decision about participation. This information sheet offers some points to 
consider for NIH staff who are considering research participation at NIH.  
First, similar to any individual who is considering research participation, you should seek 
adequate information about the study purpose, what is required of you in terms of 
procedures, interventions and time, and the potential risks and benefits of participation.  
For more information, see the NIH Clinical Center’s public website “Are Clinical Studies for 
You?” at http://www.cc.nih.gov/participate/studies.shtml.  
When you are thinking about participation in a research study that is being conducted by 
your supervisor, or others with whom you work closely in your laboratory, branch, or unit, 
you should consider some additional factors:  
A. Possible bias: Are you confident that you can be unbiased about reporting answers, side 
effects, or other information that could influence the study outcome or risk to you?  
B. Confidentiality: Has the principal investigator (PI) spoken about what information will be 
collected from you as part of the study? Has the PI discussed what information will be 
available to those within, and outside, the study team? If applicable, are you comfortable 
sharing your medical history (including, for example, mental health history or STDs) and 
your social history (e.g. substance use) with study investigators who may be your coworkers, 
or with the possibility of them discovering something about your health during the study (e.g. 
pregnancy status or a new diagnosis)? Although every effort will be made to protect your 
information and keep it private and confidential, your information may, depending on the 
nature of the protocol, become available in medical records or to authorized users outside of 
the study team. Discuss any concerns with the PI.  
C. Pressure: Do you perceive any pressure or expectations from your supervisor or 
colleagues regarding participation? Could that pressure influence your decision or make it 
difficult for you to choose whether or not to participate? Remember that it is your choice 
whether or not to participate and that your decision to participate or not should not have an 
effect, either beneficial or adverse, on your position at NIH.  

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D. Time and Compensation: Can you take time off from work to complete the study 
requirements or participate solely during non-duty hours? Can you receive compensation for 
your participation in this study? Will your supervisor give you permission to participate 
during work hours? See the NIH Policy Manual 2300-630-3 “Leave Policy for NIH 
Employees Participating in NIH Medical Research Studies.” 
E. Consent Process: Is the person obtaining your consent for the study your supervisor, a 
subordinate, or co-worker? If so, is there an independent person monitoring the consent 
process? If the study PI is a supervisor and intends to obtain consent from you, an 
independent person (e.g., through Bioethics or the NIMH Human Subjects Protections Unit 
[HSPU], or others as approved by the IRB) must monitor the consent process. If the person 
obtaining consent from you is a co-worker then an independent person (e.g., through 
Bioethics or the NIMH HSPU, or others as approved by the IRB) may be required to monitor 
the consent process, as determined by the IRB for the specific study. 
If you are thinking of enrolling as a subject at the NIH Clinical Center and you have any 
questions or concerns, please contact the Office of Human Subjects Research Protections 
(OHSRP) at 301-402-3444 and/ or the Patient Representative if you are thinking of enrolling 
as a subject at the NIH Clinical Center on 301-496-2626. If you are at a NIH site outside the 
Clinical Center then please contact local site leadership.