Study to Evaluate the Effect of Nicotinamide Riboside on Immunity
Phase: NA
Conditions: Atherosclerosis, Diabetes, Coronary Artery Disease
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

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Michael N Sack, MD, PhD 
CLINICAL RESEARCH PROJECT 
Protocol #16-H-0129 
IND #: NA 
Note: Supplement, Nicotinamide Riboside, is not subject to IND regulations as covered by 
the Dietary Supplement Health and Education Act of 1994. 
NHLBI Protocol: Study to Evaluate the Effect of Nicotinamide Riboside on Immunity 
Short Title: Nicotinamide Riboside on Immunity 
Keywords: Inflammasome, Sirt3, Nicotinamide riboside, Fasting, 
Principal Investigator: 
*Michael N. Sack, MD, PhD (E)
Cardiovascular Branch (CB) National Heart, 
Lung, and Blood Institute National Institutes of 
Health 
Building 10, Room 5-3150 
Bethesda, MD 20892 
Phone: 301-402-9259 
Associate Investigator & Research Coordinator: 
*Rebecca Huffstutler, CRNP
CB, NHLBI (E) 
Dachelle Johnson PharmD
CC Pharmacy (E) 
Jay H Chung, MD, PhD
 CB, NHLBI (E) 
Associate Investigator & Biostatistics Investigator: 
Myron A. Waclawiw, Ph.D. 
DCVS/OBR, NHLBI (E) 
*Investigators authorized to obtain informed consent
Biospecimen Tracking: 
Shahin Hassanzadeh, BS 
CB, NHLBI (E) 
Collaborator: 
Julian L. Griffin, Ph.D    
Department of Biochemistry, Cambridge 
University, Cambridge, UK 
Subjects in study at NIH: 
Number 
42 
Sex 
M/F 
Age range 
18-39 years
Multi-center trial: 
Ionizing Radiation for Research: 
Off-Site Project: 
DSMB Involvement: 
Tech Transfer: 
IND/IDE: 
No 
No 
No 
No 
CRADA 
No 

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Table of Contents 
1. Précis ........................................................................................................................................... 3 
2. Background ................................................................................................................................. 3 
3. Hypothesis ................................................................................................................................... 4 
4. Objectives .................................................................................................................................... 5 
5. Study Design and Procedures ...................................................................................................... 5 
Randomization and dispensing of study pills .............................................................................. 7 
Description of Study Population and Recruitment ...................................................................... 7 
6. Eligibility Assessment ................................................................................................................. 8 
Inclusion Criteria ........................................................................................................................ 9 
Exclusion Criteria ....................................................................................................................... 9 
7. Procedures ................................................................................................................................... 9 
8. Dietary Supplement ..................................................................................................................... 9 
9. Data and Biospecimen Management Plan ................................................................................. 11 
10.Statistical Considerations ......................................................................................................... 13 
11.Stopping Rules for Subjects ..................................................................................................... 14 
12. Data and Safety Monitoring .................................................................................................... 14 
Safety Monitoring ...................................................................................................................... 14 
Adverse Event Reporting .......................................................................................................... 14 
13. Human Subjects Protections .................................................................................................... 18 
Rationale for Subject Selection ................................................................................................. 18 
Rationale for the Exclusion of Children .................................................................................... 18 
Rationale for the Exclusion of Cognitively Impaired Subjects ................................................. 18 
Risk/Benefit Assessment ........................................................................................................... 18 
Inclusion of NIH Staff ............................................................................................................... 18 
Risks and Discomforts ............................................................................................................... 19 
Consent Processes and Documentation for NIH Employees ..................................................... 20 
14. Conflict of Interest .................................................................................................................. 20 
15. Reimbursement for Travel ...................................................................................................... 21 
16. Financial Compensation .......................................................................................................... 21 
17. References ............................................................................................................................... 21 
APPENDIX A: NIH INFORMATION SHEET ON STAFF RESEARCH PARTICIPATION 
(APRIL 2016) ................................................................................................................................ 23 

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1.
Précis
Intermittent caloric restriction or fasting has numerous health effects including the reduction in 
numerous cardiovascular disease risk factors. The cellular programs activated by caloric 
restriction are similarly turned on in preclinical studies in response to a 24-hour fast. We have 
found that a beneficial effect of 24-hour fasting is that it blunts the activation of a component of 
the immune system, termed the Nod-like receptor family protein 3 (NLRP3) Inflammasome. 
This inflammasome, as a mediator of sterile inflammation, is associated with the development of 
diabetes and atherosclerosis. At the same time, we found that refeeding after the 24-hour fast 
significantly increased NLRP3 protein levels, IL-1and TNF signaling, and that fasting blunted 
the NLRP3 inflammasome response, in association with the activation of a fasting sensing 
protein called SIRT3.1 Interestingly, a recently discovered naturally occurring form of vitamin
B3, called nicotinamide riboside (NR), has been found to activate SIRT3.2, 3 We found that NR
reproduces the NLRP3 inflammasome blunting effect of fasting when administered to primary 
human monocytes/macrophages in culture. Putting this together, it would be interesting to 
evaluate whether the administration of NR to human subjects would replicate the fasting blunting 
effect on the NLRP3 inflammasome. Interestingly, at the same time, it has recently been found, 
in a preclinical study, that the NLRP3 protein can orchestrate differentiation of naïve T- cells 
into Th2 cells. We therefore propose to more broadly examine the effects of NR administration 
on myeloid and lymphoid cell biology in healthy volunteers. 
2.
Background
Atherosclerosis and type 2 diabetes are associated with ‘sterile inflammation’ that exacerbates 
vascular injury and insulin resistance. A mechanism underpinning this involves activation of the 
innate immune system by cell surface receptor recognized damage-associated molecular patterns 
(DAMPs), which in turn, activate intracellular inflammatory proteins (the NLRP3 
inflammasome). Inflammasome activation increases the production and release of pro- 
inflammatory cytokines, including interleukin-1(IL-1) and IL18. This emerging link between 
the immune system and metabolic diseases raises the question as to whether caloric restriction 
activated pathways, which ameliorate consequences of metabolic disease,3, 4 may directly
suppress the NLRP3 inflammasome. 
Emerging data finds that mitochondrial integrity and function control multiple immunological 
effects including effects on activation of the NLRP3 inflammasome in monocytes/macrophages, 
on T-cell polarity and in the activation of mast cells. At the same time data show that fasting and 
caloric restriction improve mitochondrial integrity, in part via activation of sirtuin proteins4 and
that caloric restriction blunts systemic inflammation.5, 6 Conversely, overnutrition is linked to
activation of the NLRP3 inflammasome (sterile inflammation) and TH2 linked diseases including 
asthma.  Putting this together, we reasoned that fasting, via maintenance of mitochondrial 
integrity, would dampen the NLRP3 inflammasome compared to the effects of refeeding. This 
hypothesis was explored in an initial NHLBI protocol (14-H-0103) where we found that the 

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Michael N Sack, MD, PhD 
NLRP3 inflammasome was lower in the fasted compared to the refed state and that Sirtuin 3 
(Sirt3) activation played a role in the fasting effect. Refeeding itself also primed inflammatory 
pathways including the NLRP3 pathway and TNF signaling. Interestingly, serum obtained from 
the patients in the fasted and refed states recapitulated the effects of the inflammasome in human 
derived THP-1 monocytes and the administration of a Sirt3 activator (Nicotinamide Riboside - 
NR) could replicate the anti-inflammatory effect of fasting when administered to primary human 
monocytes/macrophages.1 NR is a naturally occurring form of vitamin B3, and it has been shown
to be a Nicotinamide Adenine Dinucleotide (NAD+) precursor that boosts cellular NAD+ levels.
NAD+ acts as an activator and substrate for sirtuins.
From our prior study we concluded that: (i) fasting and refeeding differentially regulate NLRP3 
inflammasome activation in humans; (ii) that the activation of Sirt3 by NR may have beneficial 
effects on inflammasome linked diseases and (iii) that fasting, refeeding and the activation of 
Sirt3 may play a broader role in the modulation of immune function. 
To pursue the clinical potential of Sirt3 activation on immune cell modulation we propose to 
explore the administration of NR to healthy volunteers to explore the effects on myeloid and 
lymphoid cell biology. 
Additional studies have been initiated or planned using NR to study effects on mitochondrial 
biology related conditions including aging (at the University of Colorado in Boulder – actively 
recruiting) and in heart failure (University of Washington in Seattle – protocol in developmental 
stage). Based on blood levels of NAD+ from a pilot study performed at the University of Iowa,
the dose of NR chosen by aging and heart failure studies is 1 gram daily. The PI (Sack) has also 
discussed the experience to date with Drs Christopher R. Martens (UC – Boulder) and Rong Tian 
(U. of Washington). As of May 17, 2016 the Boulder team has enrolled 20 subjects of whom 10 
subjects had been taking 1 gram of NR daily with no evidence of intolerance or side effects. The 
Seattle team has completed a pharmacokinetics study (NCT02689882) on 8 subjects taking 
incremental doses up to 1 gram bid up to 9 days. This study revealed no significant side effects 
and enrollment of the first subject on the heart failure study had been initiated. We therefore 
propose to use the 1 gram daily dose. 
3. Hypothesis
Nicotinamide riboside, as a Sirt3 activator, will mimic the beneficial immune effects of 
prolonged fasting and suppress immune activation of refeeding. 
Proposed Scientific/Clinical Innovations and Advances of the Study 
-
Evaluate whether pharmacologic activation of Sirt3, via enhancing mitochondrial integrity
will blunt sterile-inflammation linked NLRP3 inflammasome activation.
-
Expand our understanding how NR can modulate the regulation of additional innate and
adaptive immune pathways

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Michael N Sack, MD, PhD 
4. Objectives
1. Explore whether NR administration will blunt NLRP3 activation in human subjects.
2. Explore whether NR will modulate additional innate (NK cell) and adaptive (T-cell)
immune programs.
3. Employ proteomic and cytokine array analysis to obtain a broader understanding of the
NR mediated effects on mitochondrial biology in modulating immune regulation in
circulating cells and in the serum of study subjects.
5. Study Design and Procedures
The study design is a prospective, double-blind randomized crossover study with subjects 
serving as their own controls. 
Normal volunteers will be enrolled on this 3-5 week study that includes 3 visits to the NIH 
Clinical Center. Subjects may be contacted by telephone, text or email to verify study compound 
compliance, for AE/safety assessment and to remind subjects to initiate the 24-hour fast prior to 
Visit #2 and Visit #3. Email communications will be made through the NIH medical secure 
email system unless the patient declines its’ use and requests standard unsecure email. A 
schematic showing the outline of the overall study is shown below. 
The variable length of the washout and study arms phase is to allow flexibility for the 
scheduling of subject visits. The prior pharmacokinetic studies support that 7 days is more 
than sufficient to restore NAD+ levels to baseline.
The following actions will be undertaken at the defined visits: 
Arm 1 
Screening/Visit 1: 
•
Subjects will be screened for inclusion or exclusion.
•
Baseline screening laboratories performed.
•
Pregnancy testing in women of childbearing potential.

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Michael N Sack, MD, PhD 
•
Eligible subjects will be randomized to placebo (i.e. sugar tablet) or 1 gram of NR daily.
The study compound start date will be determined at this visit. Start date will be within
one week of screening visit.
•
Instruct subject on study compound administration, reinforce maintenance of stable diet
and activity level during the study participation period, and review the time of the
breakfast on day 6 (+3 days, if needed), prior to initiating the 24-hour fast.
Day 1 of Arm 1 study compound administration. 
A member of the research team may contact study subjects: 
•
to remind them which day to initiate therapy
•
to remind subjects of the 24-hour ± 2hr fast
Visit 2 : Day 7 (+ up to 3 days, if needed) of Arm 1 study compound administration 
•
Subjects will arrive at the Clinical Center after a 24-hour fast ± 2 hours with the
exception of drinking water starting the morning of day 6 (+ up to 3 days, if
needed).
•
A pill count will be performed to evaluate compliance.
•
Fasting blood draw for hepatic panel, acute care panel, insulin, growth hormone, complete
blood count, serum immune cell studies and to measure NAD levels.
•
Urine collection for ketones
•
Administer day 7 (+ up to 3 days, if needed) Arm 1 placebo/NR capsules.
•
A 500 caloric meal will be eaten.
•
Refed blood-draw for insulin, growth hormone, glucose, serum immune cell studies and to
measure NAD levels three hours ± 30 minutes after fixed caloric meal (metabolic kitchen).
•
Subject educated about washout period.
•
New bottles of study compound for Arm 2 dispensed.
Washout period of 7-14 days 
Arm 2 
Day 1 of Arm 2 study compound administration 
A member of the research team may contact study subjects: 
•
to remind them which day to initiate therapy
•
to remind subjects  of the 24-hour ± 2hr fast
Visit 3: Day 7 (+ up to 3 days, if needed) of Arm 2 study compound administration 
•
Subjects will arrive at the Clinical Center after a 24-hour fast ± 2 hours with the
exception of drinking water starting the morning of day 6 of the second study arm.
•
A pill count will be performed to evaluate compliance.
•
Fasting blood draw for hepatic function panel, acute care panel, complete blood

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Michael N Sack, MD, PhD 
count, insulin, growth hormone, serum immune cell studies and to measure NAD 
levels. 
•
Urine collection for ketones
•
Administer day 7 of Arm 2 placebo/NR capsules.
•
A 500 caloric meal will be eaten.
•
Refed blood draw for insulin, growth hormone, glucose, serum immune cell studies and to
measure NAD levels three hours ±30 minutes after fixed caloric meal (metabolic kitchen).
Off Treatment (Supplement): 
Subjects will be considered off treatment (supplement) after completion of Arm 2 study 
pills.  
Follow up: 
We will follow up the subjects for 30 days after completion of Arm 2 study pills for any 
AEs. Subject will be instructed to the contact research team if any symptoms develop 
during this 30 day period. 
 Off Study: 
Subject will be taken off study 30 days after completion of Arm 2 study pills. If a subject 
doesn’t report any AEs, we will take him/her off study on day 30 after completion of Arm 2 
study pills. If a subject reports any AEs during the 30-day follow up period then we will 
adjust off study date upon resolution/returning to the baseline of the AEs.  
Randomization and dispensing of study pills: 
The pharmacist Co-Investigator on the study will devise a randomization code in consultation 
with Dr. Myron Waclawiw (Biostatistician). This code will be kept confidential and will be 
employed by the pharmacy to dispense the study pills. For each arm, subjects would receive 
sufficient pills for 7 days of administration.  If additional pills are needed to extend the treatment 
arm by up to three days, these will be dispensed separately by the pharmacy. Subjects will take 
their study medication at home for days 1 through 6 (+ up to 3 days, if needed).  Day 7 (+ up to 3 
days, if needed) dosing will be in the clinic. Subjects will be instructed to bring their study 
medication bottle back to the clinical center for day 7 (+ up to 3 days, if needed) dosing and to not 
take the day 7 (+ up to 3 days, if needed) dose until instructed to by the study team.  If the subject 
forgets to bring the study bottle with the day 7 (+ up to 3 days, if needed) dose, the day 7 (+ up to 
3 days, if needed) dose will be ordered through CRIS from the pharmacy. A process has been 
developed by the NHLBI pharmacist to ensure the subject receives the correct study compound or 
placebo.  The day 7 (+ up to 3 days, if needed) pill for each arm will be given to the study subject 
for consumption following the 24-hour fasting research blood draw. The study pill receptacle will 
have the subject’s name, code number, prescription details (4 tablets by mouth each morning with 
or without food) and will include the arm (1 or 2).   If the study subject does not bring in the pill 
bottle, the subject will be asked to confirm the number of study doses taken over the prior 6 (+ up 

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Michael N Sack, MD, PhD 
to 3 days, if needed) days and this will be documented in the medical record. The pill bottles will 
then either be collected at the next visit or we will have the subject return by FedEx. 
The code will be shared with the statistician following the completion of studies on 20 subjects 
to evaluate observed standard deviations to assess original study assumptions and continued 
study feasibility. 
Description of Study Population and Recruitment 
Participants will be enrolled at the NIH Clinical Center. Subjects will be recruited through a 
LISTSERV email announcement and study procedures will be performed in the outpatient 
unit/day hospital at the NIH Clinical Center.  A list of healthy volunteers may also be requested 
from the NIH Office of Patient Recruitment. 
A total of 42 participants will be recruited for this study. 
6. Eligibility Assessment
The PI and/or AI will assess eligibility.  Screening will be performed under this protocol only. 
Screening studies for subject enrollment: 
i.
History and physical examination.
ii.
Screening and Research laboratory tests may include:
o
Acute Care Panel (Na, K, Cl, CO2, Creatinine, Glucose, and Urea Nitrogen)
o
Mineral Panel (Phosphorus, Magnesium, Albumin, and Calcium)
o
Hepatic Panel (Alk Phosphatase, ALT, AST, Total Bilirubin, and Direct Bilirubin)
o
CBC + Differential
o
Blood draw for immune cell studies and NAD levels
o
Urine for ketones
o Growth hormone o
Insulin level
o
Glucose
o
HCG (females of childbearing potential)
Inclusion Criteria 
As this is a pilot study, the age-range and BMI range of subjects will be restricted to potentially 
reduce metabolic variables associated with a wide age- and BMI-range. 
•
Males and females between the ages of 18 and 39
•
BMI between 18.5 and 29.9
•
Agrees to comply with study procedures and maintain current level of physical activity
and dietary intake throughout the study.
•
Female subjects of child-bearing ability willing to commit to reliable contraception while
participating in the study.

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Michael N Sack, MD, PhD 
Exclusion Criteria 
•
Subjects with an acute or chronic illness as per history, on laboratory analysis or
requiring medications to manage disease.
•
Subjects taking vitamins or supplements or any medications, except oral contraceptives,
within 4 weeks of participation into this study.
•
BMI <18.5 or >29.9.
•
Female subjects who are pregnant or lactating.
•
Subjects who have donated blood or participated in another clinical trial involving blood
draws in the last 8 weeks.
•
Subjects who use nicotine products including chewing tobacco, vaporizer, gum, cigarette
or patch form within three months.
•
Any other medical  condition that, in the opinion of the Principal Investigator, might put
the subject at risk of harm during the study or might adversely affect the interpretation of
the study data.
7. Procedures
All tests will follow NIH Clinical Center policies. Any of the listed procedures or laboratory tests 
performed within three months prior to enrollment in this protocol may/may not be repeated.  
However, if these procedures are not repeated, the prior studies (within the last 3 months) will be 
reviewed in CRIS as part of the protocol. The purpose for not repeating study procedures is to 
prevent unnecessary inconveniences, risks or discomforts for study participants and the NIH 
Clinical Center. 
i)
Blood Draws: In addition to the screening blood draw (40 mL), subjects will have 4
additional research blood draws up to 100 mL each, as described in Section 4.
ii) Urine Analysis: Subjects will be asked to provide up to three urine samples, one for
pregnancy testing as part of screening evaluation and two in the fasting state at Visits 2
and 3 as described in Section 4.
iii) 24-Hour Fasting: Subjects will be asked to fast for up to 26 hours (water intake will not
be restricted) during each of the two treatment arms.
iv) Fixed Caloric Meal: The meal will be a 500 calorie breakfast. Subjects will have a
choice of two meals.
Meal Choices 
Description of Meal 
Option 1 
•
Vegetable omelet
•
Toast with butter and jelly
•
Orange juice
Option 2 - 
•
Oatmeal with Walnuts, Brown Sugar and Dried
Cranberries
•
Milk

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Michael N Sack, MD, PhD 
8. Dietary Supplement
Niagen™ is a commercially-available form of nicotinamide riboside (NR). The nucleoside NR is 
a single chemical moiety containing nicotinamide and ribose.7 NR is a form of vitamin B3  present
in trace amounts in foods like milk, yeast extract and beer. It is also postulated that NR is 
generated in the gastrointestinal tract as part of dietary NAD+ digestion. Thus, humans are 
constantly exposed to NR from the diet, albeit at low levels. Since 2013, Niagen™ has been sold 
as a dietary supplement in the United States. Labeling guidelines recommend consumers to limit 
their intake to 2 capsules/day, which amounts to 250 mg/day. This recommended level is the 
equivalent of 3.8 mg/kg bw/day, which is 1000-fold less than the highest dose determined to be 
safe and well tolerated in rats, and a quarter of the dose proposed for this pilot clinical trial. 
There is no limit on the duration of ingestion. Limited animal model and human data exist on the 
pharmacokinetics and safety of orally administered NR. However, ChromaDex has conducted a 
recent randomized, double-blind, cross-over, pharmacokinetic study (14NBHC, unpublished 
results) which demonstrated that NR was readily absorbed and detectable in human plasma, 
white blood cells, and urine. In addition, NR was well tolerated and presented no toxicity 
following a single dose up to 1000 mg in human subjects. Moreover, in an acute toxicology 
study, rats that were given a single oral dose (5000 mg/kg) of NR did not show clinical signs of 
toxicity or mortality (unpublished results). 
Niacin is a form of vitamin B3
8 and has been used for a long time treat hypercholesterolemia and
pellagra. Niacin administration can lead to undesirable effects, such as spontaneous flushing. 
Studies in animal models suggest that flushing results from nicotinic acid-mediated activation of 
the G-coupled receptor, GPR109A.9 NR has low affinity for GPR109A, and experiments in cell
lines expressing GPR109A demonstrate that nicotinic acid, but not NR, activates the receptor. 2
Thus, based on these findings, oral ingestion of NR may not result the spontaneous flushing that 
has been associated with high doses of niacin administration. 
Multiple lines of non-clinical data suggest that NR intake does not present any potential risks and 
should be well tolerated in human subjects. The dose proposed for this study is within the doses 
tested in non-clinical studies of mice for up to 4 months, and are 300-fold below the daily dose 
that was given in rats in a 14-day dose range finder study. 
Nicotinamide, an expected metabolite of NR, is a molecule that is considered of low toxicity in 
food by several regulatory agencies including the United States Food and Drug Administration 
(FDA) and the European Food Safety Authority (EFSA). 
Because nicotinamide is a putative metabolite of NR in humans, understanding the safety profile 
of nicotinamide is relevant when assessing the safety of NR in human subjects. 
Based on the structural similarities between NR and nicotinamide, and that nicotinamide is a 
downstream metabolite of NR digestion, it is assumed that any unexpected adverse effects of NR 
may be similar to those associated with nicotinamide intake.  However, no significant adverse 

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Michael N Sack, MD, PhD 
 
effects have been reported in clinical trials which have used doses up to the equivalent of 3000 
mg/day for up to 3 years to evaluate the possible benefits of nicotinamide administration to 
patients with or at risk of developing Type 1 diabetes 10, 11. In addition, doses of 25 and 42 mg/kg 
bw/day had no effect on a variety of biochemical parameters, such as those that assessed liver 
and kidney function. 
In summary, careful analysis of all the non-clinical information available on NR has not revealed 
any potential serious toxicity that would preclude its use in healthy subjects. 
Common name: Nicotinamide Riboside Chloride 
 
Product name: Niagen 
 
Chemical name: 3-(Aminocarbonyl)-1-β-D-ribofuranosyl-pyridinium chloride (1:1) 
Dose: 1000mg daily for 7-10 days 
 
Route of administration: oral 
 
Dosing instructions: (4) 250mg study capsules daily after breakfast. 
 
Supply: Drug will be supplied by ChromaDex 
 
Manufactured by: 
W.R. Grace & Co. 1290 Industrial Way, Albany, OR 97322, 
USA 
Toxicology: None known. 
 
Drug Interactions: None known. 
 
Off-label use: Considering the clinical investigation is designed to study the relationship between 
a dietary supplement’s effect on normal structure or function in humans or to characterize the 
mechanism by which a dietary supplement acts to maintain such structure or function this study 
would not need to be conducted under an IND. Under the Dietary Supplement Health and 
Education Act of 1994, a dietary supplement is not considered a drug and is not subject to the 
premarket approval requirements for drugs if the intended use for which it is marketed is only to 
affect the structure or any function of the body (i.e., not intended to be used for a therapeutic 
purpose). Similarly, 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. 
 
9. Data and Biospecimen Management Plan 
 
Data Management and Access: 
 

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Samples will be de-identified prior to storage on the 5th floor of building 10 in laboratory for the 
principal investigator following current NIH sample storage guidelines.  Samples and data will 
be stored, using codes assigned by the investigators or their designee(s). Research samples will 
be stored using BSI in accordance with NHLBI DIR Biospecimen policy. 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. 
Primary research data will be coded by replacing individually identifying information (such as 
name) with a code that will enable the investigator to readily ascertain the identity of the subject 
through the use of a code-key, but will not reveal the identity of subjects to parties not authorized 
to have access to individual subject identifiers. 
Biospecimen Management: 
 
Blood and urine samples will be coded and stored in conformity with DIR Policy (e.g., BSI). 
Coded biospecimens may be sent to collaborators outside of the NIH with IRB approval in 
accordance with applicable NIH and DIR Policy for sharing research resources, including an 
executed material transfer agreement. 
End of study procedures: 
Data retained by the NHBLI will be stored in a password-protected database in conformity with 
NHLBI DIR policy until they are no longer of scientific value. 
Destruction of research data collected on this protocol will be consistent with NIH policy and 
upon permission of the Clinical Director. 
 
Breach of Confidentiality: 
 
PIs will report any breach of subject confidentiality or trial data to the clinical director and IRB 
per NIH policy, including NIH HRPP SOP 16 - Reporting Requirements for Unanticipated 
Problems, Adverse Events and Protocol Deviations. 
Data Sharing and Future Use of Data Data 
Sharing Plans: 
Research data may be shared with qualified non-collaborator recipients following publication of 
the primary research results after removal of PII and IRB approval (coded data) or Office of 
Human Subjects Research Protections (OHSRP) approval (unlinked data). In both situations, a 
data use agreement between the sender and the recipient will be executed. Future research use of 
data not defined in the research protocol may occur only after IRB review and approval or a 
determination from the NIH OHSRP. Refusal of a research subject participant to permit future use 
of data-will be honored. 

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Future Use of Biospecimens: 
 
Following analyses of biospecimens for primary research purposes as described in the protocol, 
remaining samples suitable for future research will be stored in manner that conforms with DIR 
policy (such as BSI) or in a publicly accessible research biospecimen repository following IRB 
approval. Biospecimens may be destroyed only when permitted by the clinical director and 
approved by the IRB. Any future research use of biospecimens not defined in the research 
protocol will occur only after IRB review and approval, if the research holds the key that 
identifies research subjects, or determination from OHSRP (non-collaborative research). 
Biospecimens will not be sent outside of the NIH for future research use without IRB approval 
and an executed agreement. Refusal of a research subject participant to allow for future use of 
biospecimens will be honored. 
Loss or destruction of samples: Should we become aware that a major breech in our plan for 
tracking and storage of samples has occurred, the IRB will be notified. 
 
Collaboration: 
 
Between NHLBI and Dr. Julian L. Griffin, Department of Biochemistry, Cambridge University, Cambridge, 
UK. This MTA is for the NHLBI to send de-identified blood and serum samples from healthy volunteers 
from this fasting and refeeding study for lipidomic and metabolomic testing. An MTA will be executed after 
Amendment D approval by the IRB. 
10. 
Statistical Considerations 
 
We propose that NR functions as a fasting mimetic and we will assess whether after refeeding 
the NLRP3 inflammasome activation (IL-1release) is blunted by NR as the primary endpoint. In 
our prior study, the mean±SD value of fasting IL-1β release was 319±513 pg/ml, while the mean 
refed value was 736±1067 pg/ml (with 417±613 pg/ml for the paired refed-fasting IL-1β release 
differences). In this placebo-controlled crossover study, we would like to detect a relative 
reduction of at least 20% in refeeding IL-1β release (from 736 to 589 pg/ml) with NR treatment 
compared to the paired responses on placebo. The crossover design has the benefit of reducing the 
influence of confounding covariates (because each subject serves as their own control) and is 
statistically efficient, requiring fewer subjects than non-crossover designs. Since estimates of 
within-subject variability for both the NR and placebo arms, between-subject variability for the 
NR arm, and between-subject covariance between NR and placebo are not available for this novel 
exploratory study, the usual crossover study sample size formulas cannot be used. Instead, we 
calculate sample size using the paired Student t-test. With a standard deviation of 276 pg/ml (45% 
of that observed for the fasting-refed differences), 80% power and an alpha=0.05, we will need 30 
subjects to detect a 20% relative decrease (absolute decrease of 147 pg/dl from 736 to 589 pg/dl) 
for the paired treatment differences in IL-1β release with NR treatment. We therefore request 
approval to enroll up to 35 normal volunteers to account for possible treatment non- compliance 
and /or study dropouts. 
 
There will be no interim efficacy look at the data in this proof-of-concept study. However, when 
20 subjects have completed the study, the protocol statistician will perform a sample size re- 

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Michael N Sack, MD, PhD 
 
calculation using only the observed standard deviation of the paired between treatment IL-1β 
changes to assess the original study assumptions and continued study feasibility. The study PI 
will remain blinded to the primary outcomes. The study will be judged feasible jointly by the 
study PI and Statistician if the new sample size calculation shows that 50 or fewer subjects can 
answer the primary hypothesis concerning IL-1β. If the study is feasible and continues, the 
sample size will not be reduced below the originally calculated requirement of 30 but, if needed, 
a request for a new larger enrollment ceiling (not to exceed 58 subjects, accounting for study 
drop-outs and non-adherers) will be presented to the IRB for consideration. 
 
Of note, the sample size recalculation was performed on October 19th, 2017 after the enrollment of 
20 subjects. The study sample size was recalculated using an updated observed standard deviation 
of the between treatment fed-fasting differences in IL-1beta levels (S = 177.002 pg/ml) based on 
17/20 evaluable subjects enrolled into the protocol.  The new calculation was performed for fed-
fasting differences rather than fed differences between treatments (a more conservative approach) 
to allow adjustment for any differences in baseline fasting IL-1beta levels between study periods. 
With an observed standard deviation of 177 pg/ml, 80% power, and a two-sided alpha=0.05, we 
will need n=36 subjects to detect a 20% relative decrease (absolute decrease of 83 pg/ml from the 
protocol-specified mean level of 417 pg/ml to 333 pg/ml) for the paired fed-fasting differences 
between treatments in IL-1beta release with NR treatment. As the study continues to be feasible 
(requires the enrollment of fewer than 50 subjects), we request approval to continue enrolling up to 
42 normal volunteers to account for possible treatment non-compliance and/or study dropouts. 
 
Primary study outcome: 
The primary study outcome will be the refeeding IL-1secretion in response to inflammasome 
stimulation in the NR treatment arm versus the same subject’s response on the placebo treatment 
arm using the nonparametric Wilcoxon Signed Rank test. 
 
Additional Analyses: 
• NLRP3 inflammasome activation in PBMC’s (IL-1in the fasting state) 
• Isolate PBMC’s to explore mitochondrial functioning and biochemistry (oxygen 
consumption rate in leukocytes) 
• Flow cytometry to explore innate and adaptive cell profiles (assessment of cell surface 
markers to assay cellular polarity and activation) 
• Negative selection to extract T-cells to investigate primary culture T-cell polarity (ELISA 
assays to measure cytokine production following T-cell activation) 
• Serum samples for SomaLogic Proteome analysis and Luminex analysis of cytokine 
levels (discovery proteomics data collection) 
• ELISPOT analysis of TH1/TH2/TH17 cytokine polarity following TCR crosslinking 
(Alternate assay to measure CD4 T-cell polarity) 
 
In this pilot study, the parametric paired Student t-test and the non-parametric Wilcoxon Signed 
Rank test will be used to analyze treatment differences in secondary outcome measurements. 
 

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11.Stopping Rules for Subjects  
• 
Pregnancy and breastfeeding 
• 
Subjects taking less than 75% of the supplement 
• 
Any other significant medical symptoms that may or not be related to the treatment and as 
determined by contact with the physician 
• 
Subjects who are found to be pregnant or wish to breastfeed during the study will 
automatically be withdrawn. A pregnancy screening will be done for all female volunteers at 
the first visit and subjects will be excluded from the study if pregnant 
 
 
12. Data and Safety Monitoring  
 
Safety Monitoring 
Accrual and safety data will be monitored by the Principal Investigator, Michael N. Sack, M.D. 
Ph.D., who will provide oversight to the conduct of this study. 
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 subject 
informed consent document will be reviewed and approved by the properly constituted IRB 
operating according to the 45 CFR 46. 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. 
Adverse Event Reporting 
 
Adverse Event (AE): Any untoward medical occurrence in a human subject, including any 
abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. 
Abnormal laboratory values: A moderate and severe abnormal laboratory value will be 
considered an AE if the laboratory abnormality is characterized by any of the following: 
• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms 
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization 
• Is judged by the Investigator to be of significant clinical impact 
• If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the subject’s outcome. 
 
Serious Adverse Event (SAE): A serious adverse event that: 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as it 

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occurred); 
• results in in-patient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant incapacity; 
• results in a congenital anomaly/birth defect; or 
• based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 
 
 
Unanticipated Problem: An UP is any incident, experience, or outcome that meets all of the 
following criteria: 
1. unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents; and 
b. the characteristics of the subject population being studied; and 
2. related or possibly related to participation in the research; and 
3. places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
 
 
Reporting of Pregnancy: 
In the event a subject becomes pregnant while on study, this event will be reported to the IRB and 
Clinical Director as an unanticipated problem. Monitoring of the pregnancy will continue until 
conclusion of the pregnancy. 
 
Unanticipated Problem that is not an Adverse Event: An unanticipated problem that does not 
fit the definition of an adverse event, but which may, in the opinion of the investigator, involves 
risk to the subject, affect others in the research study, or significantly impact the integrity of 
research data.  For example, report occurrences of breaches of confidentiality, accidental 
destruction of study records, or unaccounted-for study drug. 
Protocol Deviation (PD): Any change, divergence, or departure from the IRB approved research 
protocol. 
Non Compliance: The failure to comply with applicable NIH HRPP policies, IRB requirements, or 
regulatory requirements for the protection of human research. Noncompliance may be further 
characterized as: 
Serious non-compliance: Non-compliance that: 
a. Increases risks, or causes harm, to participants. 
b. Decreases potential benefits to participants. 
c. Compromises the integrity of the NIH HRPP. 
d. Invalidates the study data. 
Continuing non-compliance: Non-compliance that is recurring. An example may be a 
pattern of non-compliance that suggests a likelihood that, absent an intervention, non- 

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compliance will continue. Continuing noncompliance could also include a failure to 
respond to IRB requests to resolve previous allegations of non-compliance. 
Minor (non-serious) non-compliance: Non-compliance that, is neither serious nor 
continuing. 
Adverse Event Management 
 
The principal investigator and medical advisory investigator, or designee, will be responsible for 
assessing adverse events. Information on adverse events will be solicited from subjects through 
questions from study personnel and/or information volunteered by the subject. Adverse events will 
be captured from the start of the first pill taken (day 0) until 30 days following the last pill taken. 
Following this period, only serious adverse events that are unexpected and related to study pills 
will be reported. All AEs, regardless of severity, will be recorded, graded, assigned an attribution, 
verified, and followed until satisfactory resolution. 
 
In the event of any treatment-related SAEs, enrollment will be suspended until discussed with the 
IRB and Clinical Director. 
 
Grading and Attribution of Adverse Events 
 
Mild: Awareness of sign or symptom, but easily tolerated. Not expected to have a 
clinically significant effect on the patients overall health and well-being.  Not likely to 
require medical attention. 
Moderate: Discomfort enough to cause interference with usual activity or affects 
clinical status.  May require medical intervention. 
Severe:  Incapacitating or significantly affecting clinical status.  Likely requires medical 
intervention and/or close follow-up. 
Attribution of Adverse Events 
 
Relationship 
Attribution 
Description 
Unrelated to 
intervention 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related to 
intervention 
Possibly 
The AE may be related to the intervention 
Probably 
The AE is likely related to the intervention 
Definitely 
The AE is clearly related to the intervention 
 
 
NHLBI-IRB and CD reporting 
 
Serious Events 
Reports to the IRB and CD: The PI must report Serious UPs, and Serious PDs to the IRB 
and CD as soon as possible but not more than 7 days after the PI first learns of the event 
using the NIH Problem Report Form. 

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Non-serious Events 
Reports to the IRB and CD:  The PI must report all UPs that are not Serious to the IRB 
and CD, and PDs that are not Serious to the IRB, not more than 14 days after the PI first 
learns of the event using the NIH Problem Report Form. 
Deaths 
Deaths possibly, probably, or definitely related to study procedures will be reported to the 
Clinical Director within 7 days after the PI first learns of the event. 
Reports at the time of continuing IRB review:  At continuing review, the PI will 
provide to the IRB a summary of: 
• All UPs 
• All PDs 
• All AEs (except for those granted a waiver of reporting) 
 
 
Waiver of Reporting: The following adverse events will be listed in the consent and not 
reported to the IRB: 
• Vasovagal symptoms during blood draws (expected frequency 50%). 
• Transient bruising at the site of blood draws (expected frequency 50%). 
• Hunger, headache, fatigue, or irritability during fasting (expected frequency 50%). 
 
13.  Human Subjects Protections 
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.  Recruitment, enrollment and compensation of NIH employee subjects 
will be consistent with NIH Manual Chapter 2300-630-3: Leave Policy for NIH Employees. 
Rationale for the Exclusion of Children 
 
Subjects under 18 years of age will not be considered for inclusion in this protocol because there is 
no direct benefit from participating in this study and the 24-hour fast and volumes of blood levels 
drawn exceed minimal risk for children. 
Rationale for the Exclusion of Pregnant Women 
 
Subjects must not be pregnant or actively seeking pregnancy in order to participate in this study. 
NR has not been determined to be safe in pregnancy or breastfeeding. A recognized form of 
contraception must be used by subjects while enrolled. Contraception use will be determined 
during telephone screening and confirmed at the screening visit. 
Rationale for the Exclusion of Cognitively Impaired Subjects 

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Michael N Sack, MD, PhD 
 
 
Subjects with cognitive impairment will not be considered for inclusion because there is no direct 
benefit from participating in this study. 
Risk/Benefit Assessment 
 
The research involves greater than minimal risk to subjects, with no prospect of direct benefit, but 
is likely to yield generalizable knowledge (45 CFR 46.102). 
Inclusion of NIH Staff 
 
• NIH staff (employees, NIH contractors, special volunteers, guest researchers, and trainees) 
may voluntarily participate in this protocol. 
• Recruitment, enrollment and compensation of NIH staff will be consistent with the Guidelines 
for the Inclusion of Staff in NIH Intramural Research Studies (December 2015) (Appendix A of 
SOP 14F) and NIH Policy Manual Chapter 2300-630-3,:”Leave Policy for NIH Employees 
Participating in NIH Medical Research Studies” (Appendix B of HRPP SOP 14F,). 
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. 
• 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. However, all 
subjects will be made aware that there are limits to these protections. 
• The PI, through the consenting staff member will make the “NIH Information Sheet on Staff 
Research Participation” available to staff members who are considering enrolling in research. 
(SOP 14F, Appendix C; also in Appendix A of the protocol) 
Risks and Discomforts 
 
• 
Phlebotomy: Standard precautions for obtaining human blood samples will be taken. 
Transient discomfort and minor bruising may occur at the phlebotomy site.  Vasovagal 
symptoms can occur during blood drawing. Blood samples will be obtained by 
venipuncture. Blood samples will be obtained by a nurse, physician, or other skilled 
individual. A total of 440 mL of blood with be drawn for this study. The quantities of 
blood to be drawn for research purposes will be consistent with the CC policy as 
provided in Medical Administrative Series (MAS) 95-9 (revised 05/29/2012): 
a.   Subjects 18 years of age or older (index cases and relatives): It is estimated that 
100 mL will be drawn in one blood draw (but never exceeding 10.5 mL/kg or 550 
ml (whichever is smaller) over any 8-week period. 
• 
24-Hour Fast: Subjects may experience hunger, headache, fatigue, or irritability 
during fasting.  Subjects will be instructed not to take Acetaminophen (Tylenol®). 

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Acetaminophen is usually well tolerated in prescribed dose, but when taken during 
fasting may cause of drug-induced liver disease and acute liver failure. The first 
symptoms of liver damage are seen in the initial 12 to 24 hours or so after ingestion 
and include nausea and vomiting. 
• 
Urine collection: There is no risk associated with this procedure. 
Nicotinamide Riboside: NR is a dietary supplement that is currently available for 
commercial use with no safety concerns noted to date.  Consecutive doses of 1000mg 
daily of NR has not been reported in humans although there is currently an ongoing 
study at the University of Colorado using 1000 mg daily for 6 weeks.  Based on the 
structural similarities between NR and nicotinamide, and that nicotinamide is a 
downstream metabolite of NR digestion, it is assumed that any unexpected adverse 
effects of NR may be similar to those associated with nicotinamide intake. The safety 
profile of nicotinamide has been well established in multiple species and provides 
reasonable certainty that the administration of doses of NR up to 1000 mg will not 
result in an adverse health effect.  No significant adverse effects have been reported in 
clinical trials which have used doses up to the equivalent of 3000 mg/day for up to 3 
years to evaluate the possible benefits of nicotinamide administration to patients with 
or at risk of developing Type 1 diabetes.10, 11 In addition, doses of 25 and 42 mg/kg 
bw/day had no effect on a variety of biochemical parameters, such as those that 
assessed liver and kidney function. 
 
Consent Processes and Documentation for Research Subjects 
 
Each participant 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.  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. 
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 2 
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 2, 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. 
Consent Processes and Documentation for NIH Staff 
 

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If the individual requesting to participate in the protocol is a co-worker, the consent from the 
employee (co-worker) will not be obtained by the research coordinator or the staff member’s 
direct supervisor but by another research staff member who is approved for obtaining informed 
consent, and who is also not a coworker. NIH staff will be given the NIH Information Sheet on 
Staff Research Participation (See appendix A) to help them understand the possible consequences 
of participation. 
 
14. Conflict of Interest 
 
None of the members of the research team reported a potential conflict of interest.  The National 
Institutes of Health reviews NIH staff researchers at least yearly for conflicts of interest. The 
following link contains details on this process http://ethics.od.nih.gov/forms/Protocol-Review-  
Guide.pdf. This protocol has a CRADA with ChromaDex, Inc. 
 
15. Reimbursement for Travel 
 
As the study populations will be local, reimbursement for travel, food, and lodging will not be 
provided. 
 
16. Financial Compensation 
 
Subjects will be compensated for procedures that are performed that are of no direct benefit to 
the subject, although would be of generalizable benefit to enhance our understanding of 
Participants will be compensated as described in the table below: 
 
Procedures 
Inconvenience 
Units 
Compensation 
per procedure 
Frequency 
Total 
Compensation 
Medical History and physical examination 
2.5 
$25.00 
1 
$25.00 
Outpatient Visit (first hour) 
2 
$20.00 
3 
$60.00 
Outpatient Visit (additional hours up to 4 
hours) 
1 
$10.00 
8 
$80.00 
Screening Blood Draw (if needed) 
1 
$10.00 
1 
$10.00 
Research Blood Draw 
2.5 
$25.00 
4 
100.00 
24-Hour Fast 
15 
$150.00 
2 
$300.00 
Urine Sample 
1 
$10.00 
3 
$30.00 
Drug administration, General 
2 
$20.00 
14 
$280 
Maximum Compensation: 
$885.00 
 
 

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17. References 
 
1. 
Traba J, Kwarteng-Siaw M, Okoli TC, Li J, Huffstutler RD, Bray A, Waclawiw MA, Han 
K, Pelletier M, Sauve AA, Siegel RM, Sack MN. Fasting and refeeding differentially 
regulate nlrp3 inflammasome activation in human subjects. The Journal of clinical 
investigation. 2015 Nov 3;125(12):4592-600. 
2. 
Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez- 
Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, 
Schoonjans K, Sauve AA, Auwerx J. The nad(+) precursor nicotinamide riboside 
enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell 
Metab. 2012;15:838-847 
3. 
Brown KD, Maqsood S, Huang JY, Pan Y, Harkcom W, Li W, Sauve A, Verdin E, 
Jaffrey SR. Activation of sirt3 by the nad(+) precursor nicotinamide riboside protects 
from noise-induced hearing loss. Cell metabolism. 2014;20:1059-1068 

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4. 
Sack MN, Finkel T. Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harbor 
perspectives in biology. 2012;4 
5. 
Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly 
effective in reducing the risk for atherosclerosis in humans. Proceedings of the National 
Academy of Sciences of the United States of America. 2004;101:6659-6663 
6. 
Fontana L, Partridge L. Promoting health and longevity through diet: From model 
organisms to humans. Cell. 2015;161:106-118 
7. 
Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin b3 with 
effects on energy metabolism and neuroprotection. Current opinion in clinical nutrition 
and metabolic care. 2013;16:657-661 
8. 
Erdman JW, MacDonald I, Zeisel SH, International Life Sciences Institute. Present 
knowledge in nutrition. Ames, Iowa: International Life Sciences Institute; 2012. 
9. 
Benyo Z, Gille A, Kero J, Csiky M, Suchankova MC, Nusing RM, Moers A, Pfeffer K, 
Offermanns S. Gpr109a (puma-g/hm74a) mediates nicotinic acid-induced flushing. The 
Journal of clinical investigation. 2005;115:3634-3640 
10. 
Pozzilli P, Visalli N, Signore A, Baroni MG, Buzzetti R, Cavallo MG, Boccuni ML, Fava 
D, Gragnoli C, Andreani D, et al. Double blind trial of nicotinamide in recent-onset iddm 
(the imdiab iii study). Diabetologia. 1995;38:848-852 
11. 
Lampeter EF, Klinghammer A, Scherbaum WA, Heinze E, Haastert B, Giani G, Kolb H. 
The deutsche nicotinamide intervention study: An attempt to prevent type 1 diabetes. 
Denis group. Diabetes. 1998;47:980-984 

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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. 
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 

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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.