Pilot Study to Evaluate the Effect of Nicotinamide Riboside on Immune Activation in Psoriasis
Phase: NA
Conditions: Psoriasis, Atherosclerotic Cardiovascular Disease, Obesity, Dyslipidemia, Cardiometabolic Diseases
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
Pilot Study to Evaluate the Effect of Nicotinamide Riboside on Immune 
Activation in Psoriasis 
NCT number: 
 
NCT04271735 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
July 21, 2023 
 
 

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Abbreviated Title: NR in psoriasis 
Protocol: 20H0044 (P194768) 
Version Date: July 21, 2023 
 
Title: Pilot Study to Evaluate the Effect of Nicotinamide Riboside on Immune Activation in 
Psoriasis 
 
 
NIH Principal Investigator: Michael N. Sack, MD, Ph.D. 
Cardiovascular Branch, NHLBI 
Building 10-CRC, Rm 5-3342 
10 Center lane, 
Bethesda, MD 20892 
Phone: 301-402-9259 
E-mail: sackm@nih.gov 

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TABLE OF CONTENTS 
Contents 
TABLE OF CONTENTS ............................................................................................................................... 2 
STATEMENT OF COMPLIANCE ............................................................................................................... 5 
1 
PROTOCOL SUMMARY ..................................................................................................................... 6 
2 
INTRODUCTION ............................................................................................................................... 11 
2.3.1 
Known Potential Risks .................................................................................................................. 14 
Known Potential Benefits ............................................................................................................................ 15 
2.3.2 
Assessment of Potential Risks and Benefits .................................................................................. 15 
3 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 15 
5. 
STUDY POPULATION ...................................................................................................................... 17 
Rationale for the exclusion of pregnant women .......................................................................................... 18 
Rationale for the exclusion of cognitively impaired subjects ...................................................................... 18 
5.6.1 
Costs .............................................................................................................................................. 19 
5.6.2 
Compensation ................................................................................................................................ 19 
6 
STUDY INTERVENTION .................................................................................................................. 19 
6.1.1 
Study Intervention Description ...................................................................................................... 19 
6.1.2 
Dosing and Administration ........................................................................................................... 20 
6.1.3 
Dose Escalation ............................................................................................................................. 20 
6.1.4 
Dose Limiting Toxicity ................................................................................................................. 20 
6.1.5 
Dose Modifications ....................................................................................................................... 20 
6.1.6 
Drug Administration ...................................................................................................................... 20 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY .................................................... 20 
6.2.1 
Acquisition and Accountability ..................................................................................................... 20 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .................................................................... 20 
6.2.3 
Product Storage and Stability ........................................................................................................ 21 
6.2.4 
Preparation .................................................................................................................................... 21 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .................................. 21 
6.4 STUDY INTERVENTION COMPLIANCE ....................................................................................... 21 
6.5 CONCOMITANT THERAPY ............................................................................................................. 21 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 

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DISCONTINUATION/WITHDRAWAL ............................................................................................ 21 
7.1 Discontinuation Of Study Intervention ................................................................................................ 21 
7.3 LOST TO FOLLOW-UP ..................................................................................................................... 22 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 22 
8.2.1 
Clinical Evaluations ...................................................................................................................... 23 
8.2.2 
Biospecimen Evaluations .............................................................................................................. 23 
8.2.3 
Correlative Studies for Research/Pharmacokinetic Studies .......................................................... 24 
8.2.4 
Samples for Genetic/Genomic Analysis ........................................................................................ 24 
8.4.1 
Definition of Adverse Event .......................................................................................................... 24 
8.4.2 
Definition of Serious Adverse Events (SAE) ................................................................................ 24 
8.4.3 
Classification of an Adverse Event................................................................................................ 25 
8.4.3.2 
Relationship to Study Intervention......................................................................................... 25 
8.4.3.3 
Expectedness .......................................................................................................................... 26 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ............................................. 26 
8.4.5 
Adverse Event Reporting............................................................................................................... 27 
8.4.6 
Serious Adverse Event Reporting .................................................................................................. 27 
8.4.7 
Events of Special Interest .............................................................................................................. 27 
8.4.8 
Reporting of Pregnancy ................................................................................................................. 28 
8.5.1 
Definition of Unanticipated Problems (UP) .................................................................................. 28 
8.5.2 
Unanticipated Problem Reporting ................................................................................................. 28 
8.5.3 
NIH Intramural IRB Reporting of IND Safety Reports ................................................................. 29 
9 
STATISTICAL CONSIDERATIONS ................................................................................................. 29 
9.3 POPULATIONS FOR ANALYSES .................................................................................................... 30 
9.3.1 
Evaluable for toxicity .................................................................................................................... 30 
9.3.2 
Evaluable for objective response ................................................................................................... 30 
9.4 STATISTICAL ANALYSES ............................................................................................................... 30 
9.4.1 
General Approach .......................................................................................................................... 30 
9.4.2 
Analysis of the Primary Endpoints ................................................................................................ 30 
9.4.3 
Analysis of the Secondary Endpoint(s) ......................................................................................... 30 
9.4.4 
Safety Analyses ............................................................................................................................. 30 
9.4.5 
Baseline Descriptive Statistics ...................................................................................................... 30 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................................... 30 

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10.1 INFORMED CONSENT PROCESS ................................................................................................... 30 
10.1.1 
Consent/Assent Procedures and Documentation ........................................................................... 30 
10.1.2 
Consent for minors when they reach the age of majority .............................................................. 31 
10.1.3 
Telephone consent ......................................................................................................................... 31 
10.1.4 
Participation of Subjects who are/become Decisionally Impaired N/A ......................................... 31 
10.1 STUDY DISCONTINUATION AND CLOSURE .............................................................................. 32 
10.2 CONFIDENTIALITY AND PRIVACY .............................................................................................. 32 
10.3 FUTURE USE OF STORED SPECIMENS AND DATA .................................................................. 33 
10.4 SAFETY OVERSIGHT ....................................................................................................................... 33 
10.5 CLINICAL MONITORING ................................................................................................................ 33 
10.6 QUALITY ASSURANCE AND QUALITY CONTROL ................................................................... 33 
10.7 DATA HANDLING AND RECORD KEEPING ................................................................................ 34 
10.8.1 
Data Collection and Management Responsibilities ....................................................................... 34 
10.8.2 
Study Records Retention ............................................................................................................... 34 
10.8 PROTOCOL DEVIATIONS ............................................................................................................... 34 
10.9 PUBLICATION AND DATA SHARING POLICY ........................................................................... 35 
10.10.1 
Human Data Sharing Plan ...................................................................................................... 35 
10.10.2 
Genomic Data Sharing Plan ................................................................................................... 35 
10.10 
COLLABORATIONS AND AGREEMENTS ............................................................................. 35 
10.11.1 Agreement Type .............................................................................................................................. 35 
10.11 
CONFLICT OF INTEREST POLICY .......................................................................................... 35 
11 ABBREVIATIONS ............................................................................................................................. 36 
12 REFERENCES .................................................................................................................................... 37 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
x United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval. Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form 

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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
Pilot Study to Evaluate the Effect of Nicotinamide Riboside on 
Immune Activation in Psoriasis 
Study Description:          Psoriasis is a Th17 linked inflammatory disease and we find that the 
vitamin B3 analogue nicotinamide riboside (NR) blunts Th1 and Th17 
activation in ex-vivo naïve and differentiated T cells from control and 
psoriasis subjects. These findings supported the proposal of the 
following hypothesis. Supplementation with NR will blunt systemic 
immune activation in mild/moderate psoriasis. 
Objectives: 
1) Evaluate the effect of NR on Th17 biology 
2) Explore the effect of NR on neutrophils, specifically low- 
density granulocytes 
3) Evaluate whether NR modulates keratinocyte activation in skin 
lesions in psoriatic subjects 
4) Evaluate the effect of NR on HDL regulated reverse 
cholesterol transport and lipid composition 
 
Endpoints: 
The primary outcome will be the change in the TH17 cell cytokine IL- 
17 secretion in response to T-cell differentiation comparing the 
baseline versus NR or placebo. The comparisons will be performed 
using paired two-tailed Student t-tests. Significance will be tested at 
the 0.05 alpha level in this pilot study. 
Exploratory outcomes are: 
1) Evaluate the effect of NR on the T cell transcriptome 
2) Explore the effect of NR on low-density granulocytes and 
neutrophils 
Study Population: 
Up to 40 male and female subjects of all races between the ages of 
18-80 years with mild-moderate psoriasis who live locally will be 
screened. 
Phase: 
N/A 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Enrollment and study visits will take place at the NIH Clinical Center 
or via telehealth visits . 
Psoriatic Subjects 

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Description of Study 
Intervention: 
Nicotinamide Riboside Chloride 500mg or placebo twice daily by 
mouth for 28 days. 
 
Study Duration: 
            3 years 
Participant 
Duration: 
5-23 weeks 

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1.2
SCHEMA
Day -120 to Day -1 
Screening
Nicotinamide Riboside
N=18
Day 0 
Randomization
(Baseline)
Day 28
Visit 2 
Day 29 to 35
Safety Visit (if
applicable)
# in-clinic
or 
telehealth
visit =2
Placebo N=9

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
EVALUATION AND ASSESSMENTS 
 
 
Screening 
(A) 
 
 
Baseline 
Visit* 
 
28 day 
Visit * 
 
Safety visit (if 
applicable) 
PROTOCOL TIMEPOINT VISITS 
 
 
 
1 
2 
3 
 
 
 
 
D0 
D28 
 
 
Window +/- days 
 
-120Days 
 
 
+/- 7 D 
 
Assessments & Consents 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
 
x 
 
 
 
 
Medical History 
 
x 
 
 
 
 
Physical Examination 
 
X3 
 
X3 
X3 
X3 
Medication Review 
 
x 
 
x 
x 
 
Vital Signs 
 
 
 
X3 
X3 
X3 
Consent to Study 
 
x 
 
x 
 
 
Adverse Event Review 
 
 
 
 
x 
x 
CHEMISTRY LABS 
 
 
 
 
 
 
Female, Pregnancy Test (blood or urine) 
 
x1 
 
x1 
x1 
 
Acute Care Panel 
 
x 
 
x 
x 
x 
Mineral Panel 
 
 
 
x 
x 
x 
Hepatic Panel 
 
x 
 
x 
x 
x 
hs-CRP 
 
 
 
x 
x 
x 
Uric Acid 
 
x 
 
 
 
 
Fasting Lipid Panel 
 
 
 
x 
x 
 
HEMATOLOGY LABS 
 
 
 
 
 
 
CBC with differential 
 
x 
 
x 
x 
x 
Research Samples 
 
 
 
 
 
 
PBMC’s 
 
 
 
x 
x 
 
Serum 
 
 
 
x 
x 
 
Procedures 
 
 
 
 
 
 
Skin Punch Biopsy (lesion and non-lesion) 
 
 
 
X3 
X3 
 
PASI (Psoriasis Area and Severity Index) 
 
x 
 
 
 
 
Study Medication 
 
 
 
 
 
 
Dispense study pills 
 
 
 
x 
 
 
Compliance (pill count) 
 
 
 
 
x2 
 
Return of study pills 
 
 
 
 
x 
 
 
 
 
 
 
 
 
A. Labs and assessments may be used for baseline visit if performed within 14 days 
B. Unscheduled safety visit for those patients with clinically significant ongoing adverse events from month 1 visit 
or reported to site within 7 days from last dose of study drug. All procedures or testing noted above are optional. 
x1 = Pregnancy testing for women with childbearing potential 
x3 = Optional 
x2 = compliance to be greater than or equal to 75% 
*Study visits are defined by the period of time necessary to complete events described in the protocol and may span 
several days. 

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All study visits may be performed in person at the NIH CC or virtually using NIH approved 
TeleMedicine software and approved NIH TeleMedicine guidance. In the event the subject is 
not able to come to the NIH CC the consent may be obtained by phone, vital signs are optional 
and reported based on subject’s own measurements (if possible), physical exam is optional and 
none of these changes will be considered a protocol deviation. If there are remaining tablets, 
they will be returned to the research team at first possible opportunity following NIH pharmacy 
direction. 

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2 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Over the past two decades, inflammation has been identified as an important pathogenic process in 
cardiometabolic diseases (CMD) such as atherosclerotic cardiovascular disease (CVD), 
dyslipidemia, insulin resistance, diabetes and obesity. Over the last eight years, the Mehta 
laboratory within the NHLBI DIR has studied psoriasis, a common, chronic inflammatory T-cell 
skin disease associated with increased CVD and CMD as a model to understand the effect of 
chronic inflammation on these disease states. At the same time, the degree of obesity has been 
linked to the severity of psoriasis and caloric restriction ameliorates dermatologic manifestations 
of this disease. The Sack laboratory is studying the effects of caloric restriction on immune 
activation and is demonstrating the caloric-restriction mimetic vitamin B3 analogue nicotinamide 
riboside (NR) blunts both adaptive and innate immunity. Furthermore, the in-vitro administration 
of NR to CD4+ T cells extracted from psoriatic subjects blunts IL-17 production. Given this, these 
two laboratories will collaborate in a pilot study to evaluate whether the administration of a 
nutritional supplement NR has anti-inflammatory effects in a small cohort of subjects that have 
untreated mild to moderate psoriasis. 
 
2.2 
BACKGROUND 
Psoriasis is a chronic inflammatory skin disease that affects 2–3% of the US population. In addition to 
its skin and joint manifestations, psoriasis predisposes to premature cardiovascular co- morbidities 
in part through immune activation and systemic inflammation-induced atherosclerosis.1, 2 The skin- 
initiated immune activation through non-professional immune cells including keratinocytes and 
fibroblasts, initiates and amplifies innate and adaptive immune activity of monocytes/macrophages, 
neutrophils and their subsets (low-density granulocytes), and effector T-cells (predominantly Th1 
and Th17 subsets) which concurrently exacerbate local disease and initiate systemic sterile 
inflammation. The centrality of immune activation in psoriasis is reinforced by the therapeutic 
efficacy of anti-TNFD and anti-IL-17 therapy.3-5 
The contribution of caloric-load to psoriasis has been long debated, however, epidemiology and 
meta-analysis data support that the incidence of obesity is higher in psoriasis and that the greater the 
severity of psoriasis, the higher the incidence of obesity.6-8 The role of caloric excess in the 
pathophysiology of psoriasis is further strengthened by the effects of limiting calories on disease 
activity.9-11 Taken together, these data support that nutrient levels may play a role in the 
pathophysiology of psoriasis and at the same time employing strategies to mimic caloric 
restriction/fasting may contribute to disease-amelioration. 
The Sack laboratory employs fasting as a model system to investigate immune cell function and 
have identified biological pathways that explain how fasting blunts immune activation in 
monocytes/macrophages and CD4+ T cells in both healthy subjects and in those with a mild 
inflammatory disease (steroid-naïve asthma subjects). More recently we have begun to explore the 
role of a caloric restriction/fasting mimetic, nicotinamide riboside (NR – a vitamin B3 analogue and 
precursor for NAD+ biosynthesis) on immune modulation. Our initial clinic study using 1000 mg of 
NR daily blunted immune pathways important in CVD both in monocytes and CD4+ T cells, however, 
we did not investigate the effects of NR on neutrophils. 

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Given that these cell types contribute to the pathophysiology of psoriasis and that disease activity
may be ameliorated by dietary restriction, we reasoned that NR may blunt psoriasis-linked immune
activation pathways. To explore this, a collaboration was established with the Mehta laboratory and
the in-vitro effects of NR were tested on CD4+ T cells extracted from biologic treatment-naïve
psoriatic subjects. NR was found to bOXQWWKHVHFUHWLRQRI,)1ȖDQG,/-17, predominantly Th1 and
Th17 cytokines respectively. Because these cytokines are instrumental in the progression of the
dermatologic, systemic and vascular consequences in psoriasis, we propose a pilot interventional
study to explore the immunological consequences of NR supplementation in biologic naïve, mild to
moderate psoriatic subjects.
Preliminary Data:
To study the effect of NR on T cell function, blood was drawn from psoriatic subjects enrolled
on protocol 13-H-0065 and from matched normal control subjects enrolled on protocol 16-H-0126. 
Psoriatic subjects were biological anti-immune therapy naïve. Primary peripheral blood mononuclear 
cells (PBMCs) were isolated by density centrifugation. CD4+ T cells were then negatively selected 
from PBMCs and cell purity was confirmed at > 95%. 
CD4+ T cells were activated in culture on plates coated with DCD3 and DCD28 antibodies for
3 days in the presence or absence of 0.5mM NR. Alternatively they were differentiated into two T
cell subtypes by incubation with the specific polarization media ( ± NR) - Th1 (20 ng/ml IL-12 and
10 Pg/ml DIL-4) and Th17 (20 ng/ml IL-6, 2 ng/ml TGF-E1, 10 ng/ml IL-1E, 10 ng/ml IL-23, 10 
Pg/ml DIL-4, and 10 Pg/ml DIFNJ). Supernatants were collected, centrifuged to remove cells and
debris, and stored at í& The levels of cytokines, including IL-1E, IFNJ, IL-4, IL-5, IL-13, IL-17,
IL-22, IL-9, IL-2, and MIP-1E were measured by ELISA (R&D Systems). Results were normalizedto
cell number using the CyQuant cell proliferation and BCA protein assays.
A 
5000
4000
3000
B 
1500
1000
2000
1000
500
0
PSC 
PS 
0
PSC 
PS 
**
**
*
**
*
IFN Release in Th0 cells (pg/ml)
IL-17 Release in Th0 cells(pg/ml)

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*
*
C                                                               D 
15000
5000
10000 
5000 
4000 
3000 
2000 
1000 
0
PSC 
PS 
0
PSC 
PS 
*
**
**
IFN Release in Th1 cells (pg/ml)
IL-17 Release in Th17 cells (pg/ml)

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Figure Legend: A, B. IFNJ and IL-17 release in activated CD4+T cells isolated from Psoriatic subjects (PS) and control 
subjects (PSC). CD4+T cells was activated with 0.5 mM NR and 10% autologous serum for 3 days by DCD3 and 
DCD28 (n=7). C, D. IFNJ and IL-17 release in differentiated CD4+T cells isolated from Psoriatic subjects (PS) and 
control subjects (PSC). CD4+T cells was differentiated with 0.5 mM NR and specific differentiation media with 
autologous serum for 3 days by DCD3 and DCD28 (n=6). Th1 differentiation supplement (Stemcell Technologies), Th17 
differentiation supplement (R&D). PS age (y), 54.43±14.41 (range: 32-72); PS gender, 1 female and 6 males. Healthy 
volunteers (PSC) were paired with the psoriatic subjects for age (± 5 years) and sex. P value *<0.05 and **<0.01. 
 
These data show that NR blunts Th1 and Th17 activation in naïve and differentiated T cells and that 
the psoriatic subjects exhibited elevated IL-17 responsiveness, which is a consistent signature of this 
disease. These findings supported the proposal of the following hypothesis. 
 
2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 
Known Potential Risks 
Niagen has been sold as a dietary supplement in the United States since 2003. Labeling guidelines 
recommend consumers to limit their intake to 2 capsules/day (250 mg/day). This recommended 
level is the equivalent of 3.8 mg/kg body weight/day, which is 1000-fold less than the highest 
dose determined to be safe and well tolerated in rats, and there is no limit on the duration of 
ingestion. 
 
There is extensive literature on the beneficial effects of NR in animal models,12, 13 and multiple 
lines of non-clinical data suggest that it should be well tolerated in human subjects. 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). The NR dose proposed for this study is within 
the doses tested in mice for up to 4 months and is 300-fold below the daily dose that was given in 
rats in a 14-day dose range finder study. There are also accumulating data on the 
pharmacokinetics and safety of orally administered NR in humans. Recently, a 2 x 6-week 
randomized, double-blind, cross-over study was performed to assess the tolerability of chronic NR 
supplementation and its efficacy for increasing NAD+ bioavailability. Here the oral administration 
of NR 500 mg twice daily (total 1000 mg daily, Niagen, ChromaDex, Inc.) was well tolerated, 
readily absorbed, and detectable in human plasma, white blood cells, and urine.14 In a 
pharmacokinetic study of 8 healthy volunteers at the University of Washington, Seattle, the oral 
dose of NR dose was escalated from 250 mg daily to 1000 mg twice daily over a 9-day period 
with a resultant 100% increase in blood NAD+ content that highly correlated to NR levels.15 No 
adverse events were associated with NR treatment in either of these two published human studies. 
 
Niacin is a form of vitamin B3 and has been used to treat hypercholesterolemia and pellagra for 
many years. Niacin administration can lead to undesirable effects such as spontaneous flushing, 
but based on its pharmacology, NR would not be predicted to give this side effect.16, 17 Indeed, the 
incidence of flushing side effect with NR treatment was not different compared with placebo in 
the double-blind study.18 Nicotinamide, an expected metabolite of NR, is considered to be 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). Clinical trials of 
nicotinamide up to 3000 mg daily and 3 years in patients with or at risk of developing Type 1 
diabetes have not reported significant adverse effects.19, 20 In addition, doses of 25 and 42 mg/kg 
body weight per day had no effect on a variety of biochemical parameters including those 
assessing liver and kidney function. 
 

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In summary, careful analysis of the available information on NR does not reveal any potential 
serious toxicity that would preclude its use in psoriasis subjects. Given the safety and tolerability 
of NR in published human studies,18, 21 and the favorable experience with NR in our NHLBI DIR 
protocol (16-H-0129, discussed in Background section), we propose to test the effect of NR in 
psoriasis patients at a dose 500 mg twice daily, a dose that is less than what is currently approved 
for use in other active clinical studies of the aforementioned groups. 
 
The only tests and procedures done under this study are skin biopsies (optional), blood draws, 
and urine collection. The individual study procedure risks are listed below. 
Skin biopsy: Two 4mm or smaller biopsies may be collected at visit 1 and visit 2 for a total of 
four skin biopsies. This procedure will be performed under local anesthesia. The entire procedure 
takes approximately 20 minutes. Discomfort at the biopsy site is usually mild and transient. This 
can be treated with minor analgesics. Normally, the risks include a reaction to the local anesthetic 
and the slight possibilities of local bleeding or infection. Scarring always occurs at the biopsy site. 
 
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. The quantities of blood to 
be drawn for research purposes will be less than 550ml, which is consistent with the CC policy as 
provided in Medical Administrative Series (MAS) 95-9 (revised 5/29/12): for adults, no more than 
10.5mL/kd or 550ml (whichever is smaller) will be drawn for research purposes over any 8 week 
period. 
 
Known Potential Benefits 
This supplement study has no prospect of direct benefit. 
2.3.2 Assessment of Potential Risks and Benefits 
The risks of the study supplement and the minor procedures included in this protocol are 
minimal and justified by the potential benefit of expanding our understanding of how nutrient 
levels may play a role in the pathophysiology of psoriasis and at the same time employing 
strategies to mimic caloric restriction/fasting may contribute to disease-amelioration. This 
supplement has been employed at the same or higher doses in numerous studies without any 
reported adverse effects.14, 18, 21 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
The primary outcome will be the change 
NR blunts Th1 and Th17 
Evaluate the effect of NR on Th17 
in the TH17 cell cytokine IL-17 secretion 
activation in naïve and 
biology 
in response to T-cell differentiation 
comparing the baseline to NR response. 
differentiated T cells and 
psoriatic subjects exhibit 
 
 
elevated IL-17 
 
 
responsiveness, which is a 
 
 
consistent signature of this 

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disease. 
Exploratory 
 
 
 
 
The primary driver of 
psoriasis does appear to be 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Explore whether other inflammatory 
components linked to psoriasis are 
affected by NR. 
 
Evaluate the effect of NR on the T 
cell transcriptome 
 
Explore the effect of NR on neutrophils, 
specifically low-density granulocytes 
 
 
Th17, however, other 
immune signals and cell 
types are linked to psoriasis 
including, neutrophil 
activation, skin 
keratinocyte activation and 
the accumulation of HDL 
in monocytes/macrophages 
is proposed to trigger 
inflammatory pathways. 
We will explore the effect 
of NR on modulating these 
cell types and pathways as 
exploratory end points 
 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This study is a pilot, prospective, two-arm double-blind, placebo-controlled study where subjects 
immunological profile will be studied at baseline and following 4 weeks of supplementation with 
NR or placebo. The allocation of NR: placebo will be 2:1. All enrolled subjects will receive NR or 
placebo and following 4 weeks of supplement or placebo intake, research parameters will be 
compared to baseline to determine the effects of this intervention. 
 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This is a pilot study and the number of subjects were chosen to allow us to have sufficient 
samples to use RNAseq analysis to explore the effects of NR on T cell biology if the primary 
outcome of the study is confirmed. 
 
4.2 
JUSTIFICATION FOR DOSE 
Recently, a 2 x 6-week randomized, double-blind, cross-over study was performed to assess the 
tolerability of chronic NR supplementation and its efficacy for increasing NAD+ bioavailability 
by investigators at the University of Colorado, Boulder.14 They demonstrated that the oral 
administration of NR 500 mg twice daily (total 1000 mg daily, Niagen, ChromaDex, Inc.) was 
well tolerated, readily absorbed, and detectable in human plasma, white blood cells, and urine. 

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5. STUDY POPULATION 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
All protocol eligibility criteria will be met before dispensing study medication to participants or 
conducting the biopsy for the baseline visit. Patients will sign the consent prior to any screening 
tests/procedures done as part of this protocol. 
 
5.1 INCLUSION CRITERIA 
Individuals must meet all inclusion criteria listed below in order to be eligible to participate in 
the study. 
x Males and females between the ages of 18 and 80 with mild to moderate active psoriasis. 
x Female subjects of child-bearing ability willing to commit to reliable contraception while 
participating in the study. 
x Ability to provide informed consent 
x Willingness and ability to participate in required study procedures 
 
5.2 EXCLUSION CRITERIA 
x Severe psoriasis by PASI (Psoriasis Area and Severity Index) score > 12 
x Currently being treated with biologic immune modifying agents. 
x Currently on treatment for allergies or other inflammatory diseases. 
x 
 Currently taking a multivitamin, Vitamin B or tryptophan supplementation and unwilling to stop 
within 2 weeks of baseline visit.. 
x Unwillingness/inability to provide informed consent 
x ALT > x3 upper limit of normal, hepatic insufficiency or active liver disease 
x Recent history of acute gout 
x Chronic renal insufficiency with creatinine > 2.5mg/dl 
x Pregnant (or attempting to become pregnant) women 
x Current participation in another drug study 
x History of intolerance to NR precursor compounds, including niacin or nicotinamide 
x Study adherence concerns 
x Individuals with diabetes type 1 and 2 who use insulin 
x Women of child-bearing potential unwilling to use contraception or unwilling to practice 
abstinence 
x Breastfeeding women unwilling to stop breastfeeding 
x Immunization administered within 30 days of participation and no plans for immunization while 
participating in the study 
 
5.3 INCLUSION OF VULNERABLE PARTICIPANTS 
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 volumes of blood levels drawn exceed 

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minimal risk for children 
Rationale for the exclusion of pregnant women 
The subject 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 women. 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 
Subjects with cognitive impairment will not be considered for inclusion because there is no direct 
benefit from participating in this study. 
5.4 
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to: 
x Refrain from making major changes in dietary intake or physical activity 
during the 6 weeks of active study participation. 
 
5.5 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention. These subjects will sign consent and will 
receive a study id. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened at a later date at PI discretion. Individuals who do not meet criteria for participation 
based on an abnormal laboratory test result may be rescreened after one month. 
Rescreened participants will be assigned a new participant id number from the initial screening. 
 
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Subjects with mild to moderate psoriasis will be recruited from Dr. Mehta’s psoriasis clinic. We 
will also recruit subjects through NIH using traditional recruitment methods such as referrals from 
other protocols, outside physician referral and self-referral. 
With IRB approval the study may opt to use the following strategies for recruitment of patients: 
x ClinicalTrials.gov 
x Clinical Center Research Studies website 
x National Heart, Lung and Blood Institute (NHLBI) patient recruitment website 
x Twitter messages and chats with study investigators 
x Social Media posts 
x Use of CC Office of Patient Recruitment services including creation and 
distribution of study flyers and information through pre-existing recruitment 
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We expect to screen up to 40 subjects with a goal of 27 subjects (18 NR + 9 placebo) completing 
the study. 
5.6.1 
Costs 
There will be no anticipated costs that the subject will be responsible for. 
5.6.2 
Compensation 
Subjects will be compensated for some of the procedures that are performed since they may not 
provide direct benefit to the subject. They will be compensated by check or direct deposit at the end 
of the study or at the time of study withdrawal for the procedures completed. Payment will typically 
be received within 2 months of the last study visit. 
 
Procedures 
Convenience Units 
Compensation per 
procedure 
Frequency 
Total 
Compensation 
Medical History 
2.5 
$25.00 
1 
$25.00 
Screening Blood Draw (if needed) 
1 
$10 
1 
$10 
Research Blood Draw 
5 
$50.00 
2 
100.00 
Research skin biopsy 
5 
$50.00 
4 
$200.00 
Drug administration, General 
2 
$20.00 
28 
$560.00 
Maximum Compensation: 
$895.00 
 
Reimbursement for travel, food, and lodging will not be provided. 
 
6 
STUDY INTERVENTION 
6.2 
STUDY INTERVENTIONS(S) ADMINISTRATION 
6.1.1 
Study Intervention Description 
The study will use the dietary supplement Nicotinamide Riboside or a placebo capsule. Niagen®is a 
commercially-available form of nicotinamide riboside (NR). The nucleoside NR is a single chemical 
moiety containing nicotinamide and ribose.22 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 inthe gastrointestinal 
tract as part of dietary NAD+. Thus, humans are constantly exposed to NR from the diet, albeit at 
low levels. Considering the clinical investigation is designed to study the relationship between a 
dietary supplement’s effect on 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 

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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. 
 
6.1.2 Dosing and Administration 
N/A 
6.1.3 Dose Escalation 
N/A 
6.1.4 Dose Limiting Toxicity 
N/A 
6.1.5 Dose Modifications 
N/A 
6.1.6 Drug Administration 
Subjects will take two capsules by mouth (250mg NR capsules or placebo) twice daily for a total 
of 4 weeks (+/- up to 5 days if needed). Capsules must be taken whole and may be taken with or 
without food. Doses should be approximately 12 hours apart but there should be a minimum of 6 
hours between doses. If a dose is missed and it is more than 6 hours before the next dose is due 
then the dose can be taken. If a dose is missed and it is less than 6 hours before the next dose is 
due then the missed capsules should be skipped. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 Acquisition and Accountability 
Both the NR and placebo will be obtained from Chromadex. It will be stored and dispensed by the 
NIH CC Pharmacy. Unused product will be returned to the clinical center and destroyed. 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
Common name: Nicotinamide Riboside Chloride 
Product name: Niagen 
Chemical name: 3-(Aminocarbonyl)-1-ȕ-D-ribofuranosyl-pyridinium chloride (1:1) 
Daily dose: 1000 mg x 4 wk, 
Route of administration: oral 
Dosing instructions: 500 mg (2 capsules) twice daily Supply: Supplements will be obtained from Chromadex. 
Toxicology: None known 
 
Drug Interactions: None known 
The capsules will be put into individual bottles, labeled and dispensed by the NIH Clinical 
Center pharmacy. The label will include at a minimum the study ID and instructions for taking 
the supplement or placebo. 
The placebo will be manufactured and supplied by Chromadex to match the active supplement. 

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6.2.3 
Product Storage and Stability 
NR and placebo will be stored in the pharmacy at room temperature in light restricted containers. 
6.2.4 
Preparation 
N/A 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Dr. Myron Waclawiw (BioStatistical Co-Investigator on the study) will devise a randomization 
code . The code will be employed by the pharmacy to dispense the study pills. The study team will 
be blinded to the code until enrollment is complete and the assays performed for the primary end 
point. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Study capsule compliance will be assessed based on patient report and we will perform capsule 
count at Visit 2. If Visit 2 takes place remotely, the investigator will observe the research subject 
counting the remaining pills. Blood NAD+ metabolic intermediate levels will be tested at visit 2 to 
confirm compliance. 
6.5 CONCOMITANT THERAPY 
Subjects should not take any biologic immune modifying agents, other multivitamins, vitamin B 
or tryptophan supplements for the duration of the study. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation Of Study Intervention 
The supplement has a good safety record and we do not expect any significant adverse events. 
However, if a grade 3 or higher adverse event related to the supplement occurs, the study will be 
halted pending discussions with the NIH IRB and the NHLBI Clinical Director. 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
1) Subject taking less than 75% of their capsules 
2) Subject found to be pregnant or wishes to breastfeed during the study will automatically 
be withdrawn 
3) If subject no longer wish to participate 
4) Subject’s non-compliance or per PI discretion for development of a condition that may 
independently affects immune activity. 
Prior to removal from study, any subject who has started the study intervention should complete a 
safety visit. For subjects who complete the study, this would be included in Visit 2. If a subject 
requests withdrawal early for any reason, we will make every effort to have them complete an 

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unscheduled safety visit.. 
The reason for participant discontinuation or withdrawal from the study will be recorded in the 
source document. Subjects who sign the informed consent form and are randomized but do not 
receive the study intervention may be replaced. Subjects who sign the informed consent form, 
and are randomized and receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study, will be replaced until the recruitment goals of 18 NR 
and 9 placebo subjects have completed the protocol. Participants who are withdrawn for reasons 
that are temporary, such an infectious disease or administration of an immunization, may be re- 
screened and if they meet eligibility then re-enrolled with a new study id. 
 
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for the scheduled 
visits and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
x The site will attempt to contact the participant and reschedule the missed visit, specify 
time frame and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain if the participant wishes to and/or should continue in the 
study. 
x Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 attempts at contact) 
These contact attempts should be documented in the participant’s medical record or study 
file. 
x Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 
SCREENING PROCEDURES 
Subjects with mild to moderate psoriasis will be recruited from Dr. Mehta’s psoriasis clinic at the 
NIH or from outside and self- referrals If a subject is recruited from a source outside the NIH then 
the screening and/or baseline visit #1 will be in person. The remainder of the visits may be via 
telehealth. 
Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
• Email, written, in person or telephone communications with prospective subjects 
• Review of existing medical records to include H&P, laboratory studies, etc. 
 
Once the research team has identified a potential subject for the study, the subject will be asked to 
come to the NIH or complete a Telehealth Screening Visit. The study team will consent the subject, 
allowing time for the subjects to ask questions and make a voluntary decision. 
 

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Once the subject signs the consent, the following tests will be done at the Screening Visit unless any 
of the tests have been performed under another NIH protocol 2 weeks prior to signing the consent 
(unless otherwise stated). 
 
Screening Visit (May be combined with Visit 1): 
o Basic Metabolic Panel 
o Hepatic Panel + uric acid 
o CBC + Differential 
o Serum pregnancy test for women with childbearing potential (within the past 24 
hours) 
o History +/- physical exam (physical exam will not be performed at TeleHealth visit) 
 
8.2 
EFFICACY ASSESSMENTS 
This study is designed to study the relationship between a dietary supplement’s effect on structure 
or function in humans or to characterize the mechanism by which a dietary supplement acts to 
maintain such structure or function. It is not designed as an efficacy study. Therefore, visits will 
focus on safety assessments as well as the collection of research blood and skin biopsies 
(optional). These collections will be performed at the NIH CC phlebotomy department when 
feasible however collection at an outside laboratory, such as a commercial or hospital-based lab, 
may be arranged if needed. 
8.2.1 Clinical Evaluations 
Radiographic or other imaging assessments. 
N/A 
8.2.2 Biospecimen Evaluations 
Biological specimen collection and laboratory evaluations. In addition to the clinical blood 
samples, subject will have research bloods drawn within the blood withdrawal volume limits 
established by the Clinical Center. RNAseq, Flow cytometry, metabolomics, HDL cholesterol 
uptake and cytokine profiling may be performed. Skin biopsy samples may be obtained for 
culture or isolation of distinct cell populations for subsequent biochemical, cell biological and 
molecular analyses and for immune-histochemistry. With the patient’s consent, a biopsy each of 
lesional skin (where there is active psoriasis) and non-lesional sites (where there is no psoriasis) 
will be performed, and hemostasis will be achieved. The skin biopsy will be performed by a 
healthcare provider and will be used primarily for research purposes. 

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Test/assay 
Volume blood 
(approx.) 
Type of 
tube 
Collection 
point (+/- 
48hrs) 
Location of 
specimen analysis 
Immune- 
monitorin 
g 
80 mls for 
PBMC’s and 
NAD+. 
Green Tops for 
PBMC’s 
and NAD+ 
Baseline and 
4 weeks. 
10-CRC, 
Room 5-3216 Lab 
(Deliver to Dr. Sack’s 
lab) 
 
 
20mls for 
Neutrophils. 
 
Green Tops for 
Neutrophils 
 
 
 
20mls for low 
density 
granulocytes 
(LDG’s). 
 
Green Tops for 
LDG’s 
 
 
5-10mls (for 
serum) 
Red top 
 
HDL 
reverse 
transport 
2mls 
Purple top 
Baseline and 
4 weeks 
Dr. Mehta lab 
 
8.2.3 Correlative Studies for Research/Pharmacokinetic Studies 
N/A 
8.2.4 Samples for Genetic/Genomic Analysis 
N/A 
 
8.3 
SAFETY AND OTHER ASSESSMENTS 
Laboratory tests will be assessed at baseline and at 4 weeks. Adverse event review will occur at 4 
weeks. 
Counseling: Subjects should maintain a stable diet and not start any new diets or exercise 
programs for the duration of the study. 
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.4.1 Definition of Adverse Event 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.4.2 Definition of Serious Adverse Events (SAE) 

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An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life- 
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
8.4.3 Classification of an Adverse Event 
8.4.3.1 
Severity of Event 
This study will utilize the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 
v5.0) for toxicity and adverse event reporting. A copy of the CTCAE v5.0 can be downloaded from 
the https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
AEs classified as Grade 2-5 will be recorded, verified, and followed until satisfactory resolution or 
stabilization. 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 
Severity definitions found in the CTCAE v5.0 will be used for grading the severity (intensity) of 
AEs: 
1) Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2) Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL* 
3) Severe: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
4) Life- threatening: Life-threatening consequences; urgent intervention indicated. 
5) Death: Death related to AE. 
 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
8.4.3.2 Relationship to Study Intervention 
• All Grade 2-5 adverse events (AEs) must have their relationship to study intervention 
assessed by the investigator or designee who examines and evaluates the participant 
based on temporal relationship and his/her clinical judgment. The degree of certainty 

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about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician.] 
 
8.4.3.3 
Expectedness 
The PI or designee will be responsible for determining whether an adverse event (AE) is expected 
or unexpected. An AE will be considered unexpected if the nature, severity, or 
 
frequency of the event is not consistent with the risk information previously described for the study 
intervention. We expect some vasovagal symptoms during blood draws (expected frequency 50%) 
and transient bruising at the site of blood draws (expected frequency 50%). 
 
8.4.4 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 

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Investigators will assess the occurrence of AEs and SAEs at all patient evaluation time points 
during the study. Grade 2 – 5 AEs/SAEs whether volunteered by the patient, discovered by study 
personnel during questioning, or detected through physical examination, clinically significant 
laboratory test, or other means will be recorded on the appropriate case report form. .  
Information to be collected on Grade 2-5 AE/SAE includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
Grade 2-5 AEs will be followed to adequate resolution or stabilization. 
Abnormal laboratory values not associated with clinical symptoms (except  for grade 2 elevated liver 
enzymes) will be evaluated but will not be considered an AE. The laboratory results will be 
monitored by healthcare professionals and documented if clinically significant by the MD or any AIs 
in the study. 
Psoriasis is a chronic disease associated with flares and we will record this information in 
the medical record. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The PI or designee will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 days (for non-serious AEs or SAEs) after the last day of study 
participation. At each study visit, the team member will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution or 
stabilization. 
8.4.5 Adverse Event Reporting 
Grading and attribution of AE’s captured in the database will be determined by the Principal 
Investigator or Associate Investigator’s designated on the designation log. 
 
8.4.6 Serious Adverse Event Reporting 
The study investigator will immediately report to the NHLBI Clinical Director any serious 
adverse event, whether or not considered study intervention related, including those listed in the 
protocol and must include an assessment of whether there is a reasonable possibility that the 
study intervention caused the event. 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. 
Any SAE considered at least possibly related to the supplement will be reported to the DSMB 
within 14 days of the investigator being notified of the event. 
8.4.7 
Events of Special Interest 
N/A 
 
NIH Intramural IRB and NHLBI Clinical Director (CD) Reporting 

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Expedited Reporting 
Events requiring expedited reporting will be submitted to the IRB per HRPP Policy 801 
“Reporting Research Events”. 
 
Reports to the IRB at the time of Continuing Review (CR): 
The PI or designee will refer to HRPP Policy 801 “Reporting Research Events” to determine 
IRB reporting requirements. 
 
Reports to the CD: 
The PI or designee will refer to NHLBI DIR guidelines to determine CD reporting requirements 
and timelines. 
 
8.4.8 
Reporting of Pregnancy 
If pregnancy occurs during the course of this study a reportable event form will be submitted to 
the Clinical Director and the IRB. 
Pregnancy itself is not regarded as an SAE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Any SAEs associated with pregnancy (i.e. congenital abnormalities/birth defects/spontaneous 
miscarriages or any other serious events) must additionally be reported as such using the SAE 
report form. Monitoring of the pregnancy through chart review (per HIPPA guidelines) will 
continue until conclusion of the pregnancy, and then subject will be taken off study. 
8.5 
UNANTICIPATED PROBLEMS 
8.5.1 Definition of Unanticipated Problems (UP) 
Please refer to Policy 801 for current Definitions. 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and 
• Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected. 
8.5.2 
Unanticipated Problem Reporting 
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 

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(IRB) as per Policy 801. 
8.5.3 NIH Intramural IRB Reporting of IND Safety Reports 
N/A 
 
9 STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESIS 
Supplementation with NR will blunt systemic immune activation in mild/moderate psoriasis. 
 
Primary Endpoint(s): The primary outcome will be the change in the TH17 cell cytokine IL-17 
secretion in response to T-cell differentiation comparing the baseline to NR response after 28 days. 
Exploratory Endpoint(s): 
o Evaluate the effect of NR on the T cell transcriptome 
o Explore the effect of NR on low-density granulocytes and neutrophils 
9.2 
SAMPLE SIZE DETERMINATION 
Sample size calculations for this pilot study were based on the two-sample t-test assuming equal 
variances with a two-sided alpha of 0.05 and a 2:1 (unequal) allocation of subjects NR: placebo. A 
previous in-vitro study (unpublished to data) yields data for IL-17 levels (pg/ml) for T-cells 
extracted from psoriatic subjects at baseline and after 72 hours of exposure to 0.5 mM 
nicotinamide riboside (NR). The observed mean change in IL-17 cytokine release was 329 pg/ml 
(from 600 to 271 pg/ml) with a standard deviation of 185.74 for the 72-hour changes. For the 
proposed in-vivo study, we assume a similar change in mean IL-17 (and standard deviation) for 
psoriatic subjects treated with NR for 4 weeks. For the control subjects receiving placebo, we 
assume a mean baseline to 4 weeks change in IL-17 of 0 and an equal standard deviation of 
185.74 for the 4-week changes. 
 
In the table below, we present power calculations for various scenarios. With 18 subjects on NR 
and 9 on placebo, the study will have 98% power to detect a difference of 329 pg/ml in the mean 
baseline to 4-week changes between the two study groups (scenario 1). Note that there will still be 
82% power to detect a smaller mean difference of 229 pg/ml between the two study arms (a 100 
pg/ml difference less than that achieved in the in-vitro study) should the control subjects exhibit 
up to a 100 pg/ml decrease in IL-17 due to a placebo effect (scenario 2). Furthermore, even with a 
loss to follow-up of 3 subjects (2 in the NR arm, 1 on placebo), the study will have 97% power to 
detect a mean change of 329 pg/ml (scenario 3), and a reduced power just under 80% for a strong 
placebo effect with a mean difference = 229 pg/ml (scenario 4). Therefore, we request approval to 
screen up to a total of 40 subjects to account for possible treatment non- compliance and/or study 
dropouts (18 NR + 9 placebo completing study) and to achieve the objectives of this pilot study. 
 
Scenario 
 
1 
2 
3 
4 
#Subjects treated with NR 18 
18 
16 
16 
# subjects on placebo 
9 
9 
8 
8 
Difference in means 
329 
229 
329 229 
Power 
98% 
82% 97% 77% 
 

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9.3 
POPULATIONS FOR ANALYSES 
N/A 
9.3.1 Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with study 
supplement or placebo. 
9.3.2 
Evaluable for objective response 
N/A 
9.4 
STATISTICAL ANALYSES 
9.4.1 General Approach 
9.4.2 
Analysis of the Primary Endpoints 
The primary outcome will be the change in the TH17 cell cytokine IL-17 secretion in response to T- 
cell differentiation comparing baseline levels versus their respective response to NR or placebo. The 
comparisons will be performed using paired two-tailed Student t-tests or if the data is not normally 
distributed, by the Wilcoxon test. Significance will be tested at the 0.05 alpha level in this pilot study. 
9.4.3 
Analysis of the Secondary Endpoint(s) 
N/A 
9.4.4 
Safety Analyses 
N/A 
9.4.5 
Baseline Descriptive Statistics 
N/A 
 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS 
 
10.1 INFORMED CONSENT PROCESS 
 
10.1.1 
Consent/Assent Procedures and Documentation 
Informed consent will be conducted following OHSRP Policy 301- Informed Consent. 
An IRB-approved consent form will be provided to the participant electronically or by hard 
copy for review prior to consenting. The initial consent process as well as re-consent, when 
required, may take place in person or remotely (e.g., via telephone or other NIH approved 
platforms). The investigational nature and objectives of this trial, the procedures, and their 
attendant risks and discomforts and potential benefits will be carefully explained to the 
participant in a private setting. The participant will be given as much time as they need to 
review the document and to consult with their family, friends, and personal health care 
providers. In addition, a study team member will be available to answer any questions. 
A signed and dated informed consent document will be obtained by any investigator authorized 
to consent (See Key Study Personnel Page) prior to entry onto the study. Consent may be 
obtained with required signatures on the hard copy of the consent  or on the electronic 

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document.   
When a document that is in electronic format is used for obtaining  consent, this study may use 
the iMed platform which is 21 CFR, Part 11 compliant, to obtain the required signatures. 
During the consent process, participants and investigators may view the same approved consent 
document simultaneously when participant is being consented in person at the Clinical Center 
or both may view individual copies of the approved consent document on screens in their 
respective locations remotely. Signatures may be obtained either by both directly signing on the 
device that the consenting investigator is using (when in person) or through iMed Mobile 
Signature Capture  (remotely) which allows texting or emailing a link to the participant. That 
link allows the participant to review the consent, then proceed to sign on the device they are 
using. 
Whether hard copy or electronic, both the investigator and the participant will sign the 
document with a hand signature using a pen (if using hard copy), finger, stylus, or mouse (if 
electronic). 
When done remotely, if the participant prefers to sign a hard copy, they may be instructed to 
sign and date the consent document during the discussion and mail, secure email or fax the 
signed document to the consenting investigator. 
Whether in person or remotely, the privacy of the participant will be maintained. 
Finally, the fully signed informed consent document will be stored in the electronic medical 
record, and the participant will receive a copy of the signed informed consent document.  
The informed consent process will be documented on  a progress note. The date the signed informed consent 
document was received from the subject and signed by the consenting investigator will be documented in the 
consent progress note. 
10.1.2 
Consent for minors when they reach the age of majority 
 
N/A 
 
10.1.3 
Telephone consent 
Informed consent may be obtained over the telephone or by telemedicine/videocall rather than 
in person. Informed consent will be obtained per HRPP Policy 301. Subjects will be contacted 
by telephone by the PI or AIs approved to obtain consent. The consent process obtained by the 
phone or videocall will be identical to a consent obtained in person. The investigational nature 
and research, objectives of the trial, procedures, risks and discomforts will be carefully 
explained to the subject. If the subject(s) choose(s) to participate, a signed informed consent 
will be obtained. The subject will sign and date the informed consent. The informed consent 
document may then be faxed, sent via NIH secure email, and will be mailed back to either the 
investigator or to an authorized team member. The PI or AI approved to obtain consent will 
then sign and date the received consent. The original consent will be sent to medical records. 
The informed consent process will then be documented in CRIS. At this point the subject will 
be considered enrolled in the study. The subject will receive a copy of the signed consent either 
by FAX, secure e-mail, mail or by hand, at his first visit to the CC for this study. 
10.1.4 
Participation of Subjects who are/become Decisionally Impaired 

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N/A 
10.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and will 
provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
x Determination of unexpected, significant, or unacceptable risk to participants 
x Insufficient compliance to protocol requirements 
x Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB. 
 
10.2 CONFIDENTIALITY AND PRIVACY 
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff. This confidentiality is extended to cover testing of biological samples in addition to 
the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the NIH for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored in a research database in conformity with NHLBI DIR policy. Individual 
participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by clinical sites and by the research 
staff will be secured and password protected. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
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participants. 
 
10.3 FUTURE USE OF STORED SPECIMENS AND DATA 
We may share specimens and data with other researchers for future use. 
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). 
 
10.4 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise. Members of the DSMB should be 
independent from the study conduct and free of conflict of interest, or measures should be in place 
to minimize perceived conflict of interest. The DSMB will meet at least semiannually to assess 
safety and efficacy data on each arm of the study. The DMSB will operate under the rules of an 
approved charter that will be written and reviewed at the organizational meeting of the DSMB. At 
this time, each data element that the DSMB needs to assess will be clearly defined. 
The DSMB will provide its input to National Institutes of Health staff. 
 
10.5 CLINICAL MONITORING 
The monitoring of this study will be conducted by clinical research associates (CRAs)/monitors 
employed by an independent contract organization working under an agreement with NHLBI to 
monitor aspects of the study in accordance with the appropriate regulations and the approved 
protocol. The objectives of a monitoring visit will be: 1) to verify the existence of signed informed 
consent form (ICF) and documentation of the ICF process for each monitored subject; 2) to verify 
the prompt and accurate recording of all monitored data points, and prompt reporting of all SAEs; 
3) to compare abstracted information with individual subjects’ records and source documents 
(subject’s charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, and 
any other relevant original subject information); and 4) to help ensure investigators are in 
compliance with the protocol. The monitors also will inspect the clinical site regulatory files to 
ensure that regulatory requirements (Office for Human Research Protections-OHRP) and applicable 
guidelines (ICH-GCP) are being followed. Monitoring will be conducted according to the OCD 
schedule. During the monitoring visits, the investigator (and/or designee) and other study personnel 
will be available to discuss the study progress and monitoring visit. 
The investigator (and/or designee) will make study documents (e.g., consent forms and pertinent 
hospital or clinical records readily available for inspection by the local IRB, the site monitors, and 
the NHLBI staff for confirmation of the study data. 
 
10.6 QUALITY ASSURANCE AND QUALITY CONTROL 

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Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.7 DATA HANDLING AND RECORD KEEPING 
10.8.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. 
Data recorded in the electronic case report form (eCRF) derived from source documents should 
be consistent with the data recorded on the source documents. 
Clinical data and clinical laboratory data will be entered into CTDB, a 21 CFR Part 11-compliant 
data capture system. Clinical data will be entered directly from the source documents. 
10.8.2 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harmonisation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention, or as per the NIH Intramural Records Retention Schedule. No records will be 
destroyed without the written consent of the NHLBI Clinical Director. 
 
 
10.8 PROTOCOL DEVIATIONS 
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations to the NIH Institutional Review Board as per Policy 801. 
NIH Definition of Protocol Deviation 
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol. 
x Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study. 

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x Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study. 
 
10.9 PUBLICATION AND DATA SHARING POLICY 
10.10.1 Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer- 
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results information from this trial will be submitted to ClinicalTrials.gov. In addition, every 
attempt will be made to publish results in peer-reviewed journals. Study participants may be 
notified by mail or secure email when results are posted on Clinicaltrials.gov or when a 
manuscript is posted. Data from this study may be requested from other researchers 3 years after 
the completion of the primary endpoint by contacting Dr. Michael Sack at the NHLBI 
10.10.2 Genomic Data Sharing Plan 
N/A 
10.10  COLLABORATIONS AND AGREEMENTS 
10.11.1 Agreement Type 
 
CRADA: A CRADA between NHLBI and Chromadex for the conduct of this study is being executed. 
 
MTA: We will send coded PBMC for analysis of metabolic pathways to Kennedy Institute, Oxford 
University UK (Dr. Alexander Clarke). The collaborator will not have access to the code key.  Upon receipt 
of the data analysis, NHLBI will link the analyzed data to identifiers. We will not send samples outside 
NIH without an executed material transfer agreement (MTA). 
 
10.11  CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial. The study leadership in conjunction with the NHLBI has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 

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11 
ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 

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12 
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