A Crossover, Randomized Block Sequence, Double-Blind, Placebo-Controlled Trial for Nicotinamide Riboside in Subjective Cognitive Decline and Mild Cognitive Impairment in Aging
Phase: NA
Conditions: Cognition Disorders in Old Age, Mild Cognitive Impairment, Cognitive Decline
Sponsor: Steven E Arnold, MD

 
A Crossover, Randomized Block Sequence, Double-Blind, Placebo-Controlled Trial for Nicotinamide Riboside in Subjective Cognitive Decline and Mild Cognitive 
Impairment in Aging   
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A Crossover, Randomized Block Sequence, Double-Blind, Placebo-Controlled Trial for Nicotinamide Riboside 
in Subjective Cognitive Decline and Mild Cognitive Impairment in Aging   
 
NCT#04078178 
May 26, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A Crossover, Randomized Block Sequence, Double-Blind, Placebo-Controlled Trial for Nicotinamide Riboside in Subjective Cognitive Decline and Mild Cognitive 
Impairment in Aging   
Version:4.4 
Version date: May 26, 2022 
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 A Crossover, Randomized Block Sequence, Double-Blind, Placebo-Controlled Trial for Nicotinamide Riboside 
in Subjective Cognitive Decline and Mild Cognitive Impairment in Aging   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Steven E. Arnold MD 
Principal Investigator 
Massachusetts General Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Number: 2019P002668 
 
 
Version Number/Date: 4.4, May 26, 2022 
  
 
The information contained herein is confidential and proprietary in nature and will not be disclosed to any third party without 
written approval of authorized designee. This document may be disclosed to the appropriate institutional review boards or 
to duly authorized representatives of the US Food and Drug Administration or national regulatory authority under the 
condition that they maintain confidentiality.  

 
A Crossover, Randomized Block Sequence, Double-Blind, Placebo-Controlled Trial for Nicotinamide Riboside in Subjective Cognitive Decline and Mild Cognitive 
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STATEMENT OF COMPLIANCE 
 
This study will be conducted in compliance with the protocol, International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH), Good Clinical Practice (GCP), and the applicable 
regulatory requirements, United States Code of Federal Regulations (CFR) Title 45 CFR Part 46 and Title 21 CFR Parts 50, 
56, and 312. 
 
 

 
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Table of Contents 
STATEMENT OF COMPLIANCE .................................................................................................................................... 3 
LIST OF ABBREVIATIONS .............................................................................................................................................. 7 
1. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................................ 9 
1.1  INSTITUTIONAL REVIEW BOARD (IRB) ............................................................................................................... 9 
1.2  ETHICAL CONDUCT OF STUDY ............................................................................................................................. 9 
1.3  SUBJECT INFORMATION AND CONSENT ............................................................................................................ 9 
2. 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............................ 10 
2.1 BACKGROUND INFORMATION ............................................................................................................................... 10 
2.1.1  Subjective Cognitive Decline and Mild Cognitive Impairment .................................................................. 10 
2.1.2  Nicotinamide Riboside Rationale ............................................................................................................... 11 
2.1.3  Preclinical Use of Nicotinamide Riboside .................................................................................................. 11 
2.1.4 Pharmacokinetics of Nicotinamide Riboside in Humans ............................................................................ 12 
2.1.5  Prior Clinical Use of Nicotinamide Riboside ............................................................................................. 13 
3. 
SPECIFIC AIMS ....................................................................................................................................................... 13 
3.1 
OVERALL STUDY DESIGN AND PLAN ............................................................................................................... 13 
3.2 
STUDY OBJECTIVES ............................................................................................................................................... 13 
3.2.1 Standardized Cognitive, Functional, and Neuropsychiatric Outcome Measures ........................................ 14 
3.3  PROTOCOL ADHERENCE....................................................................................................................................... 15 
4.  
SUBJECT SELECTION .......................................................................................................................................... 15 
4.1 
INCLUSION AND EXCLUSION CRITERIA ........................................................................................................... 15 
4.1.1  Inclusion Criteria ........................................................................................................................................ 15 
4.1.2  Exclusion Criteria ....................................................................................................................................... 16 
4.1.2.1  
WOMEN OF CHILDBEARING POTENTIAL (WOCBP) ....................................................................... 17 
4.2  RECRUITMENT ........................................................................................................................................................ 17 
4.2.1 Recruitment of Subjects through Advertising ............................................................................................. 17 
4.2.2 Recruitment of Subjects from among the Investigator’s own Patients and MGB Providers ............... Error! 
Bookmark not defined.7 
4.2.3 Recruitment of Subjects from the Massachusetts Alzheimer’s Disease Research Center Error! Bookmark 
not defined. 
4.2.4  Recruitment of Subjects from Providers Outside of MGB ....................... Error! Bookmark not defined.7 
4.2.5  Recruitment from the CTRU Registry……………………………………………...………………....17 
4.2.6  Recruitment from the MAINAH Registry………...……………….......………………………………….18 
5.  
SUBJECT ENROLLMENT ..................................................................................................................................... 19 
5.1 
INFORMED CONSENT PROCESS .......................................................................................................................... 19 
5.2  REMUNERATION ..................................................................................................................................................... 20 
5.3 
RANDOMIZATION ................................................................................................................................................... 20 
5.4 
REASONS FOR WITHDRAWAL ............................................................................................................................. 21 

 
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5.4.1  Handling of Withdrawals ............................................................................................................................ 21 
5.5  TERMINATION OF STUDY ..................................................................................................................................... 21 
6. 
STUDY PROCEURES .............................................................................................................................................. 22 
6.1 
 SCHEDULE OF ASSESSMENTS ............................................................................................................................ 22 
6.1.1 SCREENING VISIT (DAY -28) ................................................................................................................................. 25 
6.1.2 Lead-In Visit (Day 0) .................................................................................................................................. 25 
6.1.3 Baseline Visit (Day 28), Crossover Visit (Day 84), and End of Study Visit (Day 140) ............................. 26 
6.1.4   
Block Midway Telephone Visits (Days 56 and 112) ............................................................................ 26 
6.1.5 Follow Up Visit (Day 154) ......................................................................................................................... 26 
6.1.6 Early Termination Visit .............................................................................................................................. 27 
6.1.7  PROTOCOL DEVIATIONS...................................................................................................................................... 27 
6.1.8 MISSED VISITS AND PROCEDURES .................................................................................................................... 27 
7 
CLINICAL ASSESSMENTS AND OUTCOME MEASURES ............................................................................ 27 
7.1 
CLINICAL VARIABLES ........................................................................................................................................... 27 
7.1.1  Safety Measures .......................................................................................................................................... 28 
7.1.2 Clinical Assessments ................................................................................................................................... 28 
7.1.3 Daily Outcomes .......................................................................................................................................... 32 
7.2  TRAINING AND VALIDATION ................................................................................................................................. 33 
8.  
INTERVENTIONS ADMINISTERED ................................................................................................................... 34 
8.1  INTERVENTION ....................................................................................................................................................... 34 
8.1.1  Study Product Description .......................................................................................................................... 34 
8.1.2  Drug and Placebo ........................................................................................................................................ 34 
8.1.3  ACQUISITION ........................................................................................................................................................... 34 
8.2.  Product Storage and Stability ...................................................................................................................... 34 
8.3 
DOSAGE, PREPARATION AND ADMINISTRATION OF STUDY INTERVENTION ....................................... 34 
8.4 
MODIFICATION OF STUDY INTERVENTION FOR A SUBJECT ...................................................................... 35 
8.4.1  Dosage Discontinuation .............................................................................................................................. 35 
8.5  ASSESSMENT OF SUBJECT COMPLIANCE ........................................................................................................ 35 
9. 
STATISTICAL ANALYSIS ..................................................................................................................................... 35 
9.1  BIOSTATISTICAL ANALYSIS ............................................................................................................................. 35 
10. 
SAFETY AND ADVERSE EVENTS ...................................................................................................................... 37 
10.1  POTENTIAL RISKS AND BENEFITS ..................................................................................................................... 37 
10.1.1  
Potential Risks ....................................................................................................................................... 37 
10.1.2  
Known Potential Benefits ..................................................................................................................... 39 
10.2  Data Security ............................................................................................................................................... 39 
10.2.1 
LAPTOP COMPUTERS AND IPADS ...................................................................................................... 39 
10.2.2 
Lumosity software ................................................................................................................................. 39 
10.2.3 
Fitbit activity tracker ............................................................................................................................. 40 
11. 
MONITORING AND QUALITY ASSURANCE ................................................................................................... 40 

 
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11.1  Independent Monitoring of Source Data ..................................................................................................... 40 
11.2  Safety Monitoring ....................................................................................................................................... 41 
11.3  DEFINITIONS OF AES & SAES .............................................................................................................................. 41 
11.3.1  
Adverse Event ....................................................................................................................................... 41 
11.3.2  
Serious Adverse Events......................................................................................................................... 42 
11.4  ASSESSMENT AND RECORDING OF ADVERSE EVENTS ................................................................................ 43 
11.4.1 
Assessment of Adverse Events ............................................................................................................. 43 
11.4.2  
Relatedness of Adverse Event to Investigational Protocol ................................................................... 44 
11.4.3  
Recording of Adverse Events ................................................................................................................ 44 
11.5  ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS - REPORTABLE EVENTS ...................................... 44 
11.6  SAFETY AND FEASIBILITY OF PERFORMING EXPERIMENTAL VISITS AT MGH-EAST 
(CHARLESTOWN NAVY YARD) ..................................................................................................................................... 44 
12.  BIBLIOGRAPHY ..................................................................................................................................................... 46 
 
 
 

 
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LIST OF ABBREVIATIONS  
 
AD 
 
Alzheimer’s Disease 
ADRD  
Alzheimer’s Disease Related Dementias  
AE 
 
Adverse Event/Adverse Experience  
ASL 
 
Arterial Spin Labeling 
BAI 
 
Beck Anxiety Inventory 
BDI 
 
Beck Depression Inventory 
BOLD  
Blood Oxygen Level Dependent 
BRIEF-A 
Behavioral Rating Inventory of Executive Function – Adult Version 
BVMT-R 
Brief Visuospatial Memory Test-Revised 
CBC  
Complete Blood Count 
CFR   
Code of Federal Regulations  
CRF 
 
Case Report Form 
CNS 
 
Central Nervous System 
CNY  
Charlestown Navy Yard  
Co-I 
 
Co-Investigator  
CPT 
 
Continuous Performance Task 
CSF   
Cerebrospinal Fluid  
DKEFS 
Delis-Kaplan Executive Function System 
DNA   
Deoxyribonucleic acid  
DOB  
Date of Birth 
eCRF   
Electronic Case Report Form  
EDC   
Electronic Data Capture  
FABP  
Fatty Acid Binding Protein 
FDA  
Food and Drug Administration  
GCP   
Good Clinical Practice  
GFAP  
Glial Fibrillary Acidic Protein 
GRAS  
Generally Recognized as Safe  
HIPAA  
Health Insurance Portability and Accountability Act  
HRC  
Human Research Committee  
ICF  
 
Informed Consent Form  
ICH   
International Conference on Harmonisation  
IRB 
 
Institutional Review Board 
LC 
 
Longitudinal Cohort 
LP 
 
Lumbar Puncture 
MADRC 
Massachusetts Alzheimer’s Disease Research Center 
MCI 
 
Mild Cognitive Impairment 
MFQ  
Memory Function Questionnaire 
MDU  
Memory Disorders Unit 
MGH   
Massachusetts General Hospital  
MRI 
 
Magnetic Resonance Imaging 
MRN  
Medical Record Number 
T-MoCA 
Telephone Montreal Cognitive Assessment 
MoCA            Montreal Cognitive Assessment 
N  
 
Number (typically refers to subjects)  
NAD+  
Nicotinamide Adenine Dinucleotide  

 
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NFL   
Neurofilament light-chain protein 
NMN  
Nicotinamide mononucleotide 
NR 
 
Nicotinamide riboside 
PBO 
 
Placebo 
pCASL 
Pulsed Continuous Arterial Spin Labeling  
PHRC  
Partners Human Research Committee 
PI  
 
Principal Investigator  
PT/INR 
Prothrombin Time and International Normalized Ratio  
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
rsBOLD 
Resting State Blood Oxygen Level Dependent 
rsfMRI 
Resting State Functional Magnetic Resonance Imaging  
SAE   
Serious Adverse Event  
SCD 
 
Subjective Cognitive Decline 
TMT  
Trail-Making Test 
TOPF  
Test of Premorbid Functioning 
TSH 
 
Thyroid Stimulating Hormone 
UCH-L1 
Ubiquitin Carboxy-Hydrolase-L1 
 
 

 
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1. 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
1.1  
Institutional Review Board (IRB) 
This study will be conducted in compliance with current Good Clinical Practices (GCP) and Title 21 Part 56 of 
the United States of America Code of Federal Regulations (CFR) relating to IRBs. 
 
1.2  
Ethical Conduct of Study 
The study will be conducted in accordance with GCP defined by the International Conference on Harmonisation 
(ICH) and the ethical principles of the Declaration of Helsinki. 
 
1.3  
Subject Information and Consent  
This study will be conducted in compliance with Title 21 Part 50 of the United States of America Code of Federal 
Regulations (CFR), Federal Regulations, and ICH Guidance Documents pertaining to informed consent. At the 
first visit, prior to initiation of any study-related procedures, subjects will be informed about the nature and 
purpose of the study, participation/termination conditions, and risks and benefits. Subjects will be given adequate 
time to ask questions and become familiar with the study prior to providing consent to participate. Subjects will 
give their written consent to participate in the study and will be provided with a copy of the fully executed consent 
form for their records. 
 
If the subject is not fully competent and able to provide consent, he or she will not be eligible to participate in this 
study. Our study population of scientific interest is Mild Cognitive Impairment (MCI); subjects in this category 
will be expected to have full capacity to consent unless due to another exclusionary factor.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2. 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1 Background Information 
 
2.1.1  Subjective Cognitive Decline and Mild Cognitive Impairment  
Advancing age is accompanied by variable declines in neurocognitive functioning. Some crystalized functions 
such as vocabulary and well-practiced knowledge and skills remain stable or even improve into late-life in normal, 
non-diseased brain aging. However, fluid functions such as new learning and memory, problem-solving and other 
executive functioning, attention and concentration, and psychomotor processing speed all show declines. In 
normally functioning older adults, “Subjective Cognitive Decline” (SCD*) is the most widely accepted term for 
this decline in fluid cognitive functions with age. It is a state in which patients experience declines from their 
usual levels of cognitive functioning but score in the normal range on standard cognitive tests relative to peers1. 
Their everyday independent functioning is also "normal", but they are often distressed by their perceived cognitive 
abilities. SCD may be a very early, prodromal symptom of an Alzheimer's disease (AD) or AD-related dementias 
(ADRD) for some, or, in the absence of a disease process, it is often attributed to age-related changes in brain 
metabolism, synaptic plasticity and neurochemistry1. The natural history of SCD with or without evidence of an 
AD/ADRD process is still under investigation, but risk for subsequent decline into dementia is significantly 
increased and the presence of AD/ADRD biomarkers is higher in this group.2 
 
Mild cognitive impairment (MCI) is a term used when there is clinical concern about cognitive decline and 
evidence of impairment(s) in cognitive testing, more than expected for the patient's age and educational 
background, but not so severe that the person cannot manage their daily functioning without more than minimal 
assistance. MCI is frequently, though not always, a transitional, prodromal phase of dementia due to ADRD. 
"Dementia" is present when independent daily functioning is affected.3 
 
AD/ADRDs are associated with synaptic dysfunction and loss, neuronal cell death and gliosis that particularly 
affect the cerebral association cortices. Abnormal aggregates of amyloid plaques and tau neurofibrillary tangles 
are the signature histopathological findings of AD, while other mis-folded protein aggregates such as -synuclein 
Lewy bodies and TDP-43 cytoplasmic inclusions as well as small- and micro- vessel disease are frequently 
concurrent and contributory to the overall degenerative processes. Beyond these histopathologies, it is 
increasingly recognized that a host of pathophysiological processes contribute to neurodegeneration in aging and 
AD/ADRDs, including bioenergetic/metabolic dysfunction, endoplasmic reticulum stress, inflammation, 
oxidative damage, neurovascular injury, apoptosis and more. These processes may interact with AD/ADRD 
 
 
 
*Also referred to as age-associated memory impairment, subjective cognitive concerns, impairments or complaints, subjective memory 
concerns, impairments or complaints, “senior moments” and cognitive aging.   

 
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signature histopathologies in vicious cycles, presenting considerable challenges, but also novel entry points for 
potential disease modification and neuroprotection across pathologies3. 
 
2.1.2  Nicotinamide Riboside Rationale 
Nicotinamide riboside (NR) is a form of vitamin B3, naturally found in low levels in milk, that is a precursor to 
nicotinamide adenine dinucleotide (NAD+). NAD+ is a central metabolic cofactor that functions as the primary 
electron donor in the mitochondrial respiratory chain, regulates the activity of various metabolic pathway enzymes 
in glycolysis, Kreb’s cycle, and fatty acid oxidation and enables signaling for major cellular metabolism processes 
involving sirtuins. These processes are critical for maintenance of synaptic plasticity and protection against 
neurodegeneration. Neuronal mitochondrial dysfunction occurs with advancing age, but this is especially 
pronounced in pathological brain aging, such as with AD or vascular cognitive impairment. NR is a safe, well-
tolerated, potent NAD+ precursor available as a “generally recognized as safe” (GRAS) dietary supplement. It 
has promising pharmacokinetic and systemic pharmacodynamics properties and has been shown to ameliorate 
bioenergetic, behavioral and pathological abnormalities in AD mouse models. 
 
2.1.3  Preclinical Use of Nicotinamide Riboside  
Mice expressing mutant forms of Alzheimer’s Precursor Protein, presenilin-1, and tau with a polymerase β null 
allele were used to model age-dependent neuronal death and DNA damage. Exposure to 12mM NR for 6 
months led to significant reversals in cognitive behavioral deficits, enhanced long-term potentiation and 
neurogenesis, and decreased oxidative and inflammatory damage. NAD+/NADH ratio was elevated in mice 
treated with NR compared to vehicle groups. NR-treated mice also exhibited improved cognitive performance, 
such as improved observation times in the novel-object tests and improved spatial learning in water maze tests. 
NR treatment in this model was also implicated in upregulation of neurogenesis-related genes, leading to a 9.6% 
change in hippocampal gene expression, and downregulation of pro-apoptotic p53 expression.  NR treatment 
was further linked to decreased astrocytosis and microgliosis (equivalent to wild-type controls), and 
significantly reduced levels of phospho-tau-231. NR treatment applied to human AD fibroblasts demonstrated 
reduced expression of the oxidative 8-oxo-dG DNA and reduced levels of acetylated substrate, suggestive of the 
effect of NR on upregulating NAD+-dependent sirtuin deacetylases.4  
 
Figure 1. NAD+/NADH ratio following 6 months of NR treatment (12 mM) among wild type, transgenic AD model 
mice, mice with polymerase β mutation, and AD/polymerase β hybrids simulating age-dependent neuroinflammation and 
oxidative damage. NAD+/NADH is a measure of the available pool of NAD+ and shows significant elevation in NR-
treated mice compared to vehicle controls among all models.4 
 

 
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NR has also been implicated in modifying the toxicity of amyloid plaques associated with AD. Administration 
of mg/kg/day of NR to Tg2576 AD mice led to marked changes in hippocampal long-term potentiation and 
increased expression of PGC-1α, which in turn upregulated degradation of β-secretase, a key enzyme implicated 
in amyloid plaque formation. 5  
  
2.1.4 Pharmacokinetics of Nicotinamide Riboside in Humans  
 
An open-label, non-randomized study of the pharmacokinetics of NR carried out at the University of Washington 
demonstrated both the impact of NR on NAD+ levels in humans and its tolerability. Eight subjects underwent 
dose escalation from 250 mg of NR twice daily to 1000 mg of NR twice daily over the course of nine days, with 
NR and NAD+ levels determined at baseline Day 1 and over the course of a 24-hour pharmacokinetic study on 
Day 9. No adverse events were reported in clinical laboratory values, including potassium, which had been noted 
to be elevated in previous NR studies. Slight, but significant decreases in hematocrit, hemoglobin, and platelet 
count were reported. All but one subject showed an increase in blood NR levels from baseline to Day 9, ranging 
from 10% to 127% increases. Blood NR showed exponential decline from 3 to 12 hours with a half-life of 2.7 
hours. Despite relatively fast clearance of NR, blood NAD+ levels were significantly increased to steady state (see 
Figure 3) by 35 to 168% from baseline. NR treatment did not produce side effects commonly seen in niacin 
treatment, such as flushing, pruritus, hyperglycemia, hyperuricemia, or elevation of liver or muscle enzymes. 
However, a variability in NR bioavailability was observed, suggesting that NR relies on active transport across 
intestinal mucosa, which can vary highly from person to person. 6 
 
 
Figure 2. Nicotinamide riboside (NR) enters the NAD+ salvage pathway through conversion to nicotinamide 
mononucleotide (NMN) via nicotinamide riboside kinase (NRK) or conversion to nicotinamide (NaM) via purine 
nucleoside phosphorylase (PNP). From there, NMN (or NaM after modification by NAMPT) is converted into active 
NAD+ and shunted into a variety of metabolic processes. NAD+ consuming enzymes, such as sirtuins, drain the NAD+ 
pool, which must be replenished. Declining activity of nicotinamide phosphoribosyltransferase (NAMPT) with age is 
implicated in declining levels of NAD+ with age. NR supplementation bypasses this rate-limiting step by introducing 
NAD+ precursors directly into the salvage pathway.6 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 3. Blood NR and NAD+ levels in n = 8 subjects following NR dose escalation from 250 to 1000 mg twice daily.6 
 
2.1.5  Prior Clinical Use of Nicotinamide Riboside   
While there are no reports yet of NR being used in patients with SCD, MCI or ADRDs, NR has been 
characterized to be both tolerable and effective in healthy middle-aged and older adults in improving markers of 
cardiovascular health in healthy middle-aged and older adults. A 12-week randomized, double-blind, single-
crossover trial provided 30 healthy subjects with twice daily 600 mg doses of NR for 6 weeks and 6 weeks of 
PBO. Over the course of the study, 14 treatment-emergent adverse events (AEs) were reported in 7 subjects, all 
of mild severity. During the NR treatment period, AEs included nausea, flushing, leg cramps, and increased 
bruising. During the PBO period, AEs included headache, skin rash, flushing, fainting, and drowsiness. Only 2 
subjects (less than 10%) dropped out of the study because of these AEs, both of whom were in the PBO period. 
Two out of the three instances of flushing reported also occurred during the PBO period, suggesting the AE is 
likely unrelated to treatment. No significant changes in clinical labs were observed, including renal function 
markers and blood lipid profiles. Blood NAD+ levels increased by 60% from baseline following NR treatment. 
A five-fold change in nicotinic acid adenine dinucleotide (NAAD) and a 1.5-fold change in a nicotinamide 
mononucleotide (NMN) were also detected. Adenosine and adenosine triphosphate (ATP) levels also increased 
following NR treatment, demonstrating its robust impact on metabolism. When all subjects were grouped, mean 
systolic and diastolic blood pressure was significantly lowered following NR treatment, and carotid-femoral 
pulse wave velocity, a gold-standard marker of aortic stiffness, was also reduced, although not significantly. NR 
treatment did not correspond to any significant change in total energy expenditure, oxidative fuel source, 
physical activity patterns, body mass index, glucose and insulin regulation, and exercise capacity in any 
subject.7  
 
3. 
SPECIFIC AIMS 
 
3.1 
Overall Study Design and Plan  
This is a single-site single crossover, double-blind placebo (PBO)-controlled randomized sequence block trial of 
nicotinamide riboside (NR, TruNiagen, Chromadex) vs. PBO in 40 volunteers with SCD or MCI. All 
volunteers will receive a four-week PBO-lead in and acclimatization followed by two 8-week "blocks”. Each 
block consists of either NR or PBO for an 8-week period in random assignment order. Outcomes will consist of 
standardized cognitive, neuropsychiatric, functional and biomarker assessments as well as daily cognitive, 
mood, sleep, and activity monitoring with computer-based brain games and wearable actigraphy. Due to the 
COVID-19 pandemic, some of the study visits will be completed fully or partially via Zoom videoconference to 
minimize the amount of contact between study staff and research subjects.  
 
3.2 
Study Objectives  
 

 
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The primary objective of the study will be: 
 
1. To measure the effect of NR vs PBO on RBANS.  
 
The secondary clinical objectives of the study will be: 
 
1. To measure the effect of NR vs PBO on other, standard assessments of cognition, functional activities, 
and neuropsychiatric symptoms. 
2. To measure the effect of NR vs PBO on daily assessments of cognition, functional activities, and 
neuropsychiatric symptoms. 
3. To monitor the safety and tolerability of NR in volunteers with SCD or MCI. 
 
The exploratory biomarker objectives of the study will be: 
1. To measure the effect of NR on plasma biomarkers of metabolic target engagement and central nervous 
system (CNS) neural and glial integrity measurable in blood. 
2. To measure the effects of NR on cerebral neurophysiology (in an optional sub-study) using resting state 
functional magnetic resonance imaging (rs-fMRI). Connectivity will be measured with rsBOLD and 
regional cerebral blood flow will be measured with pseudo-continuous arterial spin labeling (pCASL). 
3. To measure the effect of NR on cerebrospinal fluid (CSF) biomarkers (in an optional sub-study) of 
metabolic target engagement and emerging biomarkers of relevance to AD/ADRD.  
 
3.2.1    Standardized Cognitive, Functional, and Neuropsychiatric Outcome Measures 
The primary outcome of this study will be objective measures of cognitive performance measured with the 
Repeatable Battery for the Assessment of Neuropsychological Status15 (RBANS) at  Baseline (Day 28), Crossover 
(Day 84), and End of Study (Day 140). Other secondary outcome measures of cognition include the Trail Making 
Test (TMT)16, Delis-Kaplan Executive Function System (DKEFS)17 Verbal Fluency subtest,  a computerized 
Continuous Performance Test (CPT), and the Brief Visual Memory Task-Revised (BVMT-R)18. Subjective 
ratings of everyday cognitive functioning and independent/instrumental/basic activities of daily living will be 
measured using items from the Behavior Rating Inventory of Executive Function (BRIEF-A)19 and the Memory 
Functioning Questionnaire20 (MFQ). Ratings of mood and anxiety will be measured using the Beck Anxiety 
Inventory21 (BAI) and Beck Depression Inventory22 (BDI). These standard measures will be administered at 
Baseline (Day 28), Crossover Visit (Day 84), and End of Study (Day 140).  
 
The secondary clinical and exploratory biomarker outcomes of this study will be: 
• Performance on daily measures of cognition, functional activity, and neuropsychiatric symptoms as 
assessed by:  
o A “daily” battery of approximately 15 minutes of Lumosity brain games (Lumos Labs, Inc.). 
Subjects will be asked to complete Lumosity games at least 6 times per week.  
o Objective daily physical activity levels and sleep data collected using wrist actigraphy (Fitbit 
Charge 3).  
o Subjective mood and sleep ratings will be collected using questionnaires 6 days per week.  
• Safety and tolerability will be assessed with adverse event (AE) reporting conducted at every visit.   
• Plasma for biomarkers will be collected at baseline, crossover and end-of-study. Plasma biomarkers 
assays will consist of ultra-sensitive immunochemical measures of proteins reflecting 
neurodegeneration/neural injury (NfL, amyloid 42/40, and GFAP) as well as NAD+/NADH. 

 
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• Cerebral neurophysiology will be measured with functional MRI (optional sub-study).   
o Optional MRI will be conducted at three time points: Baseline (Day 28), Crossover (Day 84), 
and End of Study (Day 140. Each MRI scan session will include functional MRI with resting 
state BOLD (rs-fMRI) and pseudo-continuous arterial spin labeling (pCASL) sequences. rs-
fMRI measures spontaneous yet synchronized fluctuations in the BOLD signal to determine the 
strength of functional connectivity within various intrinsic brain networks (i.e., default mode 
network). pCASL quantifies regional cerebral blood flow using magnetically labeled blood 
water content and will serve as a marker of resting state cerebral perfusion that has also been 
shown to correlate with regional brain metabolism and levels of neuronal activity.  
• Cerebrospinal Fluid Biomarkers (optional sub-study): All subjects will have the opportunity to 
participate in a lumbar puncture (LP) sub-study in which they can receive 1-3 optional LPs at Baseline 
(Day 28), Crossover (Day 84), and End of Study (Day 140). A panel of CSF biomarkers will be 
measured to determine the effects of NR on pathophysiological targets relevant to aging and 
neurodegeneration, including 1) neuronal degeneration markers neurofilament light chain (NfL) and 
neurogranin, 2) classic AD biomarkers including amyloid-β42/40, total tau and phospho-tau, 3) markers 
of mitochondrial function and redox dysregulation such as 8-hydroxy-2’-deoxyguanosine (8-OHdG) 
and pyruvate/lactate, and 4) selected other biomarkers of inflammation and immune response and 
vascular injury of relevance to the aging brain and cognition. 
 
3.3  
Protocol Adherence 
Each investigator must adhere to the protocol detailed in this document and agree that any changes to the 
protocol must be approved by Internal Review Board (IRB). Each investigator will be responsible for enrolling 
only those study subjects who have met protocol eligibility criteria. 
 
 
4.  
SUBJECT SELECTION 
 
4.1 
Inclusion and Exclusion Criteria   
 
4.1.1  Inclusion Criteria  
A subject will be eligible for study participation if they meet the following: 
1) Ages 55 and up; 
2) Memory and other cognitive complaints consistent with SCD or MCI as defined: 
a. SCD will be defined as: 
i. any subjective concern of change in cognitive functioning without objective evidence of 
cognitive impairment, and  
ii. preservation of functional abilities and independence in instrumental activities of daily 
living; 
b. MCI will be defined as: 
i. a preexisting diagnosis of MCI given by a trained physician or behavioral health provider, 
or  

 
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ii. evidence of objective impairment in cognitive functioning in one or more domain with 
preservation of functional abilities and independence in instrumental activities of daily 
living as defined by the National Institute on Aging; 
3) Minimum score of 16 on the Telephone Montreal Cognitive Assessment (T-MoCA) or minimum score 
of 24 on the Montreal Cognitive Assessment (MoCA); 
4) Ability to provide direct informed consent as assessed by obtaining a score of 70% on questions 1-10, 
and 100% on questions 11-14 of the Informed Consent Worksheet after two attempts;  
5) Education level, English language skills and literacy indicates participant able to complete all assessments; 
6) Willing and able to complete all assessment and study procedures; 
7) Not pregnant, lactating, or of child-bearing potential;  
8) If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline; 
9) Basic video conferencing capabilities and a willingness to participate in a partially virtual trial. 
 
4.1.2  Exclusion Criteria  
A subject will not be eligible for study participation if they meet any of the following criteria  
1) Any specific CNS disease history other than suspected ADRD, such as major clinical stroke, brain tumor, 
normal pressure hydrocephalus, multiple sclerosis, significant head trauma with persistent neurological of 
cognitive deficits or complaints;  
2) Any impairment in instrumental activities of daily living that would indicate a level of cognitive 
impairment beyond MCI as assessed by a trained rater; 
3) Clinically significant unstable medical condition that could affect safety or compliance with the study and 
would, in the opinion of the investigator, pose a risk to the participant if they were to participate in the 
study; 
4) History of neuroimaging with evidence of major infarction, injury, infection, or other focal lesions that 
may be related to cognitive dysfunction;  
5) If participating in the optional LP sub-study, any contraindication to undergo lumbar punctures, such as:  
a. Abnormal coagulation PT/INR test result, outside of the normal range of 0.9 to 1.2 platelet 
counts below 50,000 (interpreted by a licensed study physician or nurse practitioner after reading 
test results); 
b. Platelet counts below 50,000;  
c. Use of coumadin or other blood thinner medications; 
d. Infection near the puncture site, or spinal column deformities (a licensed physician or nurse 
practitioner will examine the site visually for infection or spinal deformities before performing 
the procedure); 
e. Known allergy to Lidocaine.  
6) Major active or chronic unstable psychiatric illness (e.g. depression, bipolar disorder, obsessive 
compulsive disorder, schizophrenia) within the previous year; 
7) Current suicidal ideation or history of suicide attempt; 
8) History of alcohol or other substance abuse or dependence within the past two years; 
9) Any significant systemic illness or medical condition that could affect safety or compliance with study; 

 
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10) Laboratory abnormalities at Baseline in vitamin B12, thyroid stimulating hormone (TSH), or other 
common laboratory parameters that might contribute to cognitive dysfunction or other abnormalities in 
hematological, hepatic or renal function tests; 
11) Current use of medications with psychoactive properties that in the opinion of the principal investigator, 
may be deleteriously affecting cognition (e.g., anticholinergics, antihistamines, antipsychotics, sedative 
hypnotics, anxiolytics);  
12) Any known hypersensitivity to nicotinamide riboside, or its principal metabolite, nicotinamide 
mononucleotide;  
13) No consumption of dietary supplements containing more than 100mg niacin, nicotinamide riboside (NR), 
or nicotinamide mononucleotide (NMN) as the primary agents 30 days prior to baseline and for the 
duration of the trial.  
14) Use of other investigational agents or interventions one month prior to entry and for the duration of the 
trial; 
15) If participating in the optional MR sub-study:  
a. Any contraindication to undergo MRI studies, such as history of cardiac pacemaker or pacemaker 
wires, metallic particles in the body, vascular clips in the head, prosthetic heart valves, and/or 
severe claustrophobia impeding ability to participate in an imaging study. 
b. Age 60 and older. 
 
4.1.2.1  
Women of Childbearing Potential (WOCBP) 
For the purposes of this study, women of childbearing potential are defined as all women who are capable of 
becoming pregnant, unless they meet one of the following criteria:  
1. 12-months post-menopausal  
2. Post-hysterectomy  
3. Surgically sterile  
If a female subject does not meet these criteria and is considered of childbearing potential, they will be excluded 
from the clinical trial. 
 
4.2  
Recruitment   
Approximately 60 subjects will be screened, and after screening, approximately 40 subjects are expected to 
complete the study. All subjects will be given the option to participate in the optional repeat LP sub-study and 
the optional MRI sub-study until 12 subjects have completed each sub-study. Subjects will be given the choice 
to complete either the repeat LP sub-study, the MRI sub-study, or both.  
 
4.2.1 Recruitment of Subjects through Advertising  
Advertisement flyers will be posted on bulletin boards around MGB campuses (both the main campus and 
Charlestown campus) to advertise for the study as well posting as an advertisement on Partners Rally for Research. 
A phone number will be provided that will ring directly to the research coordinator, and voice messages can be 
left for the coordinator on a password-protected voice mailbox. The study coordinator will contact the subject and 
explain study in further detail and if the subject is interested, potentially complete a telephone prescreening.  A 
listing of the study will also be posted on the MGH ACTRU website as well the websites of our affiliates.  
 

 
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Subjects may also be recruited through the distribution of IRB approved recruitment materials at community 
outreach initiatives including informational sessions to various community partners such as city-based and non-
profit organizations. 
 
4.2.2 
Recruitment of Subjects from among the Investigator’s own Patients and MGB Providers  
Subjects will also be recruited from the outpatient clinical practices of the principal investigator (Dr. Steven 
Arnold). If the potential subject is the investigator’s patient, another member of the study or clinic staff will 
introduce the study to the patient and determine if they are interested in learning more about the study. An NP 
investigator will be made available to explain the study to the subject at their request. If the potential subject is 
not the investigator’s patient, the investigators will not directly approach the patient regarding possible 
participation in the study. Other MDU physicians (not participating directly in the study) may discuss the study 
directly with their patients, if they choose to do so. The prospective participant will be given informational papers 
to review and the study coordinator will contact them to discuss interests and research opportunities.  
 
Subjects will also be recruited from physician specialists at the Center for Alzheimer Research and Treatment 
(CART) at Brigham and Women’s Hospital, a database of patients who have indicated a prior interest in 
participating in studies at the CART, the memory disorders, neurology, psychiatry, and medicine clinics at 
Brigham and Women’s Hospital and Massachusetts General Hospital, and physicians outside of the Partners 
network. 
 
Other providers across MGB will also be made aware of the study (including key eligibility criteria) via email 
and provided a link to the Rally ad. These providers (not participating directly in the study) may discuss the 
study directly with their patients, if they choose to do so. If the prospective patient is interested, their provider 
will give them a copy of the consent form (unstamped) for review as well as a link to the Rally ad, which 
contains the research coordinator’s contact information.  
 
4.2.3 
Recruitment of Subjects from the Massachusetts Alzheimer’s Disease Research Center 
Subjects will also be recruited from an observational study that follows a longitudinal research cohort (LC) of 
approximately 400 active research participants in the Massachusetts Alzheimer's Disease Research Center (MADRC) 
recruited from the MGH’s Memory Disorders Unit clinic and other diverse sources. LC subjects are followed-up on an 
approximately annual basis, either in-person at the MGH or by means of a telephone follow-up ‘visit’. Study staff will 
only contact subjects that have indicated to the MADRC that they are interested in hearing about/participating in other 
studies. MADRC may also share information regarding our studies with their mailing list. 
 
4.2.4 
Recruitment of Subjects from Providers Outside of MGB 
Subjects will be recruited from providers outside of MGB through the use of doctor to doctor letters and/or 
sharing of IRB-approved recruitment materials. Appropriate providers who have been identified by the study 
team will be mailed IRB approved materials that introduce the study and outline the specific inclusion/exclusion 
criteria. Providers will be asked to identify eligible participants and share their information with us following all 
local policies on patient privacy including, but not limited to, obtaining written consent as needed. 
 
4.2.5 
Recruitment from the CTRU Registry 
A research volunteer registry (P2021000916) was established in 2021 to maintain a list of people interested in 
participating in clinical research with the MGH Clinical and Translational Research Unit (CTRU). The goal of 
the CTRU, located in CNY 149, is to serve the clinical and research departments, institutes, centers, programs 

 
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and labs that comprise the MGH Neuroscience community and to be a foundational component and research 
core facility within MGH’s emerging translational programs.  Eligible participants who have consented to be 
contacted for future research may be identified using data stored within the volunteer registry.  
 
4.2.6  Recruitment from the MAINAH Registry 
 
The Northern Light Health site will be recruiting from their internal research registry, the Maine Initiative for 
Neurologic Aging and Health (MAINAH). With over 800 enrollees and growing, including people from all over 
Maine, of all ages, many of whom either have family members with dementia or themselves have some cognitive 
symptoms. All enrollees have communicated interest in participating in research. MAINAH registry participants 
will be contacted using an IRB-approved email to let them know about this opportunity. 
 
 
5.  
SUBJECT ENROLLMENT 
 
5.1 
Informed Consent Process  
This study will be conducted in compliance with Title 21 Part 50 of the United States of America Code of 
Federal Regulations (CFR), Federal Regulations, and ICH Guidance Documents pertaining to informed consent.  
 
Potential subjects will be given general information about the research (e.g., through informational sheets, letters, 
or discussion with their treating physicians). If they are interested in learning more about the study, they will then 
contact the research coordinator. The research coordinator will obtain verbal consent in accordance with Partner’s 
Prescreening Guidelines prior to performing a telephone prescreening interview.  If the subject meets pre-
screening criteria, including scoring a 27 or greater on the Telephone Interview for Cognitive Status or scoring a 
3 or greater on the Cognitive Functioning Instrument, and wishes to continue the screening process, a virtual, 
Zoom videoconference screening visit will be scheduled. If the subject resides outside the state of Massachusetts, 
the screening visit will take place in person at MGH CNY campus.  
 
At the screening visit, the investigator will meet with the potential subject to review and discuss the details of 
the study using the informed consent document as a guide. A copy of the informed consent document will be 
sent to the subject before the screening visit takes place, and they will have at least 24 hours between when the 
document is received and when the screening visit is scheduled in order for the subject to have adequate time to 
fully review the Informed Consent Document.  
 
The informed consent process will be conducted using a REDCap-based electronic consent form. The consent 
form has been developed in REDCap, a secure, web-based, HIPAA-compliant, data collection platform with a 
user management system allowing project owners to grant and control varying levels of access to data collection 
instruments and data for other users. If requested by the subject, a traditional hard copy consent form will be 
provided to the subject along with any materials needed for return shipping. 
 
During the screening visit, the informed consent document will be reviewed with the participant by an 
experienced clinician investigator. The potential subject may ask to speak with the physician investigator should 
a non-physician investigator be involved in obtaining informed consent. The informed consent discussion will 
include all of the required elements of informed consent, including the purpose of the research, the procedures 

 
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to be followed, the risks and discomforts, as well as potential benefits associated with participation, and 
alternative procedures to study participation. Their questions will be answered to their satisfaction. The subject 
will be provided with adequate time to reflect on the potential benefits and risks and possible discomforts of 
participation, and to make an informed decision. 
 
After reviewing the consent form in full, the informed consent worksheet will be administered verbally to the 
participant by an experienced clinician investigator. The subject must get 70% of questions 1-10 correct, and 
100% on questions 11-14. If the subject does not get 70% of questions 1-10 correct and 100% on questions 11-
14 on the first attempt, the investigator will review the details of the study again with the subject. The subject 
will then be given another opportunity to answer the consent worksheet questions. If the subject does not 
answer 70% of questions 1-10 correct and 100% on questions 11-14 on the second try, they will be considered 
unable to consent and therefore ineligible for the study. 
 
If the participant is deemed capable of consenting, a link will be sent to the REDCap e-consent form or the 
subject will sign the provided hard-copy informed consent form. For REDCap e-consent, participant signatures 
will be obtained using electronic signature via mouse followed by electronic signature by the experienced 
clinician investigator. Signed hard-copy consent forms will be mailed back or given to the study team and 
signed by the consenting investigator upon receipt. Upon completion of the informed consent process, 
participants will be provided with an electronic copy of the signed consent form and hard copies will be stored 
in each subject’s binder. If a participant prefers a hard copy of the consent form, it will be given to them at their 
Lead-In in person visit. 
 
While some subjects will have MCI, they must be deemed capable of providing informed consent by the 
Investigators. Subjects who are not capable of providing informed consent will be excluded from this study.  
 
5.2  
Remuneration 
Subjects will receive $25 for their participation in each Visit. Subjects will receive $100 for the first optional LP 
they undergo, and $75 for each additional optional LP they elect to receive. If subjects elect to undergo all three 
LPs, they will receive a $50 LP sub-study completion bonus. If subjects elect to participate in MRIs, they will 
receive $75 for the first MRI, $100 for the second MRI, and $150 for the third MRI. Subjects will also receive 
$100 upon completion of the overall study as long as they were at least 80% compliant with all at-home study 
activities, including medication dosing, brain games, and Fitbit activity tracking. Therefore, if a subject elects to 
undergo all additional procedures and are at least 80% compliant with at-home study tasks, the maximum 
amount a subject would be eligible to receive is $925 at study completion. If a subject does not elect to 
participate in any optional procedures but is compliant with study tasks, they would be eligible to receive $300.  
We anticipate some subjects may come from outside the region and if so, appropriate travel expenses may be 
reimbursed including transportation up to $150. To minimize the inconvenience of frequent visits, meal and 
parking vouchers for use at the MGH Charlestown Navy Yard (CNY) facilities will also be offered at each visit. 
 
 
5.3 
Randomization  

 
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Subjects will be randomized into one of two counter-balanced block sequences (see Figure 4 below). 
Randomization will be done by MGH Clinical Trials Pharmacy.  
 
 
Figure 4. Study Schema 
 
5.4 
Reasons for Withdrawal  
A study subject will be discontinued from participation in the study if:  
• 
Any clinical adverse event (AE), concurrent illness, or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interest of the subject.  
• 
The subject meets any exclusion criteria (either newly developed or not previously recognized). 
• 
The subject is less than 80% or greater than 120% compliant with NR dosing.  
 
Subjects are free to withdraw from participation in the study at any time upon request.  
 
5.4.1  Handling of Withdrawals  
A subject may choose to discontinue participation in the study at any time. An Early Termination visit will 
occur when a subject withdraws consent, i.e. withdrawing his or her participation in future study procedures 
 
5.5  
Termination of Study  
This study may be prematurely terminated if, in the opinion of the investigator, there is sufficient reasonable 
cause.  
 
Circumstances that may warrant termination include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to subjects.  
• 
Unsatisfactory enrollment. 
• 
Insufficient adherence to protocol requirements.  
• 
Data that are not sufficiently complete and/or evaluable.  
 
If the study is prematurely terminated or suspended, the investigators will promptly inform the institution and 
regulatory authorities of the termination or suspension and the reason(s) for the termination or suspension. The 
IRB/IEC will also be informed promptly and provided the reason(s) for the termination or suspension by the 
investigator, as specified by applicable regulatory requirement(s). 

 
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6. 
STUDY PROCEURES   
 
6.1 
 Schedule of Assessments  
 
Days 
-28 to -1 
Day 0 
 
Day 28 
 4 days 
Day 562 
 4 days 
Day 84 
 4 days 
Day 1122 
 4 days 
Day 140 
 4 days 
Day 154 
 4 days 
Early 
Termination  
  
Screening 
Visit1 
Lead-in 
Baseline 
Block 1 
Midway  
Crossover 
(PBO/NR)  
Block 2 
Midway  
End of 
Study 
Follow 
Up1 
Informed Consent1,3 
X 
 
 
 
 
 
 
 
 
Informed Consent 
Worksheet1 
X 
 
X 
 
X 
 
X 
 
 
Demographics1 
X 
 
 
 
 
 
 
 
 
Medical History1,4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height & Weight 
 
X 
 
 
 
 
 
 
 
Vital Signs 
 
X 
X 
 
X 
 
X 
 
X 
Inclusion/ Exclusion 
Review1 
X 
X 
 
 
 
 
 
 
 
Safety Labs5 
 
X 
 
 
 
 
X 
X6 
X 
Concomitant 
Medications & 
Supplements1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical & 
Neurological 
Examination 
 
X 
X 
 
X 
 
X 
 
 
Cognitive Screening 
Measures1,7 
X 
 
 
 
 
 
 
 
 
Test of Premorbid 
Functioning   
 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispense 
Supplement/Placebo 
 
X 
X 
 
X 
 
 
 
 
Accountability and 
Compliance 
 
 
X 
X 
X 
X 
X 
 
 
X 
 

 
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Days 
-28 to -1 
Day 0 
Day 28 
 4 days 
Day 562 
 4 days 
Day 84 
 4 days 
Day 1122 
 4 days 
Day 140 
 4 days 
Day 154 
 4 days 
Early 
Termination  
 
 
Screening 
Visit1 
Lead-in 
Baseline 
Block 1 
Midway  
Crossover 
(PBO/NR)  
Block 2 
Midway  
End of 
Study 
Follow 
Up1 
Virtual Cognitive 
Assessment1,8 
  
  
X 
  
X 
  
X 
 
 
X 
Virtual 
Neuropsychiatric 
Surveys1,9 
  
  
X 
  
X 
  
X 
  
X 
Virtual Functional 
Survey1,10 
  
  
X 
  
X 
  
X 
  
X 
Blood Collection for 
Biomarker Analysis 
X 
X 
X 
X 
  
X 
Technology 
Training/Check-in 
  
X 
X 
X 
X 
X 
X 
  
  
Daily Cognitive 
Assessment11   
  
  
  
Daily Mood and Sleep 
Assessment 
  
  
  
Daily Activity 
Assessment12 
  
  
  
Lumbar Puncture13 
  
  
optional 
  
optional 
  
optional 
  
  
fMRI Scan 
  
  
optional 
  
optional 
  
optional 
  
  
Adverse Events1,14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1These visits and procedures will take place virtually via Zoom videoconference and will take place up to 4 business days prior to the office visit date. If the subject resides out of state, their screening 
visit will take place in person at MGH CNY campus. 
2Block Midway visits will be conducted over the telephone. The participant will not be required to come in MGH for these visits.  
3No study procedures apart from the telephone pre-screening visit will be performed prior to the signing of the informed consent form (ICF). All subjects will sign an ICF prior to undergoing any study 
tests or procedures.  
4After initial assessment of medical history during the screening period, updated medical history will be collected in subsequent visits.  
5 Safety labs include Hematology (CBC with differential), Complete Chemistry Panel, Liver Function Tests, B12 and TSH.  
6Safety labs will only be drawn if any labs from the End of Study (Day 140) Visit were abnormal and clinically significant.   
7Including T-MoCA (or MoCA), BDI and IADL Scale.  
8Including RBANS, CPT, BVMT, DKEFS Verbal Fluency Subtest, and Trail Making Test. 
9Including BDI/BAI. 
10Including MFQ and BRIEF-A. 
11Lumosity Brain Games (Lumos, Labs, Inc.) 
12Fitbit Charge 3 Wearable Device 
13CBC, PT/INR point of care @ Days 28, 84 and 140 if undergoing optional LP 

 
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14All adverse events that occur AFTER signing consent form until the end of the follow up visit will be included. 

 
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6.1.1 Screening Visit (Day -28) 
Subjects located outside the state of Massachusetts will complete their screening visit in person. Subjects 
located in Massachusetts will complete a virtual screening visit via Zoom videoconference. The screening 
procedures will determine the subject’s eligibility for the study and will take approximately 2 hours. 
 
The following procedures will take place at the Screening visit:  
• Obtain written informed consent from the subject after assessment of capacity to consent via the 
Informed Consent Worksheet.  
• Obtain demographics and medical history 
• Administer T-MoCA (or MoCA), BDI and IADL Scale 
• Review and document concomitant medications, supplements, and therapies 
• Assess inclusion and exclusion criteria to determine subject eligibility 
• Assess and document adverse events (AEs) after subject signs informed consent form (ICF) 
 
 
6.1.1.1 Screen Failures 
Any subject who signs consent will be considered enrolled in the study. If a subject fails screening, at a 
minimum, the following information should be captured and entered into the Electronic Data System (EDC). 
• Inclusion/Exclusion Criteria  
• Demographics   
• Reason for screen failures 
 
6.1.2 Lead-In Visit (Day 0)  
This visit will take place within 28 days of the Screening Visit. The following procedures will be performed and 
will take approximately 1.5 hours.  
 
 
The following procedures will take place at the in-person office visit: 
• Measure Vital Signs  
• Physical and Neurological examination 
• Blood draw for safety labs and biomarker analysis  
• Dispense PBO 
• Explain and practice how to use technological devices and software that will be used during study- 
computer, daily Lumosity brain games, Fitbit device, Fitbit software. 
• Administer TOPF 
• Assess inclusion and exclusion criteria to determine subject eligibility 
 
6.1.2.1  Technology Check-In Phone Calls- Days 1, 7, and 21  
At Days 1, 7, and 21 ( 1 day) during the initial Lead-in Period, a study coordinator will call the subject to 
ensure they understand how to use all technology and discuss compliance if necessary. The subjects will 
also be provided with the study coordinator’s phone number and email and encouraged to contact the 
study coordinator with questions or concerns at any time.  

 
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6.1.3 Baseline Visit (Day 28), Crossover Visit (Day 84), and End of Study Visit (Day 140)  
These visits will occur 28 days ( 4 days) after the previous visit. These visits will occur in two parts: the first 
portion will occur virtually via Zoom videoconference no more than 4 days prior to the second portion, which 
will be an office visit. The following procedures will be performed and will take approximately 2.5-6 hours 
depending on participation in LP and MRI sub-studies. If the subject has elected to participate in the LP and/or 
MRI sub-study, the visit may occur over multiple days as long as all tasks are completed during the study visit 
window. 
 
The following measures will be performed virtually via Zoom videoconferencing no more than 4 days prior to 
the office visit: 
• Assessment of capacity to consent through administration of the Informed Consent Worksheet 
• Administer cognitive assessments 
• Administer functional and mood assessments 
• Assess technology compliance 
• Assess and document AEs and changes to medical history  
• Review and document concomitant medications, supplements, and therapies 
 
 The following procedures will occur in person: 
• Measure Vital Signs  
• Perform physical and neurological examinations  
• Blood draw for biomarker analysis 
o End of Study (Day 140) only- additional tubes for safety labs  
o If undergoing LP, then an additional fingerstick for point of care, same day PT/INR will also be 
performed 
• Assess study supplement compliance  
• Dispense study supplement or PBO (except at End of Study Visit) 
• Perform optional MRI scan 
• Perform optional fasting LP  
 
6.1.4   Block Midway Telephone Visits (Days 56 and 112) 
These visits will be conducted over the phone 28 days ( 4 days) after the previous visit. The following 
procedures will be performed and will take approximately 30 minutes.  
• Assess technology and study supplement compliance  
• Review and document concomitant medications, supplements, and therapies 
• Assess and document AEs and changes to medical history 
 
6.1.5 Follow Up Visit (Day 154) 
This visit will take place after 14 days (± 4 days) following the Day 140 visit. The following procedures will be 
performed. All procedures will be performed virtually via Zoom videoconferencing or by telephone. 
• Review and document concomitant medications, supplements, and therapies 
• Assess and document adverse events (AEs) and changes to medical history 
• Debriefing with Investigator on subject’s data during trial and experience in the study  

 
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If any labs from Day 140 were abnormal and clinically significant, the subject will also be asked to come in for 
an office visit blood draw for safety labs within the Follow up visit window. 
 
6.1.6 Early Termination Visit  
If the subject withdraws from the study after the Baseline visit and before completion of all study visits, they 
will be invited to participate in an Early Termination Visit within 7 days of stopping treatment. 
 
The following procedures will be performed virtually via Zoom videoconferencing no more than 4 days before 
the in-person office visit: 
• Administer cognitive assessments 
• Administer functional and mood assessments 
• Assess technology and study supplement compliance. 
• Review and document concomitant medications, supplements, and therapies 
• Assess and document AEs and changes to medical history 
 
The following procedures will be performed at the in-person office visit: 
• Measure Vital Signs  
• Blood draw for safety labs and biomarker analysis 
• Assess study supplement compliance  
 
 6.1.7  Protocol Deviations  
A protocol deviation is any noncompliance with the current clinical trial protocol. The noncompliance may be 
on the part of the subject, the PI, or the study staff. As a result of deviations, corrective actions will be 
developed by the PI and implemented promptly. All deviations from the protocol must be addressed in the 
subject’s documents. Protocol deviations will be sent to the IRB per their guidelines and entered in the Protocol 
Deviations Log in the EDC System.  
 
 6.1.8 Missed Visits and Procedures  
Missed visits and any procedures not performed (not attempted) for reasons other than illness or injury will be 
reported as a protocol deviation. Procedures or visits not performed due to illness, injury, or disability, including 
procedures that were attempted but failed (i.e. weight unable to be obtained due to subject immobility) will not 
be reported as protocol deviations. 
 
 
 
7 
CLINICAL ASSESSMENTS AND OUTCOME MEASURES 
 
7.1 
Clinical Variables 
Assessments will be performed at designated time-points throughout the study for clinical evaluation. In 
addition to the assessments evaluated below, subjects will provide information on their demographics, past 
medical and AD history, family history, and concomitant medication usage. 
 

 
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7.1.1  Safety Measures  
 
7.1.1.1 Vital Signs, Height, Weight 
Vital signs, including systolic and diastolic blood pressure, pulse rate (radial artery)/minute, respiratory 
rate/minute, and temperature will be assessed at specified visits. Verbal weight may be documented for those 
subjects utilizing a wheelchair. Height and weight will be measured and recorded at the Lead-In only. 
 
7.1.1.2 Clinical Laboratory Assessments  
Study participants will be asked to provide approximately 13 mL of blood for safety lab analysis at the 
Lead-In visit (with an additional draw at the Follow-Up visit if any Day 140 labs are abnormal and 
clinically significant), for a total of 22 ml (about 1.5 tablespoons) throughout the study. The participant 
will have his or her whole blood collected by either a nurse or phlebotomist from a peripheral vein. Blood 
will be handled, processed, and analyzed in accordance with regulations set forth by the American Society 
for Clinical Pathology and the College of American Pathologists. 
Tests for Complete Blood Count (CBC) and Prothrombin Time and International Normalized Ratio 
(PT/INR) which are required prior to performing a lumbar puncture may be performed using CLIA 
waived point of care testing using the Sysmex XW-100 CBC analyzer and the Roche CoaguChek XS Plus 
PT/INR analyzer. This will involve an additional fingerstick blood draw.  
The investigator may order additional testing, if thought to be necessary, to further assess an adverse event 
(AE). 
 
7.1.1.3 Physical and Neurological Examination 
A physical and neurological examination will be performed at Lead-In, Baseline (Day 28), Crossover (Day 84), 
and End of Study (Day 140). The following systems will be examined: general appearance, head, eyes, ears, 
nose, throat, neck, chest, heart, abdomen, extremities, edema, peripheral vascular, skin and appendages, 
musculoskeletal, central nervous system and back.  
 
7.1.1.4 Adverse Events 
Once the informed consent form has been signed by the subject, inquiry about all adverse events (AEs) will be 
performed at each study visit. 
 
7.1.2 Clinical Assessments  
 
7.1.2.1 Neuropsychiatric and Functional Assessments  
All neuropsychiatric questionnaires will be administered via Zoom videoconference; any required materials will 
be mailed or given to subjects prior to the visit.  
 

 
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7.1.2.1.1  Beck Anxiety Inventory (BAI)   
The Beck Anxiety Inventory21 (BAI) is a 21-item, self-administered questionnaire that measures the presence 
and severity of anxiety in psychiatric populations. It was constructed to avoid confounds due to comorbidity of 
depression, and it has been found to be highly valid, reliable, and consistent23. The BAI lists 21 common 
symptoms of anxiety and asks the subject to rate the severity with which they experience each symptom (not at 
all, mildly, moderately, or severely). Scores of 0-21, 21-35, or 36-63 indicate low, moderate, or severe anxiety, 
respectively.  
 
7.1.2.1.2  Beck Depression Inventory (BDI)   
The Beck Depression Inventory22 (BDI) is a widely used assessment of depression severity used in clinical and 
research settings. It is a 21-item, self-administered rating inventory with a mean internal consistency of 0.8624.The 
BDI ranks responses to several domains of depression, including mood changes, guilt, self-image, suicidality, 
affect, and apathy on a scale from 0 to 3 and provides an assessment of the level of depression, spanning minimal 
to mild to moderate to severe depression. 
 
7.1.2.1.3  Memory Function Questionnaire (MFQ)  
The Memory Function Questionnaire20 (MFQ) is an 8 question, self-administered functional assessment which 
measures the frequency and severity of self-perceived memory-related capabilities. The questionnaire involves a 
general rating of frequency of memory problems, a retrospective intraindividual comparison of memory decline, 
an assessment of forgetting frequency, an assessment of forgetting severity, and an assessment of self-derived 
mnemonic device usage. The MFQ was determined to show high internal consisteny20 and moderate concurrent 
validity with subsequent performance on clinical measures of memory25.  
 
7.1.2.1.4  Behavior Rating Inventory of Executive Function (BRIEF-A) 
The Behavior Rating Inventory of Executive Functioning19 (BRIEF-A) is a standardized rating scale to assess 
self-regulation and executive function in everyday behaviors. It is a 75-item scale including a Behavioral 
Regulation Index consisting of inhibition, shifting, emotional control, and self-monitoring scales and a 
Metacognition Index consisting of initiation, working memory, planning/organization, task monitoring, and 
organization of material scales. This study will only use the BRIEF-A self and not the informant report.  
 
7.1.2.1.5  Lawton Instrumental Activities of Daily Living (IADL) Scale  
The Lawton Instrumental Activities of Daily Living Scale (IADL) Scale26 covers 8 domains of functioning and 
was designed to assess independent living skills in older adults27.  IADLs are more complex than basic Activities 
of Daily Living (ADLs) and are therefore more sensitive to disruption due to cognitive impairment. This scale 
takes about 10 minutes to complete and is administered by a trained rater who will determine whether participants 
are functionally impaired and therefore not eligible to participate in the study per inclusion criteria 2.  
 
7.1.2.2 Neurocognitive Assessments  
All neurocognitive assessments will be administered via Zoom videoconference.  

 
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7.1.2.2.1  Montreal Cognitive Assessment (MoCA) 
The Montreal Cognitive Assessment (MoCA)28 is a commonly used screening tool in clinical trials and research settings to 
measure potential presence of cognitive impairment. The MoCA measures five areas of cognitive function: orientation, 
visuospatial, attention and calculation, recall, and language. This measure will be completed as part of screening procedures 
carried out by the Northern Light Healthcare site and should take approximately 10 minutes.  
 
7.1.2.2.2 Telephone Montreal Cognitive Assessment (T-MoCA; also referred to as MoCA-Blind)  
The Telephone Montreal Cognitive Assessment28 (T-MoCA) is a commonly utilized abbreviated cognitive 
screener adapted from the full Montreal Cognitive Assessment for the purposes of measuring levels of cognitive 
impairment over the telephone. The telephone MoCA measures five areas of cognitive function: orientation, 
abstraction, attention and calculation, memory, and language. The telephone MoCA will take approximately 10 
minutes to complete and will be administered by experienced raters following the administration 
recommendations specified by the test publishers. The telephone MoCA will be administered only at the 
Screening visit to determine subject eligibility, and will require participants to achieve a telephone MoCA score 
of 16-22 inclusive.   
 
7.1.2.2.3  Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
The Repeatable Battery for the Assessment of Neuropsychological Status15 (RBANS) is a commonly used 25-
minute, standardized neurocognitive battery assessing functioning across multiple cognitive domains. It is 
designed to be administered repeatably, with several equivalent alternate forms available. The RBANS 
measures a total of five neurocognitive domains using twelve subtests: immediate memory (List Learning and 
Story Memory), visuospatial/constructional (Figure Copy and Line Orientation), language (Picture naming and 
Semantic Fluency), attention (Digit Span and Coding), and delayed memory (List Recall, List Recognition, 
Story Memory, and Figure Recall).  The RBANS has been shown to be effective at both detecting and 
characterizing forms of dementia. The Delayed Memory domain has been shown to be particularly sensitive to 
discriminating MCI due to Alzheimer's disease from controls, and also is predictive of cerebral amyloid 
burden15. The RBANS will be administered at Baseline, Crossover, and End of Study using alternate forms. The 
RBANS will be administered virtually via Zoom videoconference. The coding subtest response form will be 
mailed or given to subjects before their scheduled visits along with a prepaid envelope for the form to be 
returned. 
 
7.1.2.2.4  Millisecond Continuous Performance Test (CPT)  
The Continuous Performance Test is a test of sustained attention and alertness in which subjects are presented 
with a string of letters29. The subject is instructed to press a button every time they see an X and not to press it 
for any other letter. Letters are presented for five minutes. The subject is then given a brief break before 
continuing to the next part of the study, the AX task. In this section, the subject is told to press the button when 
they see an X that follow right after an A but not when there is an X that is not preceded by an A. The subject is 
then presented with another five-minute block of letters. This section of the task is also a test of inhibition and 
executive control. Task administration will utilize Millisecond Inquisit software, a computerized stimulus 
presentation platform optimized for temporally precise stimuli presentation and reaction time recording of 
psychological assessments. The CPT will be administered at Baseline (Day 28), Crossover (Day 84), and at End 

 
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of Study (Day 140). Task administration will utilize Millisecond Inquisit Lab software, a stimulus presentation 
platform optimized for temporally precise stimuli presentation and reaction time recording of digitized 
psychological assessments. Inquisit Web requires only a subject code and no personally identifiable 
information. 
 
7.1.2.2.5  Test of Premorbid Functioning  
The Test of Premorbid Functioning30 (TOPF) provides an estimate of premorbid intellectual functioning that 
allows for comparisons with an individual’s current cognitive status. The test consists of a list of 70 words that 
have atypical grapheme to morpheme translations. A premorbid estimate of intelligence is calculated based on 
the raw TOPF score (number of words correctly read) and up to 13 demographic variables. The tests 
demonstrates excellent reliability across the age groups included in this study (Ages 60-90 = 0.98-0.99), in MCI 
(0.98), and in AD (0.99)31.   
 
7.1.2.2.6   Trail Making Test  
The Trail-Making Test16 (TMT) is a graphomotor letter and number-letter sequencing task that will be 
administered to test processing speed, mental flexibility, and set-switching. The test takes approximately 5 
minutes to complete. The standard, paper version of this test cannot be administered virtually, so the oral Trail 
Making Test (45) will be used at all study visits.  
 
7.1.2.2.7  Brief Visuospatial Memory Test-Revised (BVMT-R)  
The Brief Visuospatial Memory Test-Revised18 (BVMT-R) is a test of visuospatial learning and memory with 
six equivalent alternate forms.23 The BVMT-R has three learning trials, a 25-minute delay, and then delayed 
recall and recognition trials. The visual stimuli for each learning trial will be presented digitally. The recall and 
recognition portion of this assessment will be given in the traditional, pencil and paper format and scored 
according to published administration instructions and norms. Permission to adapt BVMT-R stimuli into a 
digital format was granted by the publisher of the test. The BVMT-R will be administered at Baseline, 
Crossover visit, and at End of Study.   
 
7.1.2.4   Phlebotomy for AD Biomarkers 
Subjects will provide additional blood samples for AD biomarker analysis at Lead-In and each block visit (Day 
28 up to and including Day 140). Biomarker analysis will include NfL, Aβ42, Aβ40, tau, GFAP, neurogranin, and 
other analytes. At each block visit (Days 0-140), 30 ml (2.0 tablespoons) of blood will be collected for research 
analyses, for a total of approximately  120 ml (8 tablespoons) over the course of the study.  
 
7.1.2.5  Magnetic Resonance Imaging (MRI) 
Subjects will be given the opportunity to participate in an optional MRI sub-study at Baseline (Day 28), 
Crossover (Day 84), and/or End of Study (Day 140). Subjects electing to participate will be asked to complete 
all 3 MRIs to be part of the sub-study. Data will be collected on a 3-Tesla Siemens scanner with the following 
scan sequences: a high resolution T1-weighted scan, T2 FLAIR, resting state BOLD MRI, and pCASL at rest. 
Resting state BOLD measures low-frequency spontaneous fluctuations in BOLD signal across time, 
where correlations of this spontaneous activity between brain regions are thought to reflect functional 

 
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connectivity. The 10-minute rsfMRI scan will be acquired with whole-brain echo planar imaging (EPI) time 
series with a voxel size of 2x2x2 mm isotropic, TR/TE = 4000/30 ms, acquisition matrix = 64x64, and 40 axial 
slices. Subjects will be instructed to keep their eyes open throughout the duration of the scan. rsfMRI data will 
be processed within the FreeSurfer FS-FAST stream using standard pre-processing steps including motion 
correction, masking of non-brain tissue, registration to the anatomical high-res image, sampling to the surface, 
and surface smoothing by 5 mm. Temporal filtering to extract signals in the 0.008-0.08 Hz frequency band will 
be performed, followed by linear regression to factor out mean global signal, average signal from white matter, 
and average signal from ventricular CSF regions. To perform functional connectivity analyses, we will use a 
seed-based approach to examine temporal correlations between the mean time course within anatomically-
defined nodes and the rest of the brain.  
 
ASL-MRI is another indicator of brain function, quantifying regional cerebral blood flow, which in turn is 
linearly coupled to regional brain metabolism and neuronal activity36,37. It is especially well suited to drug trials 
in which change from baseline is of prime interest38–40. Pseudo-Continuous ASL (pCASL)40, which provides 
excellent sensitivity and temporal stability41 and accurately differentiates AD from other causes of dementia42, 
will be used in the protocol. The single shot pCASL scan will be acquired with the following parameters: 24 cm 
field of view, 2x2x2 mm isotropic, TR/TE = 4300/3.2 ms, acquisition matrix = 64x64, slice thickness = 6mm, 
temporal bolus = 1800 ms with a 1800 ms post labeling delay. Corresponding field map scans will also be 
acquired to correct for blurring and signal dropout during image processing. All data processing and analysis 
will utilize tools available through FSL’s Bayesian Inference for Arterial Spin Labeling MRI (BASIL) toolbox. 
 
7.1.2.6  Lumbar Puncture 
Subjects will have the option of participating in three lumbar punctures over the course of the study (at Days 28, 
84 and 140).  Lumbar punctures will be performed after a minimum of an 8 hour fast. The subject will be 
positioned seated or lying on his/her side on the examination table. Standard protocols will be used employing 
palpation to identify the L3-4, L4-5 or L5-S1 vertebral interspaces, sterile conditions, local lidocaine anesthesia, 
and use of the Sprotte 24-gauge needles. Lumbar punctures will be performed by qualified, experienced 
practitioners. Approximately 20 cc of CSF will be collected for analysis of various AD/ADRD, redox, and 
metabolism and other biomarkers, including NfL, 8-OHdG, pyruvate/lactate, tau, phospho-tau, amyloid-β42/40, 
and neurogranin. Subjects will also complete a brief REDCap survey after the LP in which they will answer 
questions about the tolerability of the procedure. After the LP is complete, subjects will be given time to eat 
breakfast or have a snack before continuing with the visit.  
 
If a subject has difficult back anatomy or is particularly overweight, and the physician or nurse practitioner does 
not feel comfortable performing the LP because they are not able to locate the proper lumbar landmarks, the 
subject will be scheduled to undergo the LP under fluoroscopy at MGH Interventional Radiology. Fluoroscopy 
time will vary person to person. The average radiation dose is 0.06 mSv, or the equivalent of 1 week of natural 
background radiation, per LP for a total of 0.2 mSv (3 weeks of natural background radiation) over the duration 
of the study.   
 
7.1.3 Daily Outcomes  

 
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7.1.3.1  Mood and sleep ratings 
Before beginning each Lumosity session, the subject will be asked to rate their mood and sleep. The survey will 
consist of two brief questions and require no more than two minutes of the subject’s time. 
 
7.1.3.2  Cognitive Exercises  
Each subject will be provided with a Lumosity (Lumos, Labs, Inc.) account. The subjects will be required to 
complete 6 different cognitive exercises (about 10-15 minutes) at least 6 days per week for the duration of the 
study (from Days 0 to 140).  The assigned cognitive exercises will sample the domains of attention, processing 
speed, memory, cognitive flexibility, and problem solving. Compliance can be assessed by the study 
coordinator by logging on to each subject’s Lumosity account. If the subject is not adhering to the cognitive 
exercise requirements, the study coordinator will contact the subject to remind them of proper exercise 
procedures. If a subject requires more than three such reminders, they will be considered non-compliant, and PI 
will determine if the subject should continue in the study or if their study participation should be discontinued. 
 
7.1.3.3  Daily activity and sleep tracking 
Each subject will be provided with a Fitbit Charge 4 that they will wear throughout the study. The device will 
track the participant’s heart rate, activity, and sleep. The subject will be instructed to wear their device at all 
times, except for when it is being charged and when they are bathing.  
 
7.1.3.3.1 Charging and syncing procedures  
Subjects will be instructed to ensure that the device is charged at all times. The subject will be instructed to 
charge their device when their battery is low (roughly once every 4 days) during a period of inactivity, such as 
when watching TV. The subject will be explicitly instructed not to charge their device during times of sleep. 
The subject will be instructed to sync their device at least 3 times per week. Charging and syncing compliance 
will be routinely monitored by a study coordinator. The coordinator will conduct periodic reviews of the 
subject’s charging and syncing compliance by logging onto the subject’s Fitbit dashboard. If the device has not 
been appropriately charged or synced, the study coordinator will contact the subject to remind them to sync or 
charge their device as needed. If a subject requires more than three such reminders, they will be considered non-
compliant, and the PI will determine if the subject should continue in the study or if their study participation 
should be discontinued. 
 
7.2  Training and Validation 
All evaluators must be certified by the study PI to perform cognitive and psychiatric outcome assessments. It is 
strongly preferred that a single evaluator performs all measures with a given instrument throughout the study, if 
possible.  
 
 
 
 
 
 
 

 
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8.  
INTERVENTIONS ADMINISTERED  
8.1  
INTERVENTION  
8.1.1  Study Product Description 
Niagen® is a commercially available form of nicotinamide riboside (NR) manufactured by ChromaDex, Inc. 
Niagen® is generally recognized as safe (FDA GRAS Notice No. 635) for use in a variety of media, including 
vitamin waters, protein shakes, and powdered beverages. Niagen® has five issued process and use patents in the 
United States and several others internationally.  
 
Chemical Structure of nicotinamide riboside: 
 
 
8.1.2  Drug and Placebo 
Chromadex Inc. will provide 250 mg capsules. Identical appearing capsules with only filler will be prepared as 
placebo. 
 
8.1.3  Acquisition 
When the study intervention shipment arrives at the site, the person accepting the shipment must perform an 
inventory and fill out a supplement receipt log. The contents of the shipment must be counted, verified, and 
inspected for damage. Any damaged shipments will be documented. The study supplement will be picked up 
from MGH Clinical Trials Pharmacy on the same day it will be dispensed. Detailed logs will be kept recording 
quantity of supplement dispensed and study staff in charge of supplement transport and dispensing. 
8.2.  
Product Storage and Stability 
Niagen NR is found to be stable under ambient conditions of 25 °C and 60% relative humidity for 11 months in 
a solid, powdered form. 
 
8.3 
Dosage, Preparation and Administration of Study Intervention 
Niagen NR 500 mg (two capsules) or PBO (two capsules) should be taken orally twice daily with food. The 
capsules should be swallowed whole.  
 

 
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8.4 
Modification of Study Intervention for a Subject 
Dosing may be reduced or suspended at any time by the PI or designated licensed clinician sub-investigator. 
This will be documented along with the reason(s) and dates of adjustment in the CRF for each subject requiring 
this manipulation. The PI or designated licensed clinician Sub-Investigator may reduce or suspend the dosage of 
study dietary supplement or discontinue the study supplement for AEs thought to be related to the study 
supplement or for other reasons during the trial (the reason and dates of reduction or suspension or dose 
reduction or suspension must be documented in CRF). If the AE is mild or moderate, the dosage may be re-
started after the event improves. If the AE is serious or life threatening and deemed to be definitely related to 
the dietary supplement, the study dietary supplement will be discontinued immediately. Study subjects must 
remain off the study dietary supplement permanently. Subjects may not resume study dietary supplement. All 
AEs will be followed to resolution. 
8.4.1  Dosage Discontinuation 
Reasons for discontinuation of study dietary supplement may include an AE or PI recommendation, protocol 
deviation, loss-to-follow-up, patient request, or death. All serious adverse events (SAEs) that occur in a subject 
who has discontinued early must be recorded and reported within 24-hours of awareness. Study subjects who 
discontinue study dietary supplement prematurely (early discontinuation from study) and decide not to remain 
in the study will be encouraged to return for an Early Termination Visit.  
 
8.5  
Assessment of Subject Compliance 
Subjects will be instructed to return empty and unused study dietary supplement containers at each clinic visit 
or the Early Discontinuation Visit. Research staff will review returned and unused study dietary supplement and 
log information into the reconciliation form to determine compliance. Non-compliance will be defined as taking 
less than 80% or more than 120% of study agent as determined by unused capsule counts. If a study subject is 
non-compliant with study dietary supplement, research staff should re-educate and train the subject in 
administration of study agent. If the subject’s non-compliance persists, it will be left up to the PI to determine 
whether the subject should be discontinued from the study.  
9. 
STATISTICAL ANALYSIS 
 
9.1  
Biostatistical analysis  
This is a crossover randomized controlled trial with the goal of determining the effects of a potential cognition-
enhancing dietary supplement for older adults with SCD and MCI. The primary analysis will be based on an 
intention to treat approach and will include all subjects randomized at the onset of the trial to either NR then 
placebo or placebo then NR as described below. 
 
In this study, the participants will pass through intervention blocks with administration of both NR and PBO for 
eight weeks administered in random order. The primary cognitive outcome measure will be the Total Scale 
score of the RBANS which will be administered at Baseline (Day 28), Crossover (Day 84), and End of Study 
(Day 140). The RBANS is a robust 25-minute, standardized neurocognitive battery with multiple alternate 
versions whose 12 subtests yield five Index scores, one for each cognitive domain, and the Total Scale score. 

 
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Normative data have been published for cognitively normal older adults, as well as for MCI and AD 
populations.  For example, in a study of MCI, the mean Total Score Index was reported to be 92.4 with a 
standard deviation of  9.143. Based on test-retest reliability, a minimal detectable change in community-dwelling 
older adults (including normal, MCI and mild dementia) for the Total Score is 543. A “minimum clinically 
important difference” in MCI was reported to be 8 points44. 
 
The basic data of a crossover trial are the measurements obtained in 2 or more different intervention conditions 
occurring over time. The principal goal is to compare outcomes for each condition within a randomized block 
structure while accommodating repetition within subjects and possible effects of carryover or disease 
progression. 
 
Assessment of normality of data distribution will be completed prior to inclusion in any analysis. If the 
distribution of the outcome variables (e.g., RBANS Total Score, etc) are not normal, appropriate 
transformations (e.g., logarithm, square-root, Box-Cox transformation, etc) will be applied. Data analysis at the 
individual and group levels for the primary outcome will begin with visual inspection of RBANS Total Scores 
at each assessment for differences from baseline for each measurement and differences between intervention 
conditions. Ignoring potential for carryover, a simple matched pair t-test will be performed using data from each 
condition.  Should carryover effects or other time trends be suspected, we can use a regression model adjusting 
for sequence. 
 
Mixed-effects models will be used to compare the scores at the end of each study period (Days 28, 84, and 140) 
between NR and PBO incorporating variance within and between participants. This within-patient level will 
accommodate variation resulting from the intervention crossovers as well as time effects modeled in various 
forms (e.g., linear and non-linear trends, carryover effects). Each within-subject regression coefficient will be 
treated as a random effect that can vary based on these between participant factors. The primary analysis will 
calculate the average intervention effect (i.e., will model the mean of the individual intervention effects as a 
constant). Secondary analyses will model the mean as a function of factors that vary among patients such as age 
and sex. These terms describe the main effects of these factors, their interactions with the intervention, and their 
interaction with time. The analysis will be completed using SAS PROC MIXED through a restricted maximum 
likelihood analysis with a mixed model with fixed effects for sequence and treatment. Appropriate covariance 
structure will be investigated using Akaike’s information criterion (AIC). 
 
The full multilevel model will estimate both average effects across the population of participants, as well as 
effects for individuals informed by the results on other participants. The predicted effects for an individual 
participant are weighted averages of his or her data and the averages from others. This model incorporates 
correlations among the measurements within an individual and enables comparison of the individual’s predicted 
intervention effect using the multilevel model with that from using only that individual’s data.  
 
When conducting study analyses we can also calculate 95% confidence intervals for the difference in response 
for active treatment versus placebo treatment for descriptive purposes. Similar analyses will be applied to all 

 
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outcomes. All outcomes in this pilot study are considered exploratory and no claims are attached to them, thus 
multiple comparison correction is not applied. Therefore P value <0.05 will be considered significant.  
 
Carryover is always a potential confound in crossover studies. While the pharmacokinetic half-life of NR is 
short (2.7 hours), its pharmacodynamic effects may be long-lived and we cannot exclude carryover and practice 
effects affecting measures in successive assessments if NR precedes PBO. We do not expect carryover 
pharmacological effects from PBO, but assessment practice effects might differentially affect measurements 
made in an NR intervention period that follows PBO.  This may be difficult to gauge with our primary RBANS 
outcome measure taken only once at the beginning/end of each intervention period.  However, we will have 
other resources with which to evaluate this using our exploratory outcomes, especially the daily cognition 
measures.  We will investigate various adjustments for carryover, such as discarding the first measurements in 
an intervention period on outcomes measured daily, to determine whether results are sensitive to carryover. 
These adjustments can allow for potential differential carryover by intervention regimen.  
 
10. 
SAFETY AND ADVERSE EVENTS 
 
10.1  Potential Risks and Benefits 
At screening, we will collect standardized historical, symptomatic, physical exam, and laboratory parameters to 
identify health conditions that represent risks for participation in the study's procedures. Chief among these 
would be unstable coagulopathies or anti-coagulant therapies that increase the risk of phlebotomy and lumbar 
puncture and unstable medical conditions. 
 
10.1.1  Potential Risks 
Nicotinamide Riboside: Nicotinamide riboside is well-tolerated in patients, with few adverse events reported in 
a minority (3.3%) of patients6: 
• Mild nausea 
• Mild skin rash  
• Mild flushing/hot flashes 
• Mild leg cramps 
• Increased bruising  
 
None of the reported adverse events led to discontinuation of NR during its intervention period. 
 
Phlebotomy: The risks associated with having blood drawn include bruising and local discomfort. Rarely an 
infection may occur at this site, and if an infection does occur it will be treated by the study physician.  
 
Magnetic Resonance Imaging: MRI is a safe procedure for subjects who do not have metal implants or other 
contraindications. Individuals who have electrically, magnetically, or mechanically-activated implants (such as 
heart pacemakers) or those who have clips on blood vessels in their brain will not be allowed to participate in 
the study due to risks associated with MRI scanning. The MRI will be operated in a manner accepted by the 
FDA. The protocol requires subjects to remain still within a relatively confined space during the scanning 

 
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session, and the scanner makes loud knocking and beeping sounds as it takes images. While subjects with 
severe claustrophobia are excluded from the study, some subjects may find the physical confinement or noise 
uncomfortable. Every effort will be made to enhance each subject’s comfort level, and subjects will be given 
earplugs to reduce discomfort due to noise. If a subject notices any discomfort while in the MRI scanner, (s)he 
should notify the administrator immediately. If the discomfort cannot be stopped, the scanning session will be 
stopped. The MRI has the potential, during normal routine use, to cause localized warming of the skin and 
underlying tissues. Subjects should immediately inform the study staff if they experience discomfort due to 
warming of the skin and the procedure will be stopped. 
 
Neurocognitive testing: The neurocognitive tests that will be administered to assess mental performance may be 
stressful and potentially cause anxiety, fatigue, and frustration. In our prior experience with similar protocols, 
risks have occurred infrequently and very few subjects have terminated testing. However, testing will be 
discontinued immediately upon any request by the subject to do so. With the evaluation of individuals with 
cognitive complaints, there is always the potential for a subject to enter the study with SCD and subsequently 
demonstrate a decline in cognitive performance throughout the course of the study to a level consistent with a 
diagnosis of MCI. If this occurs, a licensed clinician will meet with the subject and suggest that they see their 
primary care provider for further evaluation. 
 
Daily Cognitive Exercises: The daily Lumosity (Lumos Labs, Inc.) brain exercises may be stressful, tedious, 
and potentially cause fatigue, and frustration. However, the program was designed to resemble games and the 
duration is short, so the likelihood of these potential risks is low.  
Questionnaires: Questionnaires administered during the protocol may cause subjects to feel sad or upset about 
how their neurocognitive functioning affects their quality of life. Study staff is experienced with such 
evaluations and sensitive to these issues. Any question can be omitted per the subject’s request.  
 
Wrist Actigraphy: The wrist actigraph, the Fitbit Charge 3, may cause some minor discomfort due to prolonged 
wearing, but the risk of such discomfort will be minimized by ensuring the wristband fits the subject properly 
(e.g. is not too tight or does not cause irritation). If the subject does experience discomfort, another wristband 
will be ordered to try to eliminate the discomfort.  
 
Lumbar puncture (LP): Pain may occur during the procedure. This is usually temporary, confined to the lower 
back, and minimized with the cutaneous and soft tissue administration of 1% lidocaine as a local anesthetic. 
Short-lived LP associated headaches occur in <1%-36% of subjects with an incidence that decreases with age45–
47. Less commonly, a persistent low-pressure headache may develop as a result of a post-LP CSF leakage. 
Lower rates of post-LP headache have been noted with the atraumatic (Sprotte) 24-gauge needle that will be 
used in this study47. Potentially more serious, but very rare risks, include infection, damage to radicular nerves 
and bleeding into the lumbar CSF space. The risk of these procedure related complications is much less than 
1%.  
 
Videoconferencing: Visits that take place via videoconferencing may allow research staff to learn more about 
the subject’s home and cohabitants than an office visit. The study team will use a secure Zoom 

 
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videoconferencing platform and conduct the visit in a private location to ensure personal information about the 
subject is kept confidential. 
 
 
Other Risks: Reviewing health-related information might be stressful or make the subject feel uncomfortable. 
Subjects do not have to answer any questions they do not want to. In addition, there may be incidental medical 
findings as a result of the physical examination. 
 
10.1.2  Known Potential Benefits  
NR has been tested in a number of clinical trials in middle-aged and elderly patients and has shown to be well-
tolerated. If successful, this trial will further understanding of the effects of NR on standard and personalized 
assessment of cognitive, neuropsychiatric, and everyday functioning in brain aging. This trial is also assessing 
multiple biomarkers in concert with clinical outcomes, which will provide a detailed understanding of NR 
activity and provide a well-curated data set for the Alzheimer’s research community to improve our 
understanding of cognitive decline in aging and AD/ADRDs.  
 
10.2  Data Security 
 
10.2.1 Laptop computers and iPads 
Subjects will be given the choice to use their personal computers or study-provided laptops to use for Lumosity 
cognitive exercises. Fitbit and Lumosity are web-based applications that require no PHI or personally 
identifiable information be entered into the system, so there are no additional data safety risks to the subject if 
they use their personal computers. Older adults may have difficulty adapting to new technologies, resulting in 
increased cognitive and perceptual demands48. Because a major outcome of this trial is performance on 
computerized cognitive brain games, it is important that subjects’ performance is not influenced by the novelty 
of the study laptop.   
 
If a subject does not wish to use their personal computer, they will be provided with a study laptop. Study 
laptops will be registered under the Principal Investigator and no identifying information will be required to 
sign in.  The study subject will be provided with a password that adheres to Partners password requirements to 
log in to the computer. We will also provide an information sheet with detailed instructions on how to use the 
laptop to complete study tasks in. 
 
Subjects will sync Fitbit activity tracking through the Fitbit app downloaded to their personal mobile device by 
logging into the application with their provided, deidentified account. If a subject does not have a compatible 
smart phone, an iPad will be provided. The provided iPad will be a Partners device enrolled under Mobile Iron. 
The Fitbit app will be downloaded prior to distributing the iPad, and all other applications will be blocked from 
use.  
 
10.2.2 Lumosity software 

 
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For the successful completion of this research study, Lumos Labs will provide de-identified user accounts to the 
principal investigator. The research team at MGH will be responsible for assigning these de-identified accounts 
to research participants, as they are enrolled in the trial.  These accounts will have a generic date of birth and will 
not contain any personal health information or personally identifying information. Lumos Labs does not collect 
or store any personally identifying information of research participants. A copy of Lumos Labs Privacy Policy 
and Terms of Service will also be reviewed by the subject during the consenting process. By consenting to the 
study, the subject is also agreeing to these policies and terms.  
 
Any record of cognitive exercises and assessment data provided by Lumos Labs to MGH will be restricted 
to data created through or generated by study subjects or study subjects access to or use of Lumosity and will not 
contain personal information of other Lumosity users. Lumos Labs will send data reports via email to the study 
staff in a CSV file which will be downloaded and stored on Partners compliant workstations.   
 
10.2.3 Fitbit activity tracker  
A study coordinator will create a unique, deidentified email and password combination to create an account on 
Fitbit.com. To create an account, the following information will be required: first and last Name (a de-identified 
placeholder name], date of birth (January 01, year of birth), gender, height, and weight. The subject will be 
given the associated account information so that they are able to login, sync their device, and use the Fitbit 
dashboard. The subject will be notified that the researcher will also have full access to their account and will be 
able to freely view and download the subject’s data for research purposes. A copy of Fitbit’s Privacy Policy and 
Terms of Service will also be reviewed by the subject during the consenting process. By consenting to the 
study, the subject is also agreeing to these policies and terms.41 
 
After the subject has completed or if they are withdrawn from the study, their Fitbit account and all associated 
data will be deleted. However, prior to deleting the account, the de-identified study data will be downloaded and 
stored confidentially on Partner’s computers for study purposes.  
 
11. 
MONITORING AND QUALITY ASSURANCE 
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with all 
applicable United States Food and Drug Administration (FDA) regulations and International Conference on 
Harmonisation (ICH) guidelines. The PI will carefully monitor each subject throughout the study for possible 
adverse events. All AEs will be documented on CRFs designed specifically for this purpose. It will be important 
to report all AEs, whether serious or non-serious. 
 
11.1  Independent Monitoring of Source Data 
The PI will ultimately be responsible for the validity and integrity of the data collected at the MGH site, and for 
ensuring that the study is conducted in accordance with the IRB-approved protocol. After data is collected and 
recorded on forms, the study coordinator may input the data into the Partners approved StudyTrax EDC. Entries 
will be reviewed for accuracy and completeness by a second study coordinator. Finally, the PI or his designee 
(Co-I) will conduct monthly reviews to check that data in StudyTrax accurately reflects the data collected on the 

 
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original data capture forms. The research team (PI, Co-I, research coordinators) will subsequently meet to 
discuss the results of this review, as well as case report forms and source documentation.  
 
All electronic documentation will be stored on password-protected devices in locked cabinets located in secured 
areas. Paper forms will be stored in locked cabinets located in secured areas. 
 
Source documents that are sent to the subject (i.e. informed consent documents, cognitive testing materials) will 
be returned to the study team. To ensure validity of source documentation, the subject will put the documents 
into the envelope, seal the envelope, and sign the back of the envelope during the virtual visit. 
 
 
 
11.2  Safety Monitoring  
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with all 
applicable United States Food and Drug Administration (FDA) regulations and International Conference on 
Harmonization (ICH) guidelines. The PI will carefully monitor each subject throughout the study for possible 
adverse events. All AEs will be documented on CRFs designed specifically for this purpose. It will be important 
to report all AEs, whether serious or non-serious. 
 
 
11.3  Definitions of AEs & SAEs 
 
11.3.1  Adverse Event 
An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal 
laboratory finding, for example), symptom, or disease temporally associated with a study, use of a drug product 
or device, whether or not considered related to the drug product or device. 
 
Examples of adverse events include: new conditions, worsening of pre-existing conditions, clinically significant 
abnormal physical examination signs (i.e. skin rash, peripheral edema, etc.), or clinically significant abnormal 
test results (i.e. lab values or vital signs), with the exception of outcome measure results, which are not being 
recorded as adverse events in this trial (they are being collected, but analyzed separately). Stable chronic 
conditions (e.g. arthritis) that are present prior to the start of the study and do not worsen during the trial are NOT 
considered adverse events. Chronic conditions that occur more frequently (for intermittent conditions) or with 
greater severity are considered as worsened and therefore would be recorded as adverse events. Adverse events 
are generally detected in two ways: 
• Clinical → symptoms reported by the subject or signs detected on examination. 
• Ancillary Tests → abnormalities of vital signs, laboratory tests, and other diagnostic procedures 
(other than the outcome measures, the results of which are not being captured as AEs). 
 
If discernible at the time of completing the AE log, a specific disease or syndrome rather than individual associated 
signs and symptoms should be identified by the PI and recorded on the AE log. However, if an observed or 
reported sign, symptom, or clinically significant laboratory anomaly is not considered by the PI to be a component 

 
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of a specific disease or syndrome, then it should be recorded as a separate AE on the AE log. Clinically significant 
laboratory abnormalities, such as those that require intervention, are those that are identified as such by the PI. 
 
Subjects will be monitored for AEs from the time they sign consent until completion of their participation in the 
study (defined as death, consent withdrawal, loss to follow up, early study termination for other reasons, or 
following completion of the entire study). An unexpected adverse event is any adverse event, the specificity or 
severity of which is not consistent with the current Investigator’s Brochure. 
 
The study procedures and the well-being of all participants will be monitored closely by the MGH principal 
investigator, Steven Arnold MD, and the Co-Investigators, Nadine Schwab, PhD and Alison McManus DNP, 
FNP-BC. Throughout the course of the study, constant feedback with the subject is maintained in order to assess 
comfort and safety and to minimize risks throughout the procedure. The above investigators will be responsible 
for determining if a subject should be removed from the study. Criteria for removal include the following: 1) if a 
subject is unwilling or unable to participate in study procedures 2) if the subject refuses to participate and consent, 
3) if the subject acquires a medical condition that prohibits further participation, 4) if in the opinion of the MGH 
principal investigator, Dr. Steven Arnold, it is decided that it is not in the subject’s best interest to continue 
participation.  
 
Unanticipated problems including adverse events will be reported to the Partners Human Research Committee 
(PHRC) as described in the PHRC policy on Unanticipated Problems Involving Risks to Subjects or Others 
including adverse events. 
 
The Data Management team will be responsible for the development, execution, and supervision of plans, 
policies, programs, and practices that control, protect, deliver, and enhance the value of data and information 
assets. All data will be managed in compliance with applicable regulatory requirements. The study coordinator, 
under the supervision of the PI, will collect, transcribe, correct, and transmit the data onto source documents, 
Case Report Forms (CRFs), and/or other forms used to report, track, and record clinical research data. The study 
coordinator will be instructed to enter this information into the StudyTrax Electronic Data Capture (EDC) System. 
The StudyTrax platform provides password protection. An edit checking and data clarification process will be 
put in place to ensure accuracy of the data. Logic and range checks as well as more sophisticated rules may be 
built into the eCRFs to provide immediate error checking of the data entered. The system has the capability to 
automatically create electronic queries for forms that contain data that are out of range, out of window, missing, 
or not calculated correctly. The platform will have the ability to lock specific visits to prevent any modification 
of data once the visit is closed. Once this option is activated, every user will have Read-Only access to the data. 
The PI, Dr. Arnold, will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
11.3.2  Serious Adverse Events 
All adverse events will be reviewed by the MGH Principal Investigator, Dr. Steven Arnold, and will be reported 
to Partners IRB and to the Human Research Committee (HRC) in accordance with HRC Guidelines. A serious 
adverse event (SAE) is defined as an adverse event that meets any of the following criteria: 

 
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1. Results in death. 
2. Is life threatening: that is, poses an immediate risk of death as the event occurs. 
o This serious criterion applies if the study subject, in the view of the PI, is at immediate risk of 
death from the AE as it occurs. It does not apply if an AE hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
o Hospitalization for an elective procedure or a routinely scheduled treatment is not an SAE by this 
criterion because an elective or scheduled “procedure” or a “treatment” is not an untoward 
medical occurrence. 
4. Results in persistent or significant disability or incapacity. 
o This serious criterion applies if the “disability” caused by the reported AE results in a substantial 
disruption of the subject’s ability to carry out normal life functions. 
5. Results in congenital anomaly or birth defect in the offspring of the subject. 
6. Necessitates medical or surgical intervention to preclude permanent impairment of a body function 
or permanent damage to a body structure. 
7. Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may also be considered SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include blood dyscrasias or 
convulsions that do not result in inpatient hospitalization. 
 
An inpatient hospital admission in the absence of a precipitating, treatment-emergent, clinical adverse event 
may meet criteria for "seriousness" but is not an adverse experience and will therefore not be considered an 
SAE. An example of this would include a social admission (subject admitted for reasons other than medical, 
e.g., lives far from the hospital, has no place to sleep). 
 
The PI is responsible for classifying adverse events as serious or non-serious. 
 
11.4  Assessment and Recording of Adverse Events 
The PI will carefully monitor each subject throughout the study for possible AEs. All AEs will be documented 
on CRFs designed specifically for this purpose. All AEs will be collected and reported in the EDC system. 
 
11.4.1 Assessment of Adverse Events 
At each visit (including telephone visits), the subject will be asked if they had any problems or symptoms since 
their last visit in order to determine the occurrence of adverse events. If the subject reports an adverse event, the 
Investigator will probe further to determine: 
• Type of event 
• Date of onset and resolution (duration) 
• Severity (mild, moderate, severe) 
• Seriousness (does the event meet the above definition for an SAE) 
• Causality, relation to investigational protocol 

 
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• Outcome 
 
11.4.2  Relatedness of Adverse Event to Investigational Protocol 
 
 
1. Not Related: 
Concomitant illness, accident, or event with no reasonable association with protocol. 
2. Unlikely: 
The reaction has little or no temporal sequence from administration of the investigational 
protocol, and/or a more likely alternative etiology exists. 
3. Possibly Related: 
The reaction follows a reasonably temporal sequence from administration of the 
investigational protocol and follows a known response pattern to the suspected 
investigational protocol; the reaction could have been produced by the investigational 
protocol or could have been produced by the subject’s clinical state or by other modes of 
therapy administered to the subject. 
4. Probably Related: 
The reaction follows a reasonably temporal sequence from administration of investigational 
protocol; is confirmed by discontinuation of the investigational protocol or by re-challenge; 
and cannot be reasonably explained by the known characteristics of the subject’s clinical 
state. 
5. Definitely Related: 
The reaction follows a reasonable temporal sequence from administration of investigational 
protocol; that follows a known or expected response pattern to the investigational protocol; 
and that is confirmed by improvement on stopping of the investigational protocol, and 
reappearance of the reaction on repeated exposure. 
 
 
 
11.4.3  Recording of Adverse Events 
All clinical adverse events are recorded in the Adverse Event (AE) Log in the subject’s study binder. Study staff 
should fill out the AE Log and enter the AE information into the EDC system within 48 hours of learning of a 
new AE or receiving an update on an existing AE. 
 
Entries on the AE Log (and into the EDC) will include the following: name and severity of the event, the date of 
onset, the date of resolution, relationship to investigational product, action taken, and primary outcome of event. 
 
11.5  Adverse Events and Serious Adverse Events - Reportable Events 
The following are considered reportable events and must be reported via the EDC system within 24 hours of 
study staff being notified of the event. 
 
• All events that meet the above criteria for Serious Adverse Events 
 
11.6  Safety and Feasibility of Performing Experimental Visits at MGH-East (Charlestown Navy Yard)  
The entire study will be performed in MGH Building 149 in examination, testing and procedure rooms of the 
Neurology Service on the 2nd floor. If an emergency does occur, 911 will be called promptly, with the subject 
being managed by the study physician until paramedics arrive. This setup has been discussed with and approved 
by the nursing administration at the CNY Clinical Research Center. 

 
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