Clinical trial NCT03642990
Conditions: Chemotherapy-induced Peripheral Neuropathy Breast Cancer Metastatic Platinum-resistant Recurrent Ovarian Cancer Head and Neck Cancer Stage IV Endometrial Cancer Stage IV
Keywords: paclitaxel nicotinamide riboside NIAGEN nab-paclitaxel
Sponsor: Donna Hammond, PhD
Start date: 2019-11-08; Completion date: 2022-02-24
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this single-arm phase II trial is to determine whether nicotinamide riboside (NIAGEN®) prevents the progression of peripheral sensory neuropathy in patients receiving infusions of paclitaxel or nab-paclitaxel for the treatment of metastatic breast cancer or recurrent platinum-resistant ovarian, endometrial, peritoneal, fallopian tube cancer or metastatic head and neck cancer.

Detailed description:
Peripheral neuropathies are a dose-limiting, disabling, and debilitating side effect of virtually every known class of chemotherapeutic agent, and are referred to as chemotherapy-induced peripheral neuropathies (CIPN) (Seretny et al., 2014). The incidence and severity of CIPN increase as the cumulative dose, frequency of administration, and the number of therapeutic cycles increase. As many as 68% of patients have CIPN when assessed within 30 days of completing treatment. Patients experience paresthesias, dysesthesias (an unpleasant abnormal sensation, whether spontaneous or evoked), hyperalgesia (increased pain from a stimulus that normally provokes pain), allodynia (pain due to a stimulus that does not normally provoke pain), numbness or loss of sensation, or ongoing pain that is burning, lancinating or electric shock-like in nature. CIPN can seriously diminish a patient's quality of life, and can interfere with self-care and activities of daily living. The severity of CIPN may also necessitate reducing the dose of chemotherapeutic agent, delaying the next cycle of chemotherapy, or terminating treatment entirely (Argyriou et al., 2012; Argyriou et al., 2014; Miltenburg et al., 2014; Park et al., 2013).

Nicotinamide adenine dinucleotide (NAD+) is an essential redox coenzyme required for cell viability, basic bioenergetics, and fast axonal transport (Yang and Sauve, 2016). It plays an important role in protection against axonal injury from either mechanical or neurotoxic injury (Araki et al., 2004; Sasaki et al., 2006; Sasaki et al., 2009; Gerdts et al., 2015; Khan et al., 2014; Conforti et al., 2014; Di Stefano et al., 2015). Nicotinamide riboside (NIAGEN®) is a form of vitamin B3 and a precursor in the pathway for synthesis of NAD+ (Bieganowski et al., 2004; Trammell et al., 2016; Chi and Sauve, 2013). Oral administration of NIAGEN® increases levels of NAD+ in the blood, liver, skeletal muscle, and other tissues (Canto et al., 2012; Hamity et al, 2017; Airhart et al., 2017; Martens et al., 2018).

NIAGEN®) has been reported to prevent tactile hypersensitivity and blunt the affective dimension of nociception in a rat model of CIPN (Hamity et al., 2017) It also prevents signs of peripheral neuropathy in a mouse model of diabetes (Trammell et al., 2016) The proposed single-arm pilot phase II study will examine whether daily dosing with NIAGEN®) can prevent the progression of CIPN in persons with stage IV breast cancer or recurrent platinum-resistant ovarian, endometrial, peritoneal, or fallopian tube cancer receiving once weekly infusions of paclitaxel for 12 weeks.

In this study, persons with metastatic breast cancer, platinum-resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer, or platinum-resistant recurrent or metastatic head and neck cancer who are receiving weekly infusions of paclitaxel or nab-paclitaxel and anticipated to survive for at least 3 months will be offered the opportunity to enroll in this study when they develop a peripheral neuropathy of at least grade 1. Persons with peripheral neuropathy of no greater than a grade 2 from prior therapy may also enroll in this study if they are receiving weekly infusions of paclitaxel or nab-paclitaxel. Upon enrollment, health care providers will review the overall severity of the participant's neuropathy and assign a baseline grade. Participants will also complete two short questionnaires that will more specifically score how the peripheral neuropathy interferes with daily functions of living. A small sample of blood will be taken at the completion of the paclitaxel or nab-paclitaxel infusion to measure levels of paclitaxel. The participant will then be sent home with capsules of NIAGEN® to take twice daily. Each week upon return to the clinic a small sample of blood will be taken before the infusion of paclitaxel to measure biomarkers for NIAGEN®, and other samples of blood will be taken to evaluate clinical chemistries, kidney, and liver function. Another sample of blood will be obtained after the paclitaxel or nab-paclitaxel infusion to measure levels of paclitaxel or nab-paclitaxel. The health care provider will meet with the patient each week to score the overall severity of the peripheral neuropathy, and the participant will answer another questionnaire with more specific questions. Once a month, the participant will be asked to fill out a second questionnaire. Participants will take 300 mg/day NIAGEN® in the first week and 1000 mg/day in the subsequent 11 weeks. The study will conclude one week after the 12th infusion of paclitaxel or nab-paclitaxel. Health care providers will contact the participant at various times up to 6 months to monitor their status.

Beginning with completion of the trial by the 10th participant and continuing with each subsequent participant up to 39, we will use a Bayesian statistical approach (Lee and Liu, 2008; i.e. predictive probability) to determine whether NIAGEN® has prevented a worsening of the peripheral neuropathy. This approach we let us make an early determination of futility. We will also determine whether NIAGEN® has decreased the need to delay or diminish the doses of paclitaxel or nab-paclitaxel due to severity of the peripheral neuropathy. The results of this trial will inform the design of a subsequent randomized, placebo-controlled, blinded clinical trial.

Arms: arm 1: Daily oral administration of nicotinamide riboside 300 mg (150 mg a.m. and p.m.) for one week with dose escalation to 1000 mg (500 mg a.m. and p.m.) for remaining 11 weeks.
Interventions: intervention 1: Nicotinamide Riboside
Intervention descriptions: intervention 1: Capsule

Protocol documents:
ICF_005.pdf: 
NIAGEN® in Paclitaxel-induced  
Peripheral Neuropathy 
 
 
NCT03642990 
 
 
July 15, 2021 


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INFORMED CONSENT DOCUMENT 
 
Project Title: 
Nicotinamide riboside (NR) in Paclitaxel-induced Peripheral Neuropathy 
 
Principal Investigator: 
Alexandra Thomas, MD 
 
 
 
336-716-7217 
 
INTRODUCTION 
You are invited to be in a research study.  Research studies are designed to gain scientific knowledge 
that may help other people in the future.  You are being asked to take part in this study because you have 
breast, recurrent ovarian, endometrial, peritoneal, or fallopian tube, or recurrent or metastatic head and 
neck cancer.  Your participation is voluntary.  Please take your time in making your decision as to 
whether or not you wish to participate.  This consent form describes the research study to help you 
decide if you want to participate.  This form provides important information about what you will be 
asked to do during the study, about the risks and benefits of the study, and about your rights as a 
research subject.   
• If you have any questions about or do not understand something in this form, you should ask 
the research team for more information.   
• You should discuss your participation with anyone you choose such as family or friends.   
• Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
We are inviting you to participate in this research study because you have stage 4 breast cancer,  
platinum-resistant recurrent ovarian, endometrial, peritoneal, or fallopian tube cancer, or platinum-
resistant recurrent or metastatic head and neck cancer, are being treated for your cancer with Paclitaxel 
or Nab-paclitaxel, and are experiencing peripheral neuropathy.  Nab-paclitaxel is a different formulation 
of paclitaxel.  The symptoms of peripheral neuropathy include numbness or tingling, pricking sensations 
or muscle weakness, usually in the hands or feet.  However, peripheral neuropathy can also affect other 
areas of your body.     
 
The purpose of this research study is find out if nicotinamide riboside (NR), a nutritional supplement 
and type of vitamin B3, can prevent the progression of peripheral neuropathy in people with breast,  
recurrent ovarian, endometrial, peritoneal, or fallopian tube cancer, or platinum-resistant recurrent or 
metastatic head and neck cancer, being treated with Paclitaxel or Nab-paclitaxel.   
 
Nicotinamide riboside is considered investigational as it is being used in this research study, which 
means that it has not been approved by the U.S. Food and Drug Administration.  Nicotinamide riboside 
is currently used to increase levels of NAD+, a substance in the blood which is important in converting 
blood glucose into energy.  Increased NAD+ levels may also play a part in delaying the effects of aging, 
obesity and disease.   
 


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HOW MANY PEOPLE WILL PARTICIPATE? 
Approximately 39 people at two different research sites (The University of Iowa and Wake Forest 
University) will participate in this study, including approximately 20 people at this research site. 
 
HOW LONG WILL I BE IN THIS STUDY? 
If you agree to take part in this study, your involvement will last approximately 9 months.  This includes 
up to 12 weeks of treatment with NR, then follow-up visits at the following time points: 
 
• 7-14 days after the end of treatment 
• 30-37 days after the end of treatment (may be done by telephone) 
• 12-14 weeks after the end of treatment (may be done by clinic visit or telephone) 
• 24-26 weeks after the end of treatment (may be done by clinic visit or telephone) 
 
Each visit during treatment will last between 1-2 hours.  Each follow-up visit will also last between 1-2 
hours.  You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or safety 
consequences. 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
Before you begin the study: 
If you choose to take part in this study, you will need to have the following procedures to find out if you 
can be in the study.  Most of these procedures are part of your regular cancer care and would be done 
even if you do not join the study. 
 
• A complete physical examination, including assessment of vital signs (temperature, height, 
weight, heart rate, blood pressure, and respirations or breathing rate).  
• Blood tests (approximately 3-4 teaspoons of blood will be drawn and studied for kidney 
function, liver function, white cells, red cells, and platelets). 
• Pregnancy test for females of childbearing potential. 
• Questionnaire – one page which asks 11 brief questions about how you’re feeling.  
 
During study treatment: 
You will take the study drug, NR, by mouth twice a day while you are receiving chemotherapy in this 
study.  If your body tolerates the first dose of NR well during the first week of treatment, the dose will 
be increased for all the remaining weeks of treatment.  The number of weeks you will take the study 
drug depends on when you join the study, as you will only start taking NR once you develop significant 
symptoms of peripheral neuropathy.  If your peripheral neuropathy starts right away when you’re 
receiving chemotherapy, you will take more doses of NR.  If your peripheral neuropathy starts later, you 
will take fewer doses.  You will stop taking NR one week after your last infusion of Paclitaxel or Nab-
paclitaxel.   
 
Your physician will determine the dose and frequency of infusion with paclitaxel or nab-paclitaxel that 
is standard of care for your disease.  Once you’ve started taking the study drug, NR, the following tests 


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and procedures will be done at each weekly visit: 
 
• Complete physical exam (only on weeks 3, 6 and 9 if you are receiving weekly chemotherapy). 
• Assessment of vital signs (temperature, weight, heart rate, blood pressure, and respirations or 
breathing rate).  
• Blood tests (approximately 3-4 teaspoons of blood will be drawn and studied for kidney 
function, liver function, white cells, red cells, and platelets). 
• Blood for research tests (approximately 3 teaspoons of blood will be drawn to check the level of 
Paclitaxel and NAD+ in your blood.)  If your chemotherapy drug levels get too high or too low 
from taking the study drug, you may be removed from this study. 
• Questionnaire – one page which asks 11 brief questions about how you’re feeling.  
 
We will ask you to complete a questionnaire each time you visit.  This questionnaire will ask specific 
questions about how you’ve been feeling.  We will also provide you forms to keep track of the study 
drug that you take each day, and how much dairy you eat each day.   
 
After study treatment: 
After you’ve finished taking NR, you will have a follow-up visit 7-14 days after your last dose.  The 
following tests and procedures will be done:  
 
• A complete physical examination, including assessment of vital signs (temperature, weight, heart 
rate, blood pressure, and respirations or breathing rate).     
• Blood tests (approximately 3-4 teaspoons of blood will be drawn and studied for kidney 
function, liver function, white cells, red cells, and platelets). 
• Questionnaire – one page which asks 11 brief questions about how you’re feeling.  
 
You will also have follow-up scheduled at the time points listed below.  These may be done by a 
telephone call to see how you’re doing. 
 
• 30-37 days after the end of treatment. 
• 12-14 weeks after the end of treatment. 
• 24-26 weeks after the end of treatment. 
 
Follow-up Contact Plan: 
If we aren’t able to successfully contact you by telephone, we may send you a certified letter to your last 
known address, requesting a return receipt.   
 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  
 
Blood Draws: 


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You may experience discomfort, bruising and/or bleeding where the needle is inserted. Occasionally 
some people become dizzy lightheaded or feel faint. Infection may occur on rare occasions.  Frequent 
donation of blood can result in low iron in your blood (iron deficient anemia).   
 
Study Drug: 
There is a risk that the study drug (NR) will increase or decrease the level of paclitaxel in the blood.  An 
increase in levels of paclitaxel could result in increased peripheral neuropathy and decreased levels of 
white blood cells and red blood cells.  A decrease in levels of paclitaxel could decrease the effectiveness 
of this chemotherapy.  Your levels will be monitored weekly.   There is also a very small risk that NR 
will cause flushing (a sudden redness of the skin.)  You may also experience headache, nausea, 
vomiting, fatigue, dizziness, or loose stool.  There also may be other side effects that we cannot predict. 
You should tell the research staff about all the medications, vitamins and supplements you take and any 
medical conditions you have. This may help avoid side effects, interactions and other risks. 
 
Reproductive Risks: 
For Females: 
Due to unknown risks and potential harm to the unborn fetus, sexually active women of childbearing 
potential must use a reliable method of birth control while participating in this study and throughout the 
follow-up period. Any of the following methods have been determined to be more than 99% effective 
(<1% failure rate per year when used consistently and correctly) 
• Complete abstinence from sexual intercourse  
•  Double barrier methods: 
o  Condom with spermicide in conjunction with use of an intrauterine device 
o   Condom with spermicide in conjunction with use of a diaphragm 
• Surgical sterilization (bilateral removal of ovaries with or without hysterectomy, tubal ligation or 
vasectomy) at least 6 weeks prior to starting the study.    
• Non-hormonal intrauterine device (IUD)  
We encourage you to discuss this issue further with your physicians if you have any questions. 
 
For Males: 
Your participation in this research study may damage your sperm, which could cause harm to a child 
that you may father while on this study. Such harm may be currently unforeseeable. If you are sexually 
active, you must agree to use a medically acceptable form of birth control in order to be in this study. 
Medically acceptable contraceptives include: (1) surgical sterilization (such as a vasectomy), or (2) a 
condom used with a spermicide. Contraceptive measures such as Plan B (TM), sold for emergency use 
after unprotected sex, are not acceptable methods for routine use. You should inform your partner of the 
potential for harm to an unborn child. She should know that if pregnancy occurs, you will need to report 
it to the study doctor, and she should also promptly notify her doctor. 
 
Your Health Information: 


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Taking part in this research study may involve providing information that you consider confidential or 
private.  Efforts, such as coding research records, keeping research records secure and allowing only 
authorized people to have access to research records, will be made to keep your information safe. 
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect your 
confidential information.  A Data Safety and Monitoring Committee, an independent group of experts, 
will be reviewing the data from this research throughout the study. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. The benefits of participating 
in this study may be:  a decrease in the occurrence of your peripheral neuropathy, the chance to obtain 
the full benefit of your chemotherapy, and a dramatic improvement to your quality of life both during 
your chemotherapy and in the years that follow. 
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  Instead of being in this study, you could choose to have no treatment for your 
peripheral neuropathy, or choose to take part in a different research study, if one is available.   
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
You will not have any additional costs for being in this research study.  The study drug, nicotinamide 
riboside is being supplied by the maker of the drug, ChromaDex, Inc.  The cost of blood draws that are 
done for research only will not be billed to you or your insurance company.  However, costs for your 
regular medical care, which are not related to this study, will be your own responsibility.   
 
WILL I BE PAID FOR PARTICIPATING? 
You will not be paid for being in this research study.  However, your parking may be validated for trips 
made to the outpatient clinic for study related visits. 
 
WHO IS FUNDING THIS STUDY? 
  The study is being funded by discretionary funds available to the principal investigator. 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
Should you experience a physical injury or illness as a direct result of your participation in this study, 
Wake Forest University School of Medicine maintains limited research insurance coverage for the usual 
and customary medical fees for reasonable and necessary treatment of such injuries or illnesses. To the 
extent research insurance coverage is available under this policy the reasonable costs of these necessary 
medical services will be paid, up to a maximum of $25,000. Wake Forest University Baptist Medical 
Center holds the insurance policy for this coverage. It provides a maximum of $25,000 coverage for 
each claim and is limited to a total of $250,000 for all claims in any one year. The Wake Forest 
University School of Medicine, and the North Carolina Baptist Hospitals, Incorporated do not assume 
responsibility to pay for these medical services or to provide any other compensation for such injury or 
illness. Additional information may be obtained from the Medical Center’s Director of Risk and 
Insurance Management, at (336) 716-3467. 


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If you are injured, the insurer may require information such as your name, social security number, and 
date of birth in order to pay for your care.  This is because the insurer is required by law to report any 
payments made to cover the care of any persons who are members of a government insurance plan to the 
Department of Health and Human Services. 
You do not give up any legal rights as a research participant by signing this consent form. For more 
information on medical treatment for research related injuries or to report a study related illness, adverse 
event, or injury you should call Dr. Thomas at 336-716-0230 or 336-713-5440 (after hours.) 
 
WHAT ABOUT CONFIDENTIALITY? 
To help protect your confidentiality, we will conduct research interventions in private rooms, limit data 
collection, and store research documents in locked offices and on password-protected computers.  Study 
data will not list your name, but will identify you by a code number.  The results of this research study 
may be presented at scientific or medical meetings or published in scientific journals.  If so, your 
identity and/or your personal health information will not be disclosed unless it is authorized by you, 
required by law, or necessary to protect the safety of yourself or others.  There is always some risk that 
even de-identified information might be re-identified.  
Participant information may be provided to Federal and other regulatory agencies as required.  The Food 
and Drug Administration (FDA), for example, may inspect research records and learn your identity if 
this study falls within its jurisdiction.  ChromaDex, Inc, the maker of the study drug, may also inspect 
any part of your medical record for the purposes of auditing the conduct of the study. 
The purpose of this research study is to obtain data or information on the safety and efficacy of 
Nicotinamide Riboside; the results will be provided to the sponsor, the Food and Drug Administration 
and other federal and regulatory agencies as required. 
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a research study.  Information about the research 
and any medications or devices you are being given as a participant may also be included in your 
medical record.  This part of the medical record will only be available to people who have authorized 
access to your medical record.  If you are not a patient at this Medical Center, a medical record will be 
created for you anyway to ensure that this important information is available to doctors in case of an 
emergency. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will include 
a summary of the results.  You can search this website at any time. 
 
WILL MY HEALTH INFORMATION BE USED DURING THIS STUDY? 
In this research study, any new information we collect from you about your health or behaviors is 
considered Protected Health Information (PHI). The information we will collect for this research study 
includes: physical examination notes, blood test results, vital signs, and personal information collected 
from study questionnaires.   


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Protected Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store records of 
your Protected Health Information in a cabinet in a locked office or on a password protected computer.  
Your personal health information and information that identifies you (“your health information”) may be 
given to others during and after the study. This is for reasons such as to carry out the study, to determine 
the results of the study, to make sure the study is being done correctly, to provide required reports and to 
get approval for new products.   
Some of the people, agencies and businesses that may receive and use your health information are listed 
below.  It is possible that these entities may become aware of your participation in this study and may 
inspect and copy records pertaining to this research.  Some of these records could contain information 
that personally identifies you.  
• Representatives of Wake Forest University Health Sciences and North Carolina Baptist Hospital 
• The Wake Forest University Health Sciences and the University of Iowa Institutional Review 
Boards (committees that review and approves research studies) 
• Representatives from government agencies such as the Food and Drug Administration (FDA), 
and the Department of Health and Human Services (DHHS).  
• Laboratory staff, auditing departments, and other study representatives from the University of 
Iowa 
• ChromaDex, Inc, the maker of the study drug may also inspect any part of your medical record 
for the purposes of auditing the conduct of the study. 
Some of these people, agencies and businesses may further disclose your health information. If disclosed 
by them, your health information may no longer be covered by federal or state privacy regulations.  
Your health information may be disclosed if required by law. Your health information may be used to 
create information that does not directly identify you. This information may be used by other 
researchers. You will not be directly identified in any publication or presentation that may result from 
this study unless there are photographs or recorded media which are identifiable. 
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the participant’s 
original medical record for verification of clinical trial procedures or data, without violating 
confidentiality of the participant and to the extent permitted by other applicable laws. 
This research is covered by a Certificate of Confidentiality from the National Institutes of  
Health. The researchers with this Certificate may not disclose or use as evidence any information, 
documents, or biospecimens that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding.  For example, if there is a court subpoena, 
the researchers may not disclose your information unless you have consented for its use in this manner.   
Information, documents, or biospecimens protected by this Certificate cannot be disclosed without your 


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consent to anyone else who is not connected with the research, except if there is a federal, state, or local 
law that requires disclosure (such as to report child abuse or communicable diseases), you have 
consented to the disclosure (including for your medical treatment), or if it is used for other scientific 
research as allowed by federal regulations protecting research subjects.  
 
The Certificate cannot be used to refuse a request for information from personnel of the United  
States federal or state government agency sponsoring the project that is needed for auditing, or for 
information that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA).  
You should understand that a Certificate of Confidentiality does not prevent you from  
voluntarily releasing information about yourself or your involvement in this research. If you  
want your research information released to an insurer, medical care provider, or any other  
person not connected with the research, you must provide consent to allow the researchers to  
release it. 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal,  
state, or local law of child abuse and neglect, or harm to self or others.  The Certificate of 
Confidentiality will not be used to prevent disclosure for any purpose you have  
consented to in this informed consent document, including research data in your medical record. 
Any Protected Health Information collected from you in this study that is maintained in the research 
records will be kept for at least seven years after the study is finished. Any research information entered 
into your medical record will be kept for as long as your medical record is kept by the Medical Center. 
You will not be able to obtain a copy of your Protected Health Information in the research records until 
all activities in the study are completely finished.  
You can tell Dr. Thomas that you want to take away your permission to use and share your Protected 
Health Information at any time by sending a letter to this address: 
Alexandra Thomas, MD 
Medical Center Blvd. 
Winston-Salem, NC  27157 
However, if you take away permission to use your Protected Health Information you will not be able to 
be in the study any longer. We will stop collecting any more information about you, but any information 
we have already collected can still be used for the purposes of the research study. 
By signing this form you give us permission to use your Protected Health Information for this study. 
 
IS BEING IN THIS STUDY VOLUNTARY? 
Taking part in this study is voluntary. You may choose not to take part or you may leave the study at any 
time. Refusing to participate or leaving the study will not result in any penalty or loss of benefits to 
which you are entitled. If you decide to stop participating in the study we encourage you to talk to the 
investigators or study staff first to learn about any potential health or safety consequences.  You will be 


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given any new information we become aware of that would affect your willingness to continue to 
participate in the study. 
What if I Decide to Drop Out of the Study? 
If you decide to leave the study early, we will ask you to talk to the study doctor as soon as possible so 
that you can stop safely.  If you leave the study before the final planned study visit, the study doctor may 
ask you to complete the final visits.   
Will I Receive New Information About the Study while Participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
Can Someone Else End my Participation in this Study? 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned.  This might happen because in our judgment it would not be safe for you to 
continue, because your condition has become worse, because you are or became pregnant, or because 
funding for the research study has ended. 
WHAT IF I HAVE QUESTIONS? 
For questions about the study or in the event of a research-related injury, contact the study investigator, 
Dr. Alexandra Thomas at 336-716-0230 or 336-713-5440 after hours. 
 
The Institutional Review Board (IRB) is a group of people who review the research to protect your 
rights. If you have a question about your rights as a research participant, or you would like to discuss 
problems or concerns, have questions or want to offer input, or you want to obtain additional 
information, you should contact the Chairman of the IRB at (336) 716-4542 or the Research Subject 
Advocate at (336) 716-8372. 
  
You will be given a copy of this signed consent form. 
 


Comprehensive Cancer Center of Wake Forest University (CCCWFU) 
CCCWFU #98116 
 
WFU Version 12/13/18 
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FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
SIGNATURES 
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Prot_SAP_003.pdf: 
NIAGEN® in Paclitaxel-induced  
Peripheral Neuropathy 
 
 
NCT03642990 
 
 
March 24, 2021 


Study Number  
March 24, 2021 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
NIAGEN® in Paclitaxel-induced  
Peripheral Neuropathy 
 
 
Coordinating Center:     Holden Comprehensive Cancer Center  
 
 
 
University of Iowa 
 
 
Principal Investigator:  
Donna L. Hammond, Ph.D.  
 
 
University of Iowa 
 
 
Co-Investigator:  
Alexandra Thomas, M.D.  
 
 
Wake Forest University 
 
 
Medical Monitor: 
    Daniel Vaena, M.D. 
 
 
 
 
 
Sub-Investigators:   
 
 
 
Jesus Gonzalez Bosquet, Ph.D. M.D. (Iowa) 
 
 
Michael Goodheart, M.D. (Iowa) 
 
 
Marta Hamity, Ph.D. (Iowa) 
 
 
Emily K. Hill, M.D. (Iowa) 
 
 
Mark Karwal, M.D. (Iowa) 
 
 
Megan McDonald, M.D. (Iowa) 
 
 
Praveen Vikas, M.D. (Iowa) 
 
 
Sneha Phadke, M.D. (Iowa) 
 
 
Michael Shy, M.D. (Iowa) 
 
 
 
 
 
Christopher Nance, M.D. (Iowa) 
 
 
Susan A. Melin, M.D. (Wake Forest) 
 
 
Steven Sorscher, M.D. (Wake Forest) 
 
 
Katherine Ansley, M.D. (Wake Forest) 
 
 
Susan Williford, M.D. (Wake Forest) 
 
 
Christopher Peters, Ph.D. (Wake Forest) 
 
 
Roy Strowd, M.D. (Wake Forest) 
 
 
 
 
 
Biostatistician: 
Emine Ozgur Bayman, Ph.D. (Iowa) 
 
          OnCore Coordinator: 
Jill Kuennen, MA (Iowa) 


Study Number  
March 24, 2021 
2 
 
 
Study Number -  
 
Investigational Product - Nicotinamide riboside 
 
Clinical Phase - Phase II 
 
Sponsor - National Cancer Institute 
 
Protocol Version – March 24, 2021 
 
Confidentiality Statement:   
 
 
 
 


Study Number  
March 24, 2021 
3 
Synopsis 
Primary Objective 
 
The purpose of this single-arm phase II trial is to determine whether 
nicotinamide riboside (NR) prevents the progression of peripheral sensory 
neuropathy in patients receiving paclitaxel or nab-paclitaxel for treatment of stage IV 
breast cancer, or platinum-resistant recurrent ovarian, peritoneal, endometrial, or 
fallopian tube cancer.  A decision to propose a large multi-center phase III trial of 
nicotinamide riboside for the relief of sensory neuropathy and the experimental 
design of that trial will be based on these findings.  
 
Secondary Objectives  
 
The secondary objective of this single-arm phase II trial is to determine 
whether treatment with nicotinamide riboside can prevent reductions in the dose of 
taxane therapy due to the incidence or severity of neuropathy.  
 
Exploratory Objective 
 
The utility of the Total Neuropathy Score – clinical (TNS-c) questionnaire to 
monitor the progression of peripheral sensory neuropathy will be explored. 
 
Primary Outcome Variables 
 
The primary outcome variable is binary (yes/no) and defined as no worsening 
of the grade of peripheral sensory neuropathy, scored according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 guidelines, from the 
initiation of NIAGEN® treatment to the conclusion of NIAGEN® treatment 7 to 14 
days after the final taxane infusion.    
 
Secondary Outcome Variables 
 
Secondary outcome variables for this trial include (1) the percentage of 
patients that experience a dose reduction of taxane therapy due to neuropathy; (2) 
the incidence of dose reduction events due to neuropathy (each occasion of dose 
reduction is a separate event); (3) the total cumulative dose of taxane administered, 
and (4) the score on the 11-item NTX subscale of the FACT&GOG-NTX 
questionnaire determined at the conclusion of NIAGEN® treatment 7 to 14 days after 
the final taxane infusion. 
  
Study Duration 
 
Study duration is expected to be no longer than three years from enrollment of 
the first subject to completion of followup on the last subject. 
 


Study Number  
March 24, 2021 
4 
Study Design 
 
The study design is an open-label, prospective non-randomized, single-arm 
phase II trial. 
 
Study Population 
 
This trial will be conducted in English-speaking patients who are 18 to 85 
years old with a diagnosis of stage IV (metastatic) breast cancer, platinum-resistant 
recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer, or platinum-
resistant recurrent or metastatic head and neck cancer who are receiving 
intravenous infusions of paclitaxel or nab-paclitaxel as treatment.  To enroll, the 
patient must report at least a grade 1 peripheral neuropathy after initiation of 
paclitaxel or nab-paclitaxel therapy or present with a residual CIPN ≤ 2 from prior 
therapy, scored according to the CTCAE guidelines for peripheral sensory 
neuropathy.  
 
Number of Participants 
 
We anticipate that 39 patients will develop grade 1 neuropathy and meet 
eligibility requirements for enrollment in this study during the three years of the study. 
 
Number of Study Sites 
 
There will be two study sites:  University of Iowa Hospitals and Clinics, Iowa 
City, IA and Wake Forest Baptist Medical Center, Winston-Salem, North Carolina. 
 
 
 
 
 


Study Number  
March 24, 2021 
5 
Study Calendar 
Study Treatment Days a 
(± 2 days) 
EO
T 
 
Follow - up 
Study Procedures 
Screeningb  
1 j 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
7-14 
days 
after 
last 
taxan
e 
dose 
30-37 
days 
after 
last 
dose 
of 
NIAGE
N h 
12-14 
week 
Post 
treat
ment 
follow 
up h 
24-
26 
week 
Post 
treat
ment 
follo
w up 
h 
Scoring of Peripheral 
Neuropathy by CTCAE f 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Complete NTX subscale 
of FACT&GOG 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Progress Note e 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Recording of Dairy 
Intake 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Collect Drug Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Recording of NIAGEN® 
Self-Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical Exam, 
including weight e; 
height only at screening 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
ECOG Performance 
Status e 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Review of AEs and 
SAEs c/d 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pretreatment NAD level g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Taxane infusion a 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-treatment taxane 
level g 
 
X i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pregnancy  
(serum or urine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Number  
March 24, 2021 
6 
a The calendar is based a treatment program of 12 weekly infusions.  However, for 
any one patient, weeks on therapy may range from as few as 1 to as many as12. 
The actual number and timing of planned taxane infusions is at the physician’s 
discretion in accordance with standard of care for that disease.   For those treatment 
programs in which infusions may occur every other week, or several weeks in a row 
followed by one week “off”, all indicated measures will be taken at the time of visit.    
 
b All screening assessments may be collected up to 3 days prior to the screening 
visit. 
 
c To use  CTCAE version 4.03 guidelines . 
 
d All serious adverse events will be reported within 24 hours of the discovery of the 
event.  See Appendix B. 
 
e Include testing of Creatinine, NA, K, Co and BUN. 
 
f Scoring of Peripheral Neuropathy by CTCAE can be done by oncologist or nurse. 
 
g See Appendix C for lab procedures. 
 
h This may be collected per phone interview. 
 
i On Day 1, this level needs to be collected 30 ± 10 minutes after the paclitaxel dose, 
prior to starting NR.  Thereafter, this blood sample needs to be collected 30 ± 10 
minutes after the paclitaxel dose.  For patients receiving nab-paclitaxel, the blood 
sample needs to be collected between 15 and 30 min after infusion ends. 
 
j Screening and Treatment Day 1 visits may be combined. 
Dispense  
75 mg capsules of 
NIAGEN® k 
 
X 
 
 
 
 
 
 
 
- 
 
 
 
 
 
 
 
Dispense  
250 mg capsules of 
NIAGEN® k 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Chemistry e  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CBC, differential, 
Platelets  
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AST, ALT, Alk-Phos, 
Bili, Albumin   
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Scoring of neuropathy 
by Total Neuropathy 
Score – clinical l 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 


Study Number  
March 24, 2021 
7 
 
k On day 1, a one week supply (or enough to get patient to next visit) of the 75 mg 
capsules will be dispensed.  Thereafter, a one-month supply or (on the last visit) 
enough of the 250 mg capsules to supply the patient through day 7 after the final 
taxane infusion will be dispensed.  Treatment with NIAGEN® will conclude 7 days 
after the last, planned infusion of taxane.  Treatment with NIAGEN will not exceed 12 
weeks. 
 
l Assessment of neuropathy by a clinician trained in the neurological assessment 
procedures using the Total Neuropathy Score - clinical 
 
 
 
 
 
 


Study Number  
March 24, 2021 
8 
 
Study Schema  
 
      ENROLLMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≥Grade 1 paclitaxel -
induced neuropathy  after 
starting paclitaxel or nab-
paclitaxel therapy for 
metastatic breast cancer,  
platinum resistant 
recurrent ovarian, 
peritoneal, endometrial, 
or fallopian tube  cancer; 
or platinum-resistant 
current or metastatic 
head and neck cancer; ≤  
Grade 2 if pre-existent
Treatment with NR:
Weekly clinical, AE and 
serologic evaluation
Post-treatment clinical, 
AE and serologic 
evaluation


Study Number  
March 24, 2021 
9 
Abbreviations 
Abbreviation  
Explanation 
FACT&GOG-NTX 
Functional Assessment of Cancer 
Therapy Gynecologic Oncology Group – 
Neurotoxicity questionnaire 
CIPN 
Chemotherapy-induced peripheral 
neuropathy 
CTCAE 
Common Terminology Criteria of 
Adverse Events  
FDA 
Food and Drug Administration 
TNS-c 
Total neuropathy score – clinical 
questionnaire 
GMP 
Good manufacturing practices 
NAD 
Nicotinamide adenine dinucleotide 
IRB 
Institutional Review Board 
NR 
Nicotinamide Riboside 
NMNAT1 
Nicotinamide nucleotide adenylyl 
transferase 1 
SARM 
sterile-motif containing and armadillo-
motif containing protein  
UIHC 
University of Iowa Hospitals and Clinics 
HCCC 
Holden Comprehensive Cancer Center 
AE 
Adverse event                                           
SAE 
Serious adverse event 
1-MeNAM 
1-methyl-nicotinamide 
2-PY 
N-methyl-2-pyridone-5-carboxamide 


Study Number  
March 24, 2021 
10 
 
Glossary of Terms 
Glossary 
Explanation 
Allodynia 
Pain due to a stimulus that does not 
normally evoke pain. 
dysesthesias 
An unpleasant abnormal sensation, 
whether spontaneous or evoked.   
hyperalgesia 
Increased pain produced by a stimulus 
that does  not normally cause pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Number  
March 24, 2021 
11 
Table of Contents 
Synopsis ..................................................................................................................... 3 
Study Schema ............................................................................................................ 8 
Abbreviations ............................................................................................................. 9 
Glossary of Terms .................................................................................................... 10 
Table of Contents ..................................................................................................... 11 
1 - Introduction ....................................................................................................... 13 
2 - Background ....................................................................................................... 13 
3 - Rationale/Significance ...................................................................................... 22 
3.1 Problem Statement ..................................................................................... 22 
3.2 Purpose of Study/Potential Impact .............................................................. 23 
3.3 Potential Risks and Benefits........................................................................ 23 
4 - Study Objectives ............................................................................................... 24 
4.1 Hypothesis .................................................................................................. 24 
4.2 Primary Objective ........................................................................................ 24 
4.3 Secondary Objectives ................................................................................. 24 
4.4 Exploratory Analysis .................................................................................... 24 
5 - Study Design ..................................................................................................... 24 
5.1 General Design ........................................................................................... 24 
5.2 Outcome Variables ...................................................................................... 25 
5.3 Study Population ......................................................................................... 25 
6 - Methods ............................................................................................................. 28 
6.1 Treatment - Drug ......................................................................................... 28 
6.2 Assessments ............................................................................................... 29 
6.3 Study Procedures ........................................................................................ 30 
6.3.2 Informed Consent ..................................................................................... 30 
6.4 Statistical Method ........................................................................................ 32 
7 - Trial Administration .......................................................................................... 35 
7.1 Institutional Review Board (IRB) Review ..................................................... 35 
7.2 Subject Confidentiality ................................................................................. 36 
7.3 Unanticipated Problems .............................................................................. 36 


Study Number  
March 24, 2021 
12 
7.4 Data Quality Assurance .............................................................................. 36 
7.5 Study Records ............................................................................................. 37 
7.6 Study Monitoring ......................................................................................... 38 
7.7 Data Safety Monitoring Plan........................................................................ 38 
7.8 Study Modification ....................................................................................... 38 
7.9 Study Discontinuation ................................................................................. 38 
7.10 Study Completion ...................................................................................... 38 
7.12 Funding Source ......................................................................................... 39 
7.13 Publication Plan ........................................................................................ 39 
References ............................................................................................................... 40 
APPENDIX A - PERFORMANCE STATUS CRITERIA ............................................ 45 
APPENDIX B  - Trial-Specific Data and Safety Monitoring Plan .............................. 46 
APPENDIX C – Lab Manual ..................................................................................... 50 
APPENDIX D - List of Tables ................................................................................... 53 
APPENDIX E – FACT/GOG – NTX subscale ........................................................... 54 
APPENDIX F – Total Neuropathy Score – clinical version ....................................... 55 
 
 
 


Study Number  
March 24, 2021 
13 
1 - Introduction 
 
This document is a protocol for the conduct of research in human subjects.  
The purpose of this document is to ensure that the research protocol is conducted in 
accordance with all institutional and governmental regulations, and with the approval 
of the Institutional Review Board. 
2 - Background 
2.1 Background/prevalence of research topic 
2.1.1.  Chemotherapy-induced peripheral neuropathy (CIPN) is a significant health 
care problem. 
         Peripheral neuropathies are a dose-limiting, disabling, and debilitating side 
effect of virtually every known class of chemotherapeutic agent.  When assessed 
within 30 days of completing therapy, 68% of patients have CIPN [1].  Although the 
specific characteristics of CIPN are a function of the agent, the incidence and 
severity of CIPN increase as the cumulative dose, frequency of administration, and 
the number of therapeutic cycles increase.  Patients experience paresthesias, 
dysesthesias (an unpleasant abnormal sensation, whether spontaneous or evoked), 
hyperalgesia (increased pain from a stimulus that normally provokes pain), allodynia 
(pain due to a stimulus that does not normally provoke pain), numbness or loss of 
sensation, or ongoing pain that is burning, lancinating or electric shock-like in nature.  
These signs occur first in the distal hands and feet and progress proximally in a 
stocking and glove distribution as far as the knees and elbows, reflecting the 
selective vulnerability of the longest nerves.  CIPN can seriously diminish a patient's 
quality of life, and can interfere with self-care and activities of daily living.  The 
severity of CIPN may also necessitate reducing the dose of chemotherapeutic agent, 
delaying the next cycle of chemotherapy or terminating treatment entirely [2-5].  Less 
well appreciated is the persistence of CIPN for months to years after completion of 
chemotherapy in as many as 30% of cancer survivors [1, 2].  Given that advances in 
cancer diagnosis and treatment of cancer have increased the number of survivors to 
nearly 14.5 million in 2014 [6], up to 4.5 million survivors may suffer from CIPN after 
their treatment is completed. 
2.1.2.  Therapeutic options for CIPN remain an unmet medical need.  
         CIPN can no longer be considered a toxic side effect of chemotherapy to be 
"endured" as the price for longer survival or managed simply by reducing the dose or 
frequency of chemotherapy.  The American Society of Clinical Oncology considers 
the development of adjuncts for the prevention and relief of CIPN as essential for 
patient care [7].  Much effort has gone into testing drugs like gabapentin, lamotrigine, 
and amitriptyline (used to treat other sensory neuropathies) only to learn that they 
are largely ineffective against CIPN.  Perhaps this is not surprising given that the 
number needed to treat to demonstrate benefit by these drugs in those neuropathies 
is 4 to 5 [8-10].  At present, duloxetine is the only evidence-based treatment for the 
prevention or relief of CIPN in patients [4, 11, 12].  However, while duloxetine 


Study Number  
March 24, 2021 
14 
ameliorated CIPN produced by platinum compounds, it was no better than placebo in 
relieving CIPN produced by taxanes [13]. Moreover, its efficacy was subsequently 
linked to the emotional health of the patient [14].   Given that the peripheral 
neuropathies induced by the different classes of chemotherapeutic agent are 
mechanistically distinct [15], it is unlikely that one agent will uniformly relieve CIPN 
produced by different classes of chemotherapy.   Thus, effective treatment for CIPN 
remains a significant unmet need in healthcare.   
2.1.3.  Bioenergetic deficits in CIPN and the protective role of nicotinamide adenine 
dinucleotide (NAD+) 
 
Multiple mechanisms are implicated in the development and maintenance of 
CIPN [15-18].  In the case of paclitaxel, these mechanisms include bioenergetic 
deficits arising from mitochondrial dysfunction and nitro-oxidative stress that may 
contribute to the axonal degeneration, slowing of nerve conduction velocity, and 
epidermal nerve fiber loss observed in CIPN.  In recent years, evidence has accrued 
that nicotinamide adenine dinucleotide (NAD+), an essential redox coenzyme 
required for cell viability, basic bioenergetics and fast axonal transport [19, 20], plays 
an important role in protection against axonal injury from either mechanical or 
neurotoxic injury [21-25].  Maintenance of NAD+ has also been shown to be 
protective in mitochondrial disease [26].   
 
The neuroprotective role of NAD+ first came to light with the Wallerian 
degeneration slow mouse, in which axons degenerate much more slowly after 
transection.  This effect is attributed to a chromosomal aberration that causes 
overexpression of a biosynthetic enzyme for NAD+ (NMNAT1, Nicotinamide 
nucleotide adenylyl transferase-1) in axons and mitochondria [27], and enhances 
NAD+ biosynthesis.  Conversely, axonal injury is accompanied by rapid degradation 
of another isoform of this NAD+ biosynthetic enzyme (NMNAT2) [21-24, 28].  Injury 
or chemotherapeutic agents can also lead to decreased NAD+ in axons due to 
activation and polymerization of sterile-motif-containing and armadillo-motif 
containing protein (SARM), which is required for Wallerian degeneration [25].  
Surgically transected nerves can be rescued from degeneration in vitro by lentiviral 
introduction of a NAD+ biosynthetic gene and the addition of NAD+ precursors (e.g. 
nicotinic acid or nicotinamide) [23].   
2.1.4.  Nicotinamide riboside is a source of NAD+. 
 
 
Any process that consumes NAD+ demands compensatory de novo synthesis 
from dietary tryptophan or synthesis from one of three vitamin precursors:  nicotinic 
acid, nicotinamide, or the more recently discovered vitamin nicotinamide riboside 
(Fig. 1).  Nicotinamide riboside is a naturally occurring precursor of NAD+; small 
quantities are present in whey and milk [29, 30].  Now considered a third major form 
of vitamin B3 [31], it is readily available to consumers commercially as NIAGEN® 
[25]. 
 
2.2  Preclinical Experience 


Study Number  
March 24, 2021 
15 
 
The efficacy of NIAGEN® was tested in a rodent model of CIPN in which 
female Sprague-Dawley rats received three intravenous injections of paclitaxel of a 
span of five days for a total dose of 19.8 mg/kg [32].  As per FDA guidelines for 
scaling doses among species [33], this dose of paclitaxel scales to 120 mg/m2 body 
surface area and approximates that used in humans to treat breast cancer [34, 35].  
Paclitaxel-treated rats develop tactile hypersensitivity and exhibit place escape-
avoidance behaviors to repetitive stimulation of the hindpaw with a filament that is 
not noxious when used in untreated rats.  When administered prophylactically for 
seven days before injection of paclitaxel and continuing for 11 days thereafter, once 
daily oral administration of 200 mg/kg NIAGEN® prevented the development of 
tactile hypersensitivity and blunted escape-avoidance behaviors in these rats.  When 
administered therapeutically 14 days after paclitaxel, when tactile hypersensitivity 
was well-established, once daily oral administration of 200 mg/kg NIAGEN® 
progressively alleviated tactile hypersensitivity in 50% of the rats and blunted place 
escape-avoidance behaviors.  The prophylactic dose regimen increased levels of 
NAD+ in the blood of rats by 40% when assessed after three weeks administration.  
This dose of NIAGEN® scales to 32 mg/kg in human. 
The efficacy of NIAGEN® was also tested in a mouse model of prediabetes 
and Type 2 diabetes [36].  Dietary supplementation with ~185 mg/kg nicotinamide 
riboside for eight weeks decreased weight gain, hepatic steatosis, circulating 
cholesterol levels and alanine aminotransferase levels.  It improved non-fasting 
glucose levels and tended to normalize hemoglobin A1c.  It also prevented the 
slowing of sensory nerve conduction velocity, protected against the loss of 
intraepidermal nerve fibers, and reversed heat insensitivity that are hallmarks of 
Type 2 diabetes. 
A study was conducted to determine whether the beneficial effect of 
NIAGEN® was due to an inhibition of the actions of paclitaxel.  As myelosuppression 
is a hallmark of paclitaxel treatment, this study determined whether NIAGEN® 
treatment interfered with the myelosuppressive effects of paclitaxel.  Female rats 
were dosed with 200 mg/kg/day NIAGEN® orally or with water for one week prior to 
i.v. injection of three divided doses of paclitaxel (cumulative dose of 19.8 mg/kg) and 
continuing for 6 days after the first dose of paclitaxel.   Blood samples were drawn at 
the end of the study for a complete blood count.  In NR-treated rats, paclitaxel 
reduced numbers of white blood cells, red blood cells, hemoglobin and hemocrit to 
the same extent as in vehicle-treated rats.  These data suggest that NIAGEN® will 
not interfere with the chemotherapeutic actions of paclitaxel. 
Complementary in vitro studies were conducted to determine whether 
NIAGEN® would induce transcript for or inhibit the activity of the P450 enzymes 
involved in metabolism of paclitaxel.  No induction of transcript for CYP1A2, 
CYP2B6, CYP3A4, or CYP2C8 occurred in primary hepatocytes isolated from three 
different human donors following incubation with 0.34, 3.4 or 34 µM NIAGEN®.   
Assay of lactate dehydrogenase release following three days’ incubation of primary 
hepatocytes from three different donors did not identify any cytotoxic effects of 0.34, 


Study Number  
March 24, 2021 
16 
3.4 or 34 µM NIAGEN®.   Concentrations of NIAGEN® as high as 33 µM did not 
inhibit CYP2C8 or CYP3A4 activity in human liver microsomes.  To further test for 
possible inhibition, a time-dependent assay was conducted in which NIAGEN® was 
incubated in human liver microsomes for 30 minutes with and without NADPH.  
Unlike the positive controls, concentrations as high as 50 µM NIAGEN® did not 
inhibit CYP2C8 or CYP3A4, and no leftward shift was observed in the presence of 
NADPH.  These data provide further support for the expectation that NIAGEN® will 
not interfere with the chemotherapeutic actions of paclitaxel. 
Additional in vivo studies were conducted to determine whether NIAGEN® 
would promote tumorigenesis or interfere with the chemotherapeutic actions of 
paclitaxel.  For these studies, the carcinogen N-methyl-nitrosourea was injected in 
female rats to induce cancer in the chain of mammary glands.  This is a well-
established rodent model of breast cancer [37].  The first set of studies examined 
whether NIAGEN® would facilitate tumorigenesis.  For these studies, groups of 14 
rats received vehicle or 200 mg/kg NIAGEN® once daily beginning 6 weeks after 
injection of MNU to assess the effects of NIAGEN®  on the natural progression of 
tumor development.  At this time-point, only a few rats exhibited palpable tumors.  
These rats continued treatment with vehicle or NIAGEN® for another 5 weeks, at 
which time they were euthanized.  Dependent measures included number of 
palpable tumors, size of tumors, number of tumors/rat and total tumor load for the 
cohort.  This experiment was replicated twice.  The results indicated that five weeks 
treatment with NIAGEN® did not alter tumor growth compared to vehicle-treated rats.  
The second set of studies examined whether NIAGEN® would interfere with the anti-
tumor effects of paclitaxel.  For these studies, 25 rats were treated with MNU and 
upon the appearance of a palpable tumor received a cumulative dose of 19.8 mg/kg 
paclitaxel over five days.    Daily treatment with 200 mg/kg NIAGEN® did not 
interfere with the ability of paclitaxel to decrease in tumor growth and did not 
interfere with tumor growth in rats as compared to values in vehicle treated rats. 
These data indicate that NIAGEN® will neither interfere with the effects of paclitaxel, 
nor facilitate tumor growth. 
 
Preclinical studies concluded that NIAGEN® was not cytotoxic as determined 
by its lack of activity in a bacterial reverse mutagenesis assay, an in vitro 
chromosome aberration assay, and an in vivo micronucleus assay.  Acute toxicity 
testing of a single oral dose of 5000 mg/kg in male and female Sprague-Dawley rats 
identified no gross pathological changes in the subsequent 14 days.  A 14-day 
repeat dose study [38] of 2500 and 5000 mg/kg/day in male and female Sprague 
Dawley rats identified an 8% reduction in weight and feed consumption at the 
highest dose in male rats.  No adverse effects were observed in female rats.  A 90-
day subchronic toxicity study was conducted with 300, 1000 and 3000 mg/kg/day in 
male and female rats. There was no mortality at any dose.  In male rats, the two 
lowest doses caused a < 10% loss in weight and the highest dose caused a 17% 
decrease in body weight.  Female rats exhibited no weight loss.   Significant changes 
in hematological and clinical chemistry parameters occurred at the 1000 and 3000, 


Study Number  
March 24, 2021 
17 
but not 300 mg/kg, doses in male and female rats.  All three doses produced 
significant decreases in organ weights in male rats, but only marginal effects in 
female rats.  At the 3000 mg/kg/day dose, histopathological findings included 
centrilobular hepatocellular hypertrophy in both male and female rats, as well as 
degeneration or atrophy of seminiferous tubules in male rats and hypertrophy of 
corpora lutea in female rats 
 
An OECD-compliant rat developmental toxicity study was conducted in which 
pregnant Sprague-Dawley rats were administered 0, 325, 750 or 1500 mg /kg/day 
NIAGEN® by gavage from gestational day 5 – 19.  Although no morbidity/mortality or 
adverse clinical signs were reported in the dams at any dose level, the NOAEL for 
dams and fetuses was determined to be 350 mg/kg/day and 750 mg/kg/day, 
respectively.  These values were established due to observations that dams (1) 
exhibited treatment-related significant reductions in maternal body weight, corrected 
for body weight gain, and feed consumption at 750 and 1500 mg/kg/day and (2) a 
significant decrease in maternal uterine weights and an increase in late resorptions 
in dams occurred at 1500 mg/kg/day. Fetuses exhibited a significant decrease in 
fetal weights and an increase in the incidence of fetal anasarca at 1500 mg/kg/day. 
Fetuses also exhibited significant increases in minor anomalies, such as extra, 
accessory and rudimentary ribs at 1500 mg/kg/day, which were attributed to 
maternal stress evidenced by decrease in body weight and food consumption in the 
dams.  
 
An OECD-compliant one-generation reproduction study in was conducted in 
rats.  NIAGEN® was mixed in an experimental diet at 0, 3000, 6000, and 12000 ppm 
and provided (ad libitum) to male and female rats (n=25 rats/sex/group).  No 
treatment-related clinical signs or mortalities were observed at any of the doses 
tested.  At 12,000 ppm, a significant treatment-related decrease in body weight (4.6 
to 6.5%) was observed in males from treatment Day 43 to 92 (measured at weekly 
intervals), when compared to control group. The decrease was <10% and therefore 
considered to be not adverse.  The food consumption was unaffected in males at all 
of the doses tested. In females, body weights and food consumption were unaffected 
during pre-mating, gestation and lactation periods.  With respect to fertility 
parameters, the duration of gestation (gestation length), pre-coital time, and fertility 
indices were not affected by the treatment at all doses tested, when compared to the 
control group.  The survival indices of the pups were unaffected by the treatment at 
all the doses tested, when compared to the control group.  At first observation on 
Day 1 of littering, no abnormalities were observed in live and dead pups at all the 
doses tested.  Finally, there were no test item-related changes in terminal body 
weights/organ weights, gross and histopathology endpoints in adult rats of either 
sex. The pups sacrificed at weaning did not reveal any gross abnormalities.  The 
above results support a NOAEL for fertility and reproductive performance of 12,000 
ppm (equal to 675.21 mg/kg/day in males and 1,088.38 mg/kg/day in females) under 
the testing conditions and doses employed. 


Study Number  
March 24, 2021 
18 
 
A safety pharmacology screening study was conducted to quantify the in vitro 
effects of NIAGEN® on the potassium-selective IKr current generated in normoxic 
conditions in stably transfected Human Embryonic Kidney cells (HEK 293 cells). The 
hERG assay is used to assess the potential of a compound to interfere with the 
rapidly activating delayed-rectifier potassium channel. NIAGEN®, over the range of 
concentrations tested in this study (0.034 to 1.03 mM), caused no inhibition of hERG 
tail current density. 
 
2.3 Clinical Experience 
2.3.1.  Single-dose, double-blind, randomized, cross-over pharmacokinetic study in 
healthy adults  [39] 
 
The safety, pharmacokinetics and efficacy of single administration of three 
dosages of NIAGEN® was studied in healthy human subjects (ages 30 – 55 years) in 
a randomized, double-blind three-arm crossover trial [39].  Results indicate that 
NIAGEN® is metabolized similarly to nicotinamide in healthy humans and can be 
utilized as a form of Vitamin B3. Urine and plasma concentrations of nicotinamide 
riboside metabolites  nicotinamide, N-methyl-nicotinamide, N-methyl-4-pyridone-5-
carboxamide and N-methyl-2-pyridone-5-carboxamide exhibited a dose dependent 
relationship for each collection time (0-6 hr, 6-12 hr, and 12-24 hr) following 
treatment with 100 mg, 300 mg, or 1000 mg NIAGEN®.  Increased levels of 
nicotinamide, N-methyl-nicotinamide, N-methyl-4-pyridone-5-carboxamide and 
N-methyl-2-pyridone-5-carboxamide are indicative of underlying increases in cellular 
NAD+ concentrations. 
 
No clinically adverse effects on hematology, clinical chemistry, urinalysis or 
liver or kidney function parameters were noted.  Evaluation of vital sign measures 
showed that there were no differences between 100 mg, 300 mg or 1000 mg 
dosages of NIAGEN® in systemic blood pressure, diastolic blood pressure, or heart 
rate. All values for blood pressure and heart rate were at a normal and acceptable 
range for healthy adults.  There were no between group differences in hemoglobin, 
hematocrit, numbers of white blood cells or red blood cells, mean corpuscular 
volume, mean corpuscular volume, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, red cell distribution width, platelets, 
lymphocytes, or monocytes in 100 mg, 300 mg and the 1000 mg dosages of 
NIAGEN®, except for neutrophils.  Participants administered 300 mg of NIAGEN® 
showed an increase while participants administered with 1000 mg of NIAGEN® 
showed a decrease in neutrophils resulting in a significant difference between these 
two groups (p=0.04). However, this difference is most likely due to one individual 
with a low level of neutrophils in the NIAGEN® 1000 mg dosage group that was not 
considered clinically significant.  Levels of aspartate aminotransferase, alanine 
transaminase, γ-glutamyl transaminase, total bilirubin, creatinine, and estimated 
glomerular filtration rate, as well as the electrolytes sodium, potassium, and chloride 


Study Number  
March 24, 2021 
19 
were not different at 24 hour post-dose between the 100 mg, 300 mg or the 1000 mg 
dosage groups of NIAGEN®.  
 
 A total of 18 adverse events (AE) were reported by 10 participants during the 
study. All AEs ranged in severity from mild to moderate. A total of 5 AE’s were 
reported by 5 participants receiving the 100 mg dose of NIAGEN®. Two of these 
were categorized as General Disorders and Administration Site Conditions (feeling of 
warmth and tiredness).  Because these were not seemingly dose-dependent, both 
AE’s were interpreted by the contract research organization as unlikely related to the 
100 mg dose of NIAGEN®.  One AE was categorized as Skin and Subcutaneous 
Disorder and another as Nervous System Disorder.  Both were considered to be 
“unlikely” related to the 100 mg dose of NIAGEN®.  One AE categorized as 
Investigations (decrease in hemoglobin) was classified as “possibly” related to the 
study product and the participants were withdrawn from the study.  Seven 
participants receiving the 300 mg dose of NIAGEN® reported 9 AEs. Four of these 
AEs were categorized as Nervous System Disorders (headache) and were classified 
as “unlikely” related to the study product.  Two AEs were categorized as General 
Disorders and Administration Site Conditions (flushing and feeling warm) and were 
categorized as “unlikely” related to the study product.  Two AEs were classified as 
Gastrointestinal disorders (soft/loose stools) and were considered “unlikely” related 
to the study product.  One AE was categorized as Investigations (decrease in white 
blood cell count) and was considered “possibly” related to test item administration.   
Four participants reported 4 AEs after receiving 1000 mg NIAGEN®.  Two of these 
were categorized as “General Disorders and Administration Site Conditions” (feeling 
hot) and were categorized as unlikely related to study product, one AE was 
categorized as a “Nervous System Disorder” (headache) and unlikely related to 
study product, and one AE was categorized as “Investigations” (low hemoglobin) and 
unlikely related to study product, however, this participant was withdrawn from the 
study.  All AEs were resolved without the need for intervention and there was no 
association between AE severity and dose.  No SAEs were reported during the 
study.   
2.3.2. Six-week randomized, placebo-controlled, double blind, crossover study in 
healthy midlife and older adults  [40] 
 
In a 6-week randomized, placebo-controlled, double blind, crossover study, 
after preliminary screening for inclusion/exclusion criteria, 30 healthy midlife and 
older adult men and women (ages 55 – 80 years) were randomized to one of two 
groups (Group A or Group B) [40]. Group A received placebo for 6 weeks followed 
by NIAGEN® (500 mg, 2x/day) for 6 weeks [40] (NCT02921659).  Group B received 
the same treatments in the opposite order.  Due to the length of the placebo period 
and relatively short half-life of NAD+, a carryover effect between phases was not 
expected; therefore, a washout period between phases was not included.  The 
dosing regimen with NIAGEN® produced a 60% increase in levels of NAD+ in 
peripheral blood mononuclear cells (PBMC).  All AEs were rated as mild-to-moderate 
in severity.  The majority of AEs occurred during the placebo intervention, and were 


Study Number  
March 24, 2021 
20 
classified as unrelated to NIAGEN® supplementation.  No effect of NIAGEN® was 
observed on body mass at any time point during the study.  Heart rate stayed within 
normal ranges at all time points and no treatment by time interaction was observed.  
Blood pressure remained stable and within normal physiological values at all time 
points under both treatment conditions.  All hematological, metabolic (e.g., liver and 
kidney function), and lipid profiles remained within the normal reference range during 
both treatment conditions.  In summary, findings suggest that 6 weeks of 1,000 
mg/day oral NIAGEN® supplementation is safe and well tolerated and does not alter 
blood chemistry or markers of renal and liver function in middle-aged and older 
adults. 
2.3.3  An eight-week, repeat-dose, randomized, placebo-controlled, double blind, 
parallel group pharmacokinetic study in healthy adults. 
 
A randomized, double-blind, placebo-controlled, parallel group study was 
conducted in which healthy subjects ingested placebo, 100, 300, or 1000 mg 
NIAGEN®/day (n=30/group) for eight weeks [ChromaDex study 15NRHC].  Plasma 
and urine samples were obtained for assessment of metabolites including the 
primary metabolite 1-methyl-nicotinamide (1-MeNAM), and the secondary metabolite 
N-methyl-2-pyridone-3/5-carboximide (2-PY).  Levels of NAD+ in red blood cells and 
of nicotinamide in plasma were also determined.  Additional exploratory analyses of 
resting energy expenditure, C-reactive protein, and amino acid metabolism were 
conducted.  The accompanying safety assessment included hematology and clinical 
chemistry panels, as well as kidney and liver function tests. 
 
Compared to values in the placebo control group; daily ingestion of either 300 
or 1000 mg/day NIAGEN® resulted in a (1) dose-dependent increase in levels of 1-
meNAM in plasma and urine, and (2) dose-dependent increase in levels of 2-PY in 
plasma and urine.  Levels of nicotinamide in plasma were significantly increased only 
after ingestion of 1000 mg/day NIAGEN®; urine levels were not determined.  Doses 
of 300 mg or 1000 mg/day NIAGEN® increased NAD+ levels in red blood cells by 
44% and 132%, respectively.  This increase was evident within one week and 
remained unchanged for the duration of the study.  These findings document the 
absorption and metabolism of NIAGEN®, and the ability of both 300 and 1000 
mg/day to achieve the desired increase in NAD+ levels.  They also suggest that 1-
meNAM or 2-PY can be used to document drug exposure given the difficulty in 
measuring nicotinamide riboside in blood. 
 
Exploratory analysis of resting energy expenditure (i.e. energy utilization while 
awake but at rest, not actively digesting food and at thermoneutrality) did not identify 
any significant differences for any dose compared to placebo.  Exploratory analysis 
of amino acid levels identified no significant effects of any dose of NIAGEN® on 
amino acid metabolism.  Finally, no dose of NIAGEN® affected high sensitivity C-
reactive protein. 
 
With respect to safety, a total of 95 adverse events (AE) among 61 unique 
participants were reported in this study.  All were classified as mild to moderate and 
resolved by the end of the study.  Of the 26 AE documented in the 100 mg NIAGEN® 


Study Number  
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21 
group, 24 were reported as being unlikely or not related to the study product. The 2 
AEs reported as being possibly related (leg pain, high blood pressure) were both 
mild in intensity.  Of the 27 AEs documented in the 300 mg NIAGEN® group, 25 were 
reported as being unlikely or not related to the study product. The 2 AEs reported as 
being possibly related (nausea, muscle pain) were both mild in intensity.  Of the 22 
AEs reported in the 1000 mg NIAGEN® group, 19 were reported as being unlikely or 
not related to the study product. The 3 AEs reported as being possibly related (sore 
back, muscle soreness, nausea) were all mild in intensity.  Of the 20 AEs reported in 
the placebo group, 16 were reported as being unlikely to the study product. Of the 4 
AEs reported as being possible related, 3 were mild in intensity (rash, raised liver 
function tests, nausea) and 1 was moderate in intensity (upset stomach). 
 
With respect to hematology, significant differences were identified in (1) 
participants’ white blood cell count between the 300 mg NIAGEN® and placebo 
group at week 8; (2) red cell distribution width between the 1000 mg NIAGEN® group 
and placebo group from screening to week 8; and (3) eosinophil count between the 
1000 mg NIAGEN® group and 100 mg NIAGEN®, 300 mg NIAGEN®, and placebo 
group were identified.  However, these remained within healthy clinical values for all 
groups.  As such, these results were not deemed to be clinically significant. No other 
significant between-group differences were found in the hematology parameters of 
participants.  
 
With respect to clinical chemistry, the significant difference in participants’ 
ALT between the 1000 mg NIAGEN® group and the 100 mg NIAGEN® and placebo 
group at baseline to week 1, and between the 1000 mg NIAGEN® group and 100 mg 
NIAGEN® group and placebo group from baseline to week 2, as well as a significant 
between-group difference in AST between the 1000 mg NIAGEN® group and 100 mg 
NIAGEN® and placebo group at baseline to week 2 remained within healthy clinical 
values for all groups. As such, these results were not deemed to be clinically 
significant. No other significant between-group differences were found in the clinical 
chemistry parameters of participants.    
 
No significant difference between-groups in mean systolic blood pressure, 
mean diastolic blood pressure, mean heart rate, weight, or body mass index were 
identified among the 140 participants.  
2.3.4.  Open label escalating dose trial in healthy adults  
 
Eight healthy adult men and women (ages 21 – 50 years) were entered into 
an open label study of the safety and pharmacokinetics of escalating doses of 
NIAGEN® [41].  Subjects received 250 mg daily on days 1 and 2, 250 mg twice daily 
on days 3 and 4, 500 mg twice daily on days 5 and 6, and 1000 mg twice daily on 
Days 7 and 8.  On day 9, subjects received a single dose of 1000 mg.   No AEs 
attributable to NIAGEN® were reported during dose escalation of NIAGEN® to 1000 
mg orally twice daily.  Serum levels of creatine kinase, glucose, uric acid and alanine 
aminotransferase were unchanged.  Serum potassium decreased by an average of 
0.4 mEq/L.  Although this small decrease was statistically significant, the individual 
levels remained in normal range and the decrease was not considered clinically 


Study Number  
March 24, 2021 
22 
significant.  Serum levels of sodium, chloride, urea nitrogen, creatinine, lactate 
dehydrogenase or aspartate aminotransferase were unchanged.  There were no 
significant changes in blood pressure, body temperature, body weight, white blood 
cell differential or white blood cell count.  However, very small, albeit statistically 
significant, decreases in hemoglobin, hematocrit and platelet count were observed.   
 
This dose regimen increased levels of NAD+ in PBMC by two-fold.  Of note, 
despite the instability of NIAGEN® in blood, this study also attempted to quantitate 
plasma levels of nicotinamide riboside.  Following the final dose of 1000 mg 
NIAGEN®, plasma levels of nicotinamide riboside were increased in four of the eight 
participants with a Cmax of 3 hr and a half-life of 2.7 hr.  However, these values were 
at the limit of detection of the assay. 
2.3.5  Phase II studies in patients with skin cancer 
 
Two placebo-controlled phase II studies [42] of patients with a prior history of 
skin cancer and current actinic keratoses, which are predictive of non-melanoma 
skin cancers, demonstrated a 30% reduction in new actinic keratoses in patients 
taking 1 g/day of the NAD+ precursor nicotinamide.  A recent phase III study [43] of 
386 patients with a prior history of skin cancers demonstrated that daily oral 
administration of up to 1 g/day nicotinamide for one year decreased the rate of new 
nonmelanoma skin cancers by 23% and that of new actinic keratoses by 12%.   
 
 
3 - Rationale/Significance 
3.1 Problem Statement 
 
Peripheral neuropathies are a dose-limiting, disabling, and debilitating side 
effect of virtually every known class of chemotherapeutic agent.  Relatively few 
patients escape CIPN.  Patients experience paresthesias, dysesthesias, 
hyperalgesia (increased pain produced by a stimulus that does not normally cause 
pain), allodynia (pain due to a stimulus that does not normally evoke pain), 
numbness or loss of sensation, or ongoing pain that is burning, lancinating or electric 
shock-like in nature.  CIPN can seriously diminish a patient's quality of life, and can 
interfere with self-care and activities of daily living.  The severity of CIPN may also 
necessitate reducing the dose of chemo­therapeutic agent, delaying the next cycle of 
chemotherapy or terminating treatment entirely.  Given that advances in cancer 
diagnosis and treatment of cancer have increased the number of survivors to nearly 
14.5 million in 2014 [6], up to 4.5 million survivors may suffer from CIPN after their 
treatment is completed. 
 
The American Society of Clinical Oncology considers the development of 
adjuncts for the prevention and relief of CIPN as essential for patient care.  Much 
effort has gone into testing drugs like gabapentin, lamotrigine, and amitriptyline 
(used to treat other sensory neuropathies) only to learn that they are ineffective 
against CIPN. Thus, effective treatment for CIPN remains a significant unmet need in 
healthcare.   


Study Number  
March 24, 2021 
23 
 
3.2 Purpose of Study/Potential Impact 
 
The purpose of this study is to test the hypothesis that nicotinamide riboside 
(NIAGEN®) will prevent the progression of sensory neuropathy in breast cancer 
patients or patients with platinum-resistant recurrent ovarian, peritoneal, endometrial, 
or fallopian tube cancer receiving paclitaxel or nab-paclitaxel.  These findings will 
dictate whether there is adequate evidence to support the conduct of a placebo-
controlled, phase III trial and drive the design of that study.  
 
3.3 Potential Risks and Benefits 
3.3.1 Potential Benefits 
 
At present, there are no evidence-based efficacious treatments for the 
prevention or relief of CIPN in patients.  The only possible exception is duloxetine [8], 
for which the effect was not large. The development of a therapeutic agent that can 
prevent CIPN or reverse established CIPN will be transformative for the patient, the 
oncologist, and for cancer treatment.  It will permit patients to obtain the full benefit of 
chemotherapy and dramatically improve their quality of life both during therapy and 
in the years that follow.   A finding that nicotinamide riboside is efficacious would also 
support further phase II and phase III trials of efficacy in treating peripheral 
neuropathies induced by other chemotherapies and for other types of cancers.  In 
addition, it will provide data to support or refute the hypothesis that an elevation of 
NAD+ is a mechanism by which neuroprotection occurs, leading to the proposal of 
more mechanistic studies in patients.  Identification of the mechanism of action will 
guide the development of an entirely new class of therapeutic agent to address a 
significant unmet need in cancer care.   
3.3.2 Potential Risks 
 
There is a risk of a small amount of brief pain during venipuncture to obtain a 
blood sample.  The first blood sample will be obtained during a standard of care 
blood draw at the start of the visit.  The second sample will be obtained at the end of 
the infusion of taxane.   
 
Either an increase or decrease in paclitaxel concentrations could confound 
interpretation of the efficacy of NIAGEN®.  A false negative finding could occur if 
peripheral sensory neuropathy worsens or there is a further decrease in white blood 
cells, red blood cells and hematocrit should the levels or bioavailability of free 
paclitaxel increase due to displacement from plasma proteins.  A false positive 
finding could occur if plasma concentrations of paclitaxel decrease.  Therefore, 
although paclitaxel concentrations are not monitored as standard of care for 
treatment of breast cancer, blood levels of paclitaxel will be measured at the end of 
each taxane infusion.  With enrollment of the 10th patient, enrollment will pause so 
that an interim analysis of paclitaxel levels in all 10 patients receiving NIAGEN® can 
be conducted. 


Study Number  
March 24, 2021 
24 
 
There is a small risk that NIAGEN® may enhance oncogenesis.  Published 
data indicate that increasing NAD+ levels, either by administration of nicotinamide or 
NIAGEN®, decreases metastases, increases survival, and interferes with cancer 
progression [44-46].  Two phase II studies [42] and one phase III study [43] have 
demonstrated that oral administration of up to 1 g of nicotinamide daily for one year, 
significantly decreased the rate of new nonmelanoma skin cancers by 23% and the 
number of new actinic keratoses by 12%.    
 
There is minimal risk that NIAGEN® will cause flushing.  Unlike niacin or 
nicotinic acid, NIAGEN® does not activate GPR109A and therefore does not cause 
flushing [47]. 
 
4 - Study Objectives 
4.1 Hypothesis 
 
We hypothesize that daily administration of NIAGEN® will prevent the 
progression of sensory neuropathy in stage IV breast cancer patients, platinum-
resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer patients, 
or platinum-resistant recurrent or metastatic head and neck cancer patientsreceiving 
paclitaxel or nab-paclitaxel.  
4.2 Primary Objective 
 
The purpose of this single-arm phase II trial is to determine whether 
nicotinamide riboside prevents the progression of peripheral sensory neuropathy in 
patients receiving paclitaxel or nab-paclitaxel for treatment of stage IV breast cancer, 
platinum-resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube 
cancer, or platinum-resistant recurrent or metastatic head and neck cancer.  A 
decision to propose a large multi-center phase III trial of nicotinamide riboside for the 
relief of sensory neuropathy and the experimental design of that trial will be based on 
these findings.  
4.3 Secondary Objectives  
 
The secondary objective of this single-arm pilot phase II trial is to determine 
whether treatment with nicotinamide riboside can prevent reductions in the dose of 
taxane therapy due to the incidence or severity of neuropathy.  
4.4 Exploratory Analysis  
 
An exploratory analysis will be conducted to determine whether the Total 
Neuropathy Score – clinical version (TNS-c) [48] is an instrument can be used in 
subsequent studies to detect changes in neuropathy over time. 
 
 
5 - Study Design 
5.1 General Design 


Study Number  
March 24, 2021 
25 
 
This unblinded, prospective non-randomized and single-arm pilot phase II trial 
is designed to obtain preliminary data to determine whether a phase III randomized 
controlled trial should be proposed and to drive the experimental design of that trial.  
The trial will include a pause in enrollment after the 10th patient to enable a safety 
assessment to ensure that NIAGEN® does not adversely affect the plasma 
concentrations of paclitaxel. 
5.1.1 Study Duration 
 
The study will be open for enrollment for 3 years or until 39 patients have 
completed the study.  Patients will receive NIAGEN® for approximately 12 weeks 
concomitant with their scheduled taxane infusions, with the final followup scheduled 
24 to 26 weeks after the end of treatment.  
5.1.2 Number of Study Sites 
 
There will be two study sites:  University of Iowa Hospitals and Clinics, Iowa 
City, IA and Wake Forest Baptist Medical Center, Winston-Salem, North Carolina. 
5.2 Outcome Variables 
5.2.1 Primary Outcome Variable 
 
The primary outcome variable is binary (yes/no) and defined as no worsening 
of the grade of peripheral sensory neuropathy, scored according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 guidelines, from the 
initiation of NIAGEN® treatment to the conclusion of NIAGEN® treatment.   It will be 
determined on an end-of-treatment visit scheduled 7 to 14 days after the final taxane 
infusion.  
5.2.2 Secondary Outcome Variables  
The secondary outcome variables are: 
• Percentage of patients that experience a neuropathy-driven dose reduction.  
Dose reduction is defined as a 15% decrease from initial intended dose 
prescribed at baseline (including discontinuation of therapy) due to the 
peripheral neuropathy.  
• Incidence of dose reduction (each reduction is a single event). 
• Cumulative dose of paclitaxel administered after NIAGEN® therapy is started. 
• Change in the score on the11-item NTX subscale of the FACT&GOG-NTX 
questionnaire determined from baseline to follow-up. 
 
5.3 Study Population 
 
This trial will be conducted in patients who are 18 to 85 years old with a 
diagnosis of stage IV breast cancer, platinum-resistant recurrent ovarian, peritoneal, 
endometrial, or fallopian tube cancer, or platinum-resistant recurrent or metastatic 
head and neck cancer who are receiving intravenous infusions of paclitaxel or nab-
paclitaxel at the University of Iowa Hospitals and Clinics or the Wake Forest Baptist 
Medical Center.  To enroll, the patient must have metastatic breast cancer, platinum-


Study Number  
March 24, 2021 
26 
resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer, or 
platinum-resistant recurrent or metastatic head and neck cancer and report at least a 
grade 1 peripheral neuropathy after initiation of paclitaxel therapy, scored according 
to the CTCAE version 4.03 guidelines for peripheral sensory neuropathy. Patients 
with recurrent disease may also be enrolled if they have residual CIPN from prior 
chemotherapy that is ≤ grade 2. 
5.3.1 Number of Participants 
 
 
We estimate that 72 new patients with metastatic breast cancer or platinum-
resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer will be 
placed on paclitaxel or nab-paclitaxel at either the University of Iowa Hospitals and 
Clinic or Wake Forest Baptist Medical Center over the course of three years. The 
incidence of CIPN in patients receiving taxanes ranges from 57% to 83% [52, 53].  In 
a large study of breast cancer patients receiving 12 weekly infusions of 80 mg/m2 
paclitaxel, 38%, 21%, and 9% developed a sensory neuropathy of grade 1, 2, or 3 
[54].  Finally, a recent study of weekly taxanes in breast cancer patients documented 
that 28% of patients developed grade 2 and 17% developed grade 3 neuropathy 
when placed on weekly paclitaxel [55].  Thus, we expect that 60% (43 patients) will 
develop grade 1 neuropathy or greater within 9 weeks, most likely after the 5th or 6th 
infusion, and become eligible for enrollment. 
         Of the 43 patients with neuropathy, we anticipate that 90% will meet eligibility 
requirements and consent to participate.  We anticipate minimal, if any, loss to 
follow-up as they will meet with their physician within 14 days of the final infusion of 
taxane.  Thus, we expect to have 39 patients complete the 12 weeks of paclitaxel 
therapy.  Our primary outcome variable will be binary (yes/no) for each patient.  A 
"favorable outcome" is defined as no worsening of the grade of sensory neuropathy, 
as defined by the CTCAE guidelines for scoring peripheral sensory neuropathy, from 
the initiation of NIAGEN® treatment to the visit that occurs within 14 days of the final 
infusion of taxane.  An "unfavorable outcome" is defined as otherwise.   
5.3.2 Eligibility Criteria 
 
Decisions about eligibility will be made by the research nurse and verified by 
the treating physician.  To be eligible, patients must: 
• Be able to give written informed consent and HIPAA authorization 
• Be 18 to 85 years old 
• Have been diagnosed with stage IV breast cancer of any type,  platinum-
resistant recurrent ovarian, peritoneal, endometrial, or fallopian tube cancer, 
or platinum-resistant recurrent or metastatic head and neck cancer and are 
anticipated to survive for at least three months 
• Have an ECOG Performance Status of 0-2 
• Able to take medication orally – up to four capsules in the morning (am) and 
four capsules in the evening (pm). 


Study Number  
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27 
• Be undergoing infusions of paclitaxel or nab-paclitaxel for treatment of breast 
cancer,  platinum-resistant recurrent ovarian, peritoneal, endometrial, or 
fallopian tube cancer, or platinum-resistant recurrent or metastatic head and 
neck cancer and be determined to have at least a grade 1 neuropathy based 
on the CTCAE version 4.03 guidelines for peripheral sensory neuropathy.  
Breast cancer patients may also be treated concomitantly with monoclonal 
antibodies to HER2 such as trastuzumab (Herceptin) and pertuzumab 
(Perjeta).  Patients with platinum-resistant ovarian, peritoneal, endometrial, or 
fallopian tube cancer or platinum-resistant recurrent or metastatic head and 
neck cancer may also be treated concomitantly with a vascular endothelial 
growth receptor 2 inhibitor such as bevacizumab (Avastin) or a checkpoint 
inhibitor. 
• Females must be either postmenopausal for at least 1 year or surgically 
sterile for at least 6 weeks.  Females of childbearing potential must have a 
negative pregnancy test at screening to be eligible for study participation, and 
agree to take appropriate precautions to avoid pregnancy from screening 
through follow-up.    
• Males must agree to take appropriate precautions to avoid fathering a child 
from screening through follow-up.  The following methods have been 
determined to be more than 99% effective (<1% failure rate per year when 
used consistently and correctly) [56] and are permitted under this protocol for 
use by the patient and his/her partner: 
 
Complete abstinence from sexual intercourse when this is in line with the 
preferred and usual lifestyle of the patient 
 
Double barrier methods 
-  Condom with spermicide in conjunction with use of an intrauterine device 
-  Condom with spermicide in conjunction with use of a diaphragm 
• 
Surgical sterilization (bilateral oopherectomy with or without hysterectomy, 
tubal ligation or vasectomy) at least 6 weeks prior to taking study treatment. 
In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up levels of luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), and/or estradiol 
Non-hormonal intrauterine device used as directed by provider placing this is 
also acceptable. 
5.3.3 Exclusion Criteria 
• Pre-existent peripheral neuropathy that is unrelated to chemotherapy 
• Pre-existent chemotherapy-induced peripheral neuropathy greater than grade 
2 
• Known metastases to the brain, spinal cord or peripheral nerves, or 
leptomeningeal disease 
• Concurrent administration of a poly (ADP-Ribose) polymerase inhibitor (e.g. 
olaparib, rucaparib) 


Study Number  
March 24, 2021 
28 
• Concurrent administration of a platinum-based chemotherapy 
• Diabetes managed by medication  
• Neutrophils < 1,000 cells/m3 
• Hemoglobin < 8.0 g/dcl 
• Platelets < 100,000 cells/m3 
• Creatinine clearance < 30 ml/min 
• AST or ALT values > 2.5 X upper limits of normal 
• Total bilirubin > 2.0 X upper limits of normal 
• Heavy alcohol use defined at > 8 drinks/week by women or 12 drinks/week by 
men 
• Chronic pain greater than 3 months duration within the past year. 
• Severe psychiatric illness 
• Pregnancy 
• Current imprisonment 
• Limitations of self-expression, defined as an inability to answer questions 
posed by physicians, nurses, care-givers, or other members of the 
investigative team or an inability to describe somatosensations. 
• Known HIV, not on therapy 
• Regular use of nutritional supplements that contain nicotinamide or 
nicotinamide riboside within the previous 30 days 
• Use of duloxetine (Cymbalta®) within the previous 30 days 
• Pancreatic insufficiency requiring exocrine enzyme replacement therapy 
• GI conditions where malabsorption of B complex vitamins is known to occur.   
• Breastfeeding  
 
6 - Methods 
6.1 Treatment - Drug 
6.1.1 Identity of Investigational Product/New Drug 
 
NIAGEN® manufactured by ChromaDex and provided as capsules. 
6.1.2 Dosage, Admin, Schedule (if applicable) 
 
Dosing will begin upon documentation of at least a grade 1 peripheral 
neuropathy and conclude one week after the 12th or last infusion of paclitaxel or nab-
paclitaxel therapy.  An initial total daily dose of 300 milligrams taken orally during the 
first week of therapy will escalate to a total daily dose of 1 gram taken orally for all 
subsequent weeks of the trial.  The daily dose will be taken as two divided doses at 
roughly 12 hr intervals.  If a patient vomits or misses a dose they will be directed to 
resume with the next scheduled dose.   


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The physician may choose not to escalate to the 1 gram dose.  If, following 
dose escalation, the treating physician believes that the 1 gram dose has significant 
adverse effects, they may return the patient to the 300 mg dose. 
6.1.3 Method of Assignment/Randomization  
 
Not applicable.  This is a single-arm, unblinded, and non-randomized study. 
6.1.4 Blinding and Procedures for Unblinding  
 
Not applicable 
6.1.5 Packaging/Labelling 
 
ChromaDex will provide NIAGEN® as bottles of capsules containing either 75 
mg or 250 mg of the product.  NIAGEN® capsules will be dispensed by the 
Investigational Pharmacy at each site.  A four week supply will be dispensed to 
patients every four weeks while on study. When less than four weeks of treatment 
remains, a quantity will be dispensed that is sufficient to complete treatment through 
one week after the last taxane infusion.  
6.1.6 Storage Conditions 
 
Drug should be stored at room temperature, protected from light.  Drug will be 
under the control of the Investigational Pharmacy at each site.  Unused drug will be 
returned to ChromaDex in Irvine, CA. 
6.1.7 Concomitant therapy 
 
Patients will be treated in accordance with the standard of care for metastatic 
breast, or platinum-resistant ovarian, peritoneal, endometrial, or fallopian tube 
cancer.  After enrollment in the study and for the duration of the study, they will be 
requested not to supplement the dose of nicotinamide riboside with nicotinamide 
riboside that can be purchased over the counter or on the internet. Compliance will 
be determined through discussion and documented in the review of concomitant 
medications at each visit.  Dairy intake will be queried at each visit. ~1 mg of 
NIAGEN® is present in four 8 oz glasses of milk [30]. 
6.2 Assessments 
6.2.1 Efficacy 
 
The efficacy of NIAGEN® to prevent the progression of CIPN will be 
determined by the grade of peripheral sensory neuropathy, scored according to the 
CTCAE guidelines, and patient responses to the 11-item NTX subscale of the 
FACT&GOG-NTX questionnaire.  Exposure to NIAGEN® will be monitored by 
measurement of NAD+ in red blood cells and N-methyl-nicotinamide in the blood.  
These assessments will be made at each visit. 
6.2.2 Safety 
 
Paclitaxel is highly bound to protein.  While unlikely, NIAGEN® could compete 
for plasma protein binding sites and as a result increase the concentration of free 
paclitaxel and potentially worsen the sensory neuropathy in patients as well as 
exacerbate paclitaxel-induced myelosuppression.  Conversely, NIAGEN® could 
induce the P450 (CYP3A and CYP28A) enzymes that metabolize paclitaxel, 


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decreasing its plasma concentrations and compromising therapy.  The latter is of 
minimal concern given that in vitro studies in human liver microsomes concluded that 
NIAGEN® neither inhibits nor induces these enzymes.  Nonetheless, paclitaxel 
concentrations and complete blood counts will be monitored on each visit. 
       6.2.2.1 Adverse Events Definition and Reporting 
 
Adverse effects will be monitored at each visit by the Principal Investigator.  
The Data Safety and Monitoring Plan (Appendix B) describes the HCCC 
requirements for Adverse Event (AE) reporting and Serious Adverse Event (SAE) 
reporting. 
6.2.3 Pharmacokinetics of Taxanes 
 
Two 5 ml blood samples will be collected at each time point indicated on the 
schedule of events. Each set of blood will be drawn within 30 ± 10 min of the end of 
each infusion of paclitaxel and between 15 and 30 minutes after each infusion of 
nab-paclitaxel, and submitted for measurement of paclitaxel concentration.   See 
Appendix C. 
6.2.4 Biomarkers  
 
Although a method that diminishes the instability of NR in blood has recently 
been identified [41], NR levels in blood will not be measured.  The published method 
has not been validated as reproducible and sufficiently sensitive.   In addition, due to 
clinic scheduling constraints patients may be sampled as soon as the first hour or as 
late as 9 hours after their morning dose.  The results are anticipated to be quite 
variable as a result.  In its stead, the levels of NAD+ and N-methyl-nicotinamide will 
serve as biomarkers to ascertain exposure levels to NIAGEN®.  The increase in 
levels of NAD+ and N-methyl-nicotinamide are very consistent and achieve steady 
state that is independent of time of dosage.  The methods of quantitation are also 
validated.  Levels of NAD+ and N-methyl-nicotinamide will be measured via blood 
obtained prior to therapy along with standard of care labs when the patient arrives for 
their visit.  Two 3-ml samples will be collected.   See Appendix C. 
6.3 Study Procedures 
6.3.1 Study Schedule 
 
See Study Calendar in Synopsis.  
6.3.2 Informed Consent 
 
After the physician has confirmed the presence of grade 1 or higher CIPN or 
the existence of a preexisting CIPN of no greater than grade 2, he or she will inform 
the patient of the possibility of participation in the study.  Any patient who expresses 
interest will be referred to the research study nurse for further description of the trial.  
The research study nurse or treating physician will obtain informed consent.  
6.3.3 Screening and Enrollment 
 
The research study nurse will review the patient's electronic medical record to 
determine the patient's eligibility.  


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Laboratory assessments completed within 3 days of enrollment will include 
serum or urine pregnancy test for females of childbearing potential, as well as renal 
and hepatic function.  See Study Calendar for detailed list of screening items to be 
collected. 
 
When all inclusion/exclusion criteria have been met, the patient will be 
considered enrolled.  
6.3.4 On Study Visits 
 
Patients will be scheduled to receive an intravenous infusion of paclitaxel or 
nab-paclitaxel in accordance with standard of care for that disease as determined by 
the physician.  The schedule of taxane infusion may include a periodic scheduled 
week “off” from infusion.  Daily dosing with NIAGEN® will begin on Treatment Week 
1, Day 1 following completion of the infusion of paclitaxel or nab-paclitaxel.  It will 
continue for one week after the last scheduled infusion of taxane.  At each visit, the 
grade of the patient’s peripheral sensory neuropathy will be determined per the 
CTCAE guidelines and the patient will complete the 11-item NTX subscale of the 
FACT&GOG questionnaire. Review of drug administration, dairy intake, collection of 
vital signs, liver function tests, complete blood counts, and adverse events will occur 
at each visit.  Clinical chemistries will be assessed at each visit.  Scoring of sensory 
peripheral neuropathy by CTCAE guidelines and the FACT&GOG NTX subscale, as 
well as the ECOG Performance Status can be determined by either the oncologist or 
the research nurse on the weeks when the oncologist is not seeing the patient.  In 
addition, a clinician trained in the neurological assessment procedures will assess 
the neuropathy on enrollment, after the first week of NIAGEN®, at monthly intervals 
thereafter, and at the end of treatment visit using the TNS-c questionnaire.  Patients 
will not be required to come in for measurement on their scheduled week “off.” 
  
 
At each visit, blood from a sample drawn prior to initiation of the scheduled 
infusion of paclitaxel or nab-paclitaxel will be sent for analysis of the levels of NAD+ 
and N-methyl-nicotinamide, and a sample drawn at the end of the taxane infusion 
will be sent for analysis of paclitaxel levels.  Also, patients will be asked to bring their 
drug diary and any remaining NIAGEN® in at each visit.  Seven to 14 days after the 
last taxane infusion and again 12 to 14 weeks and 24 to 26 weeks after the last 
taxane infusion the study research nurse will contact the patients during their 
scheduled follow-up visit and ask them to complete the CTCAE and NTX subscale 
questionnaire.   
6.3.5 End of Study and Follow-up 
 
Seven to 14 days after the last infusion of taxane, and again 12 to 14 weeks 
and finally 24 to 26 weeks after the last infusion of paclitaxel or nab-paclitaxel, the 
research study nurse will contact the patients during their scheduled follow-up visit, 
score their peripheral sensory neuropathy as per the CTCAE guidelines for 
peripheral sensory neuropathy, and obtain their response on the 11-item NTX 
subscale of the FACT&GOG questionnaire.  Patients will be specifically asked if they 
have continued nicotinamide riboside of their own volition at the follow-up visits at 


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12-14 weeks and 24-26 weeks. Patients will also be contacted 30-37 days after the 
last dose of NIAGEN® to assess for any adverse events. This contact can be made 
by phone contact if the patient is not scheduled for a standard of care office visit 
during this timeframe. 
 6.3.6 Removal of subjects (Stopping rules) 
 
Subjects will be removed from the study if they develop a hypersensitivity 
reaction at the time of the taxane infusion.  In this event, NIAGEN ® administration 
will cease, and an end of study visit to assess the primary outcome will be scheduled 
one week later.  Further followup will not occur as the patients will be placed on a 
different chemotherapy.   
 
Subjects will also be removed from the study should any hematological or 
non-hematological laboratory values meet criteria for exclusion from the study 
(section 5.3.3).  For the first 10 subjects enrolled, subjects will also be removed if 
plasma levels of paclitaxel increase or decrease more than 2 S.D. of the group mean 
pre-NIAGEN® levels.  Patients enrolled thereafter will be removed if plasma levels of 
paclitaxel fall outside the bounds established by iterative refinement of the predictive 
probability of paclitaxel levels.  Finally, subjects will be removed for any other 
unacceptable toxicity in the opinion of the attending physician.   
6.4 Statistical Method 
6.4.1 Statistical Design 
 
The purpose of this study is to determine whether NIAGEN® prevents the 
progression of peripheral sensory neuropathy in patients receiving paclitaxel or nab-
paclitaxel for treatment of breast cancer or platinum-resistant recurrent ovarian, 
peritoneal, endometrial, or fallopian tube cancer. The study is designed as a single-
arm, observational phase II trial. A decision to propose a phase III trial of 
nicotinamide riboside for the relief of sensory neuropathy at the end of the proposed 
study will be based on the findings of this phase II trial with predictive probability 
approach using the Bayesian analysis. 
6.4.2 Sample Size Considerations 
 
We estimate that 72 new patients at the University of Iowa Hospitals and 
Clinics will be placed on paclitaxel or nab-paclitaxel in the course of 24 months.  An 
additional number of new patients will be placed on this therapy at Wake Forest 
Baptist Medical Center.   The incidence of CIPN in patients receiving taxanes ranges 
from 57% to 83% [52, 53].  In a larger study of breast cancer patients receiving 12 
weekly infusions of 80 mg/m2 paclitaxel, 38%, 21%, and 9% developed a sensory 
neuropathy of grade 1, 2, or 3 [54].  Finally, a recent study of weekly taxanes in 
breast cancer patients documented that 28% of patients developed grade 2 and 17% 
developed grade 3 neuropathy when placed on weekly paclitaxel [55].  Thus, we 
expect that 60% (43 patients) will develop grade 1 neuropathy or greater within 9 
weeks, most likely after the 5th or 6th infusion, and become eligible for enrollment. 
         Of the 43 patients with neuropathy, we anticipate that 90% will meet eligibility 
requirements and consent to participate.  We anticipate minimal, if any, loss to 


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follow-up as they will meet with their physician within 14 days of the final infusion of 
taxane.  Thus, we expect to have 39 patients at the University of Iowa Hospitals and 
Clinics complete the 12 weeks of paclitaxel therapy, and the maximum sample size 
of the study is assumed as 39 patients.   
6.4.3 Planned Analyses 
6.4.3.1 Primary Analyses 
 
The primary analysis will be based on the predictive probability approach 
using the Bayesian analysis for this phase II trial [57].  Compared to the traditional 
Simon's optimal or MiniMax design [58] with two pre-determined time points for 
evaluation of efficacy, the Bayesian design allows more frequent monitoring.  Based 
on the historical data, it was assumed that 50% of the patients' grade of peripheral 
neuropathy would not worsen if they do not receive NIAGEN® treatment.  We also 
assumed the NIAGEN® treatment would increase the favorable outcome rate to 
70%.  Bayesian inference interprets the probability as a degree of belief, and 
unknown parameters are random variables with prior probability distributions.  
Therefore, instead of a fixed favorable outcome rate of 50% for the no NIAGEN® 
treatment group, a weakly informative (i.e. very large standard deviations) [59] prior 
distribution centered on the 50% favorable outcome estimate was used.  A vague 
Beta prior distribution with parameters 0.5 and 0.5 (Beta (α=0.5, β= 0.5)) provides a 
mean 50% and standard deviation 35%, and was used.  As is typical for phase II 
trials, both type I and type II error rates were assumed to be 10%.  In addition, the 
maximum sample size was assumed 39, and the trial will be monitored continuously 
after enrolling the first 10 patients.  Under these assumptions, according to the 
Bayesian predictive probability design, the following rejection regions are calculated: 
(favorable outcome/current sample size) 1/10, 2/11, 3/13, 4/15, 5/16, 6/18, 7/20, 
8/21, 9/23, 10/24, 11/26, 12/27, 13/29, 14/30, 15/31, 16/32, 17/33, 18/34, 19/35, 
20/36, 21/37, 22/38, 23/39.  The trial will be stopped and the NIAGEN® treatment 
will be deemed ineffective the first time the number of favorable outcomes falls into 
the rejection region.  Accordingly, the trial will be stopped for futility if only 1 
favorable outcome is observed out of the first 10 patients, or 2 favorable outcomes 
are observed out of the first 11 patients, and so on.  Otherwise, the trial will continue 
until enrolling the maximum sample size of 39 patients.  If at the end of the trial, 
NIAGEN® treatment prevents the progression of CIPN in 24 or more patients, out of 
39, NIAGEN® will be considered effective and we will recommend proceeding to the 
phase III trial.  
 
The determination of futility will be based on the Bayesian predictive 
probability approach, as defined above. Such determination will be informed by 
verification that (1) each patient in the analysis had adequate exposure to NIAGEN® 
as validated by levels of NAD+ in red blood cells and N-methyl-nicotinamide in 
plasma and (2) plasma levels of paclitaxel were within the 95% confidence limits of 
the baseline values determined for the patients enrolled.   
 
If a patient discontinues NIAGEN® treatment or supplements their own during 
the protocol, follow-ups will continue until the 8th day after the last infusion of taxane 


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for the primary analysis.  The primary outcome of change in grade of sensory 
neuropathy will be assessed at that time regardless of the patient's discontinuation or 
supplementation of the NIAGEN® treatment.   
6.4.3.2 Secondary Objectives Analyses 
         The secondary endpoints are the percentage of patients experiencing a 
neuropathy-driven dose reduction, the incidence of dose reduction (each reduction is 
a single event), the cumulative dose of taxane administered after NIAGEN® therapy 
is started, and the change in the score on the11-item NTX subscale of the 
FACT&GOG-NTX questionnaire determined from baseline to follow-up.  First, the 
Shapiro-Wilks test will be used to determine if the change in the score on the11-item 
NTX subscale of the FACT&GOG-NTX questionnaire and actual and planned 
cumulative doses of paclitaxel are normally distributed.  Then, based on the 
normality assumption, paired t-test or Wilcoxon sign rank test will be used to 
compare whether differences in the actual vs. planned cumulative dose of paclitaxel 
and the change on the score on the11-item NTX subscale of the FACT&GOG-NTX 
questionnaire are different from zero.  A one-sample test of proportions (Binomial 
test) will be used to determine if the proportions of patients experiencing a dose-
reduction differs from 17% and if the incidence of individual dose reductions differs 
from 16%.    
6.4.3.3 Safety 
 
Studies of the pharmacokinetics of Taxol® indicate that plasma levels of 
paclitaxel vary greatly among a population of patients receiving a standardized 
dose.  Efforts to model a personalized dose to achieve a defined plasma level of 
paclitaxel yielded doses that differed by as much as four-fold in the population of 
patients [60].  Of note, the plasma levels of paclitaxel also vary greatly week-to-week 
for individual patients receiving a standardized dose [61, 62].  Therefore, a hybrid of 
frequentist and Bayesian approaches will be used to monitor plasma levels of 
paclitaxel in patients.  For patients 1 through 10, paclitaxel levels that fall outside 2 
S.D. of the group mean of baseline (pre-NIAGEN®) values will be considered 
aberrant and this finding communicated  to the treating oncologist and DSMC.  With 
the enrollment of patient 11, and concordant with initiation of the Bayesian analysis 
of the primary outcome measure, a Bayesian model of predictive probability for 
paclitaxel levels in this patient population will be developed.  This model will be 
iteratively refined as additional data on paclitaxel levels are obtained with continued 
enrollment of new patients.  The attending oncologist and the DSMC will be notified 
of patients whose paclitaxel levels lie outside these bounds. 
6.4.3.4 Analysis of Subject Characteristics 
• Age 
• Gender 
• Race 
• Ethnicity 


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• Breast cancer receptor status 
• Type and stage of breast cancer 
• Type and stage of ovarian cancer 
• Type and stage of endometrial cancer 
• Type and stage of fallopian tube cancer 
• Type and stage of peritoneal cancer 
• Type and stage of head and neck cancer 
 
 
6.4.3.5 Interim Analysis  
 
Interim analysis is not applicable to the design of this phase II trial, which will 
use a Bayesian model to evaluate outcome on a patient by patient basis after 
enrollment of the first ten patients.  An interim analysis of paclitaxel levels in the first 
10 patients will be conducted as part of ongoing safety assessment. 
 
6.4.3.6 Health economic evaluation 
Not applicable 
6.4.4 Subsets and Covariates 
 
Not applicable 
6.4.5 Handling of Missing Data 
 
Given that these patients routinely have several clinic appointments each 
month and this is not a randomized study, the loss to follow-up rate is expected to be 
low in this study. To prevent missing data, every effort, including phone call 
reminders to patients will be made. Loss to follow-up, missing data and the reasons 
leading to loss of follow-up or data will be recorded. In case of missing data, we will 
impute missing data using different methods. Because of the repeated measures 
nature of the data, the ‘last observation carried forward’ method will be utilized [63].  
As a sensitivity analysis for the missing data, study results will be compared for the 
following two conditions:  1) patients with missing primary outcome variable are 
excluded from analyses; and 2) results with last observation carried forward. 
Robustness of the results under both scenarios will be assessed.     
 
7 - Trial Administration 
7.1 Institutional Review Board (IRB) Review 
 
 
This study will be reviewed and overseen by the Holden Comprehensive 
Cancer Center, and also by the University of Iowa Institutional Review Board (IRB). 
As patients will also be enrolled at Wake Forest Baptist Health Center, the 
enrollment and treatment of patients at that site will also be reviewed and overseen 
by the Wake Forest University IRB. 


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7.2 Subject Confidentiality 
 
 
Discussions with the patient, by the physician or the research nurse, will occur 
in a private room to minimize the risk of loss of privacy.  Personal information about 
the patient will not be discussed with individuals outside the study team.  The risk of 
loss of confidentiality will be minimized by use of data collection forms that contain 
only a study ID, and not the subject's name or medical record number. The patient 
will provide a preferred method of communication for follow-up about the study. 
7.3 Unanticipated Problems 
 
Unanticipated problems will be communicated by letter and email to all 
members of the study team.  A response and plan of action will be developed 
through consultation among team members, the Data and Safety Monitoring 
Committee and the IRB.  The study team will communicate the problem and the 
proposed resolution to the FDA (Food and Drug Administration) as applicable. 
7.4 Data Quality Assurance 
 
Quality of data collection will be ensured by training the study dedicated 
research nurses in administration of the questionnaires and completion of the data 
collection forms. Protocols will be developed and validated for measurement of 
paclitaxel concentrations and levels of NAD+ and its metabolites.  Measurements of 
paclitaxel or of NAD+ and its metabolites will be made by a single laboratory.  
Collection of blood samples will be done by a trained phlebotomist.   All samples will 
be blinded for analysis.  The investigational drug will be prepared by the 
manufacturer according to GMP (Good Manufacturing Practice) standards, and 
dispensed by the Investigational Pharmacy at each site.  .  Additional information on 
monitoring by the HCCC is provided in the Data Safety and Monitoring Plan 
(Appendix B).  
7.4.1 Data Collection 
 
The Methods section describes data collection in more detail.  Briefly, the 
electronic medical record will be the source of research materials about the age, 
gender, racial and ethnic identity, type of breast cancer, treatment, and doses of 
paclitaxel administered to the patients.  The results of the CTCAE sensory 
neuropathy, the score on the11-item NTX subscale of the FACT&GOG-NTX 
questionnaire, and the score on the TNS-c questionnaire will be recorded on data 
collection forms, will be recorded on data collection forms, which will document the 
presence and severity of peripheral sensory neuropathy.  Blood levels of NAD+ and 
N-methyl-nicotinamide will be determined using tandem mass spectrometry by 
Keystone Bioanalytical, a GLP-compliant CRO specializing in quantitative LC/MS/MS 
method development, validation and analysis, and the data returned to the research 
team for entry on the data collection form and analysis.  Levels of paclitaxel after 
infusion will also be determined by the Department of Pathology at Wake Forest 
using a laboratory developed test that has been validated, and results communicated 
to the designated research study nurse for entry on the data collection form and 
analysis.  All data will be de-identified.   Data will be collected at each visit and again 


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7-14 days, 12-14 weeks, and 24-26 weeks after the last visit.  These forms will be 
retained for at least 7 years after completion of the study in compliance with NIH 
guidelines for data retention, and then destroyed by shredding.   
7.4.1.1 Access to Source 
 
The data collection form, questionnaires, telephone survey, laboratory 
analyses of paclitaxel and NAD+ and its metabolites, and the patients' electronic 
medical record will serve as sources of data.  These materials will be filed at the 
treating physician’s site.   Access to the electronic medical record will be restricted to 
health professionals involved in the clinical care of the individual, as well as to Dr. 
Thomas, Dr. Hammond, the research coordinator, and the research nurse.  The data 
collection forms will be accessible to all members of the investigative team, with the 
identity of the individual, access date and time logged.  Study nurses at each site will 
abstract data from the data collection forms and enter the data into the study 
database for analysis.   Drs. Hammond and Thomas will permit trial related 
monitoring, audits, IRB review and regulatory inspection, providing direct access to 
all related source documents. 
 
7.4.1.2 Data Storage/Security 
 
The study identification number and the patient's name will be stored in a 
password protected file on a password protected computer within a locked office.  
This file will be stored separately from the data collection forms and database.  Only 
Dr. Hammond, Dr. Thomas and the research coordinator will have access to that file.  
Paper forms will be stored in locked cabinets in locked offices.  Electronic files will be 
kept in password protected files on a password protected computer in a locked 
office, and a backup copy placed on a remote server configured to secure sensitive 
health care information.  Only patient identification numbers will be associated with 
the data, there will be no direct patient identifiers stored within the study database.  If 
laptop computers are used, they will be encrypted.  
7.5 Study Records 
 
The following are considered study records and will be maintained for the 
duration of the study and retained for at least 7 years after completion of the study:  
• informed consent form 
• electronic medical record 
• data collection form 
• CTCAE questionnaire 
• 11-item NTX subscale of the FACT&GOG-NTX questionnaire  
• TNS-c questionnaire 
• chromatograms of NAD and N-methyl-nicotinamide in blood 
• chromatograms of paclitaxel in blood 
• follow-up survey 


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• all IRB correspondence 
7.5.1 Retention of Records 
 
All study records and documents, whether arising at the University of Iowa or 
Wake Forest University, that pertain to the conduct of the study including: data 
collection forms, source documents, and IRB correspondence will be retained by the 
Principal investigator for at least 7 years following the completion of the study.  
Movement or destruction of records will require consent of Dr. Hammond. 
7.6 Study Monitoring 
 
The Holden Comprehensive Cancer Center will assist with monitoring of the 
study to ensure compliance and quality of data collection.  Review of records will 
occur at each study site and will be conducted by a Clinical Research 
Auditor/Monitor not affiliated with the study.  The Medical Monitor for this study will 
be Daniel Vaena, M.D. 
 
7.7 Data Safety Monitoring Plan 
 
The Data Safety and Monitoring Committee of the Holden Comprehensive 
Cancer Center will be used (refer to Appendix B).  
7.8 Study Modification 
 
All study modifications will only be made by the principal investigators after 
consultation with the investigative team and the Holden Comprehensive Cancer 
Center.  All protocol modifications will be submitted to the local IRB for information 
and approval in accordance with local requirements.  IRB approval will be obtained 
before any changes are implemented, except for changes necessary to eliminate an 
immediate hazard to a study participant.  If recommended, modifications to the dose 
or frequency of administration of NIAGEN®  will be communicated by phone to the 
patient within 24 hrs of approval and confirmed with the patient at the time of the 
next clinic visit.  
7.9 Study Discontinuation 
 
This study will be discontinued if the Bayesian analysis of favorable 
outcomes, defined as a failure of CIPN to worsen, does not support continued 
enrollment of patients.  According to the Bayesian predictive probability design, the 
following rejection regions are calculated: (favorable outcome/current sample size) 
1/10, 2/11, 3/13, 4/15, 5/16, 6/18, 7/20, 8/21, 9/23, 10/24, 11/26, 12/27, 13/29, 14/30, 
15/31, 16/32, 17/33, 18/34, 19/35, 20/36, 21/37, 22/38, 23/39.  For example, if only 1 
favorable outcome is obtained in the first 10 patients enrolled, the trial will be halted 
for futility.  It will also be discontinued if NIAGEN® is determined to worsen the 
progression of CIPN in an unacceptable number of patients in the opinion of the 
physician investigators.   
7.10 Study Completion 


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39 
 
The study completion will be defined as the completion of the data collection 
and the final analysis. The principal investigator will notify the IRB of the study 
completion. 
 
7.12 Funding Source 
 
This study is funded by the National Cancer Institute. 
 
 
7.13 Publication Plan 
 
Primary responsibility for publication of the results lies with the Principal 
Investigators, Dr. Alexandra Thomas and Dr. Donna Hammond and the investigative 
team.  There are no restrictions on publication by the National Cancer Institute.  
ChromaDex, as supplier of the compound, will have 3 months to review the 
manuscript prior to submission, but will be unable to restrict publication of the 
findings or modify the findings or conclusions of the study.  


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Lavoie Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, 
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Smith EM, Pang H, Ye C, Cirrincione C, Fleishman S, Paskett ED, Ahles T, 
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Fehrenbacher JC. Chemotherapy-induced peripheral neuropathy. Prog Mol 
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Carozzi VA, Canta A, Chiorazzi A. Chemotherapy-induced peripheral 
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Flatters SJ. The contribution of mitochondria to sensory processing and pain. 
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Ruggieri S, Orsomando G, Sorci L, Raffaelli N. Regulation of NAD 
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Yang Y, Sauve AA. NAD+ metabolism: Bioenergetics, signaling and 
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Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and 
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Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation 
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death pathway linking injury and disease. Nat Rev Neurosci. 2014;15:394-409. 
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Di Stefano M, Nascimento-Ferreira I, Orsomando G, Mori V, Gilley J, Brown 
R, Janeckova L, Vargas ME, Worrell LA, Loreto A, Tickle J, Patrick J, Webster JR, 
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and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in 
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Trammell SA, Yu L, Redpath P, Migaud ME, Brenner C. Nicotinamide riboside 
is a major NAD+ precursor vitamin in cow milk. J Nutr. 2016;146:957-63. 
31. 
Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a vitamin 
B3 with effects on energy metabolism and neuroprotection. Curr Opin Clin Nutr 
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32. 
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Thompson HJ. Mammary Cancer in Rats. In: Teicher BA, editor. Tumor 
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Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen 
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Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, 
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nicotinamide reduces actinic keratoses in phase II double-blinded randomized 
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tumorigenesis through DNA damage. Cancer Cell. 2014;26:826-39. 
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Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, 
Yagi T, Felding-Habermann B. Mitochondrial complex I activity and NAD+/NADH 


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Kuroi K, Shimozuma K, Ohashi Y, Hisamatsu K, Masuda N, Takeuchi A, 
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Kraff S, Nieuweboer AJ, Mathijssen RH, Baty F, de Graan AJ, van Schaik RH, 
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Res. 2001;7:3942-9. 


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62. 
Nokihara H, Yamamoto N, Ohe Y, Hiraoka M, Tamura T. Pharmacokinetics of 
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63. 
Little RJA, Rubin DB. Statistical analysis with missing data. 2nd ed. Hoboken, 
N.J.: Wiley; 200. 381 p. 
 
 


Study Number  
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APPENDIX A - PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (e.g., light housework, 
office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry 
out any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable 
assistance and frequent medical 
care. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to 
bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 


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APPENDIX B  - Trial-Specific Data and Safety Monitoring Plan 
 
Type of Clinical Trial: 
  Investigator-initiated (UI/HCCC) 
 Investigator-initiated, participating site 
 Pilot study 
 phase I 
  phase I/II 
 phase II 
 phase III 
 Interventional Treatment 
 Non-Interventional 
 Compassionate-use/Expanded Access  
 Interventional Non-Treatment 
 
 
 
 
Study risk-level:  
 
 Level 1—low risk of morbidity or death, * <1% of death or any adverse event  
  Level 2—risk of death* <1% or any adverse event 1% – 5%  
 Level 3—risk of death* 1% – 5% or grade 4 – 5 SAE 1% – 5%  
  Level 4—risk of death* >5% or grade 4 – 5 SAE >5%  
 Drugs being used on a “compassionate” basis  
* Risk of death” refers specifically to 100-day treatment-related mortality 
___________________________ 
 
Reporting and Monitoring Requirements:  
All institutional investigator initiated trials (IITs), regardless of assigned risk level are 
subject to routine DSMC monitoring activities which may include but are not limited 
to review of signed consent documents, eligibility and adverse event reporting.  
 
All institutional IITs have the following reporting requirements as part of their 
DSMP: 
• Provide an annual progress report to the DSMC and PRMC 
• Register subjects in HCCC’s Clinical Trial Management System, OnCore 
• Document Adverse Events  
• Document protocol deviations  
 
 


Study Number  
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Selected monitoring strategy based on risk-level:  Risk Level 4 
Interventional treatment trials involving investigational agents or devices with a risk 
of death* (>5% or grade 4 – 5 SAE >5%), e.g. all investigator initiated INDs, most 
Phase I/II trials, gene therapy, gene manipulation or viral vector systems high-risk 
clinical procedures if performed solely for research purposes.  The use of a new 
chemical or drug for which there is limited or no available safety data in humans. 
 
Study Safety Review 
The DSMC Chair (or designee), will review study data (provided by the PI/available 
in OnCore) and communicate with the PI at least biannually.  In addition, Dr. Vaena 
of the University of Tennessee will visit the University of Iowa and Wake Forest 
Baptist Health to review safety data on a quarterly basis and communicate his 
findings to Drs. Hammond and Thomas.  A copy of this communication will be 
forwarded to the DSMC and PRMC Chairs.   
 
Additional Reporting Requirements:  
- A scanned copy of the completed eligibility checklist, with screening information 
and enrolling physician’s signature, will be attached in OnCore for ongoing review 
by DSMC staff.  
- Serious adverse events will be entered directly into an OnCore SAE report by the 
research team.  OnCore will send an automatic notification to the DSMC 
Chair/acting Chair and staff for review.  
- The DSMC utilizes a risk-based monitoring approach.  The trial's research 
records will be monitored at minimum twice per year.  Monitoring may be done 
more frequently depending on the protocol, risks to subjects, reported 
serious/adverse events, patient population and accrual rate.   Records for a 
minimum of 25% of subjects will be monitored for the entire study.    
 
Routine Adverse Event Reporting 
 
For non-serious Adverse Events, documentation must begin from the first day of 
study treatment and typically continue through the 30 day follow-up period beginning 
one week after treatment is discontinued.  
 
Collected information should be recorded in the electronic/Case Report Forms 
(eCRF/CRF) for that subject. A description of the event, its severity or toxicity grade 
(according to NCI’s Common Toxicity Criteria (CTCAE), onset and resolved dates (if 
applicable), and the relationship to the study drug should be included. 
Documentation should occur in real time. The principal investigator has final 
responsibility for determining the attribution of the event as it is related to the study 
drug. 


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Serious Adverse Event Reporting 
For any experience or condition that meets the definition of a serious adverse event 
(SAE), recording of the event must begin after signing of the informed consent and 
continue through the 30 day follow-up period after treatment is discontinued.  
Investigators must report to the DSMC any serious adverse events (SAE), whether 
or not they are considered related to the investigational agent(s)/intervention (21 
CFR 312.64).  
 
An adverse event is considered serious if it results in ANY of the following 
outcomes:   
1. Death 
2. A life-threatening adverse event  
3. An adverse event that results in inpatient hospitalization OR prolongation of 
existing hospitalization for ≥ 24 hours  
4. A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered serious when, 
based upon medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
 
SAEs must be reported via an OnCore SAE Report within 24 hours of learning of the 
event. 
ChromaDex requires safety reporting to follow the requirements specified under 21 
CFR § 312.32 IND safety reporting.  ChromaDex will also be notified of all SAEs.  
Notifications should be sent to:  
 
Sarah Garthe, M.S. 
Regulatory Affairs Manager 
 
10005 Muirlands Blvd., Suite G 
 
Irvine, CA 92618 USA 
 
SarahG@chromadex.com 
 
www.chromadex.com 
 
  
Tel: +1.612-512-8251. 
 
 
 
 


Study Number  
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Data Monitoring and Management  
All studies that undergo PRMC review and/or utilize HCCC Clinical Research 
Services (CRS) resources are required to register subjects in OnCore. Subject 
registration includes the following: 
• Consent date and the IRB approved consent used  
• Date of eligibility and eligibility status (eligible, not eligible) 
• On study date and subject’s disease site (and histology if applicable) 
• On treatment date (if applicable)  
 
Subject Data 
In addition to the subject registration and subject status data entered in OnCore for 
all HCCC trials, research staff also enters the subject study data into electronic case 
report forms (eCRFs) for HCCC investigator initiated studies. eCRFs are approved 
by the PI and statistician prior to study activation to ensure the most effective data 
acquisition. All information on eCRFs will be traceable to the source documents 
which are generally maintained in the subject’s file. eCRF data are expected to be 
entered into OnCore within 30 calendar days after a subject’s study visit.  
 
Forms Monitoring 
OnCore eCRF data are monitored on a routine basis (dependent on accrual) to 
ensure all mandatory fields are entered completely, accurately and within time 
requirements. The assigned DSMC monitor manages the logistics associated with 
the data monitoring review. Once the clinical trial is identified for monitoring, the 
monitor arranges for a selection of cases to review from among the subjects 
registered in OnCore.  As part of the forms monitoring process, the assigned monitor 
will issue queries within the eCRF to resolve missing, incomplete and/or incorrect 
information. A member of the research team is expected to respond to monitoring 
queries within 14 business days.  
 
This process can often identify a misunderstanding or deficiency in protocol 
requirements early in the study and can improve data quality.  
 
Final Reports 
A summary of each subject’s data record is continually available to the PI, research 
staff, and DSMC from OnCore’s Biostat Console. The availability of this information 
is a valuable tool for the preparation of final reports and manuscripts as well as 
ongoing deficiency reports. 
 
 


Study Number  
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APPENDIX C – Lab Manual 
Keystone Bioanalytical, a GLP-compliant contract research organization will 
be used for measurement of the NAD+ in red blood cells and N-methyl-
nicotinamide in blood (Biomarker samples).  Measurement of paclitaxel levels 
in blood will be conducted by the Department of Pathology at University of 
Iowa (Pharmacokinetic samples).  
 
Refer to Section 6.2.4 Biomarkers 
Refer to Study Calendar – Pre-Treatment NAD+ levels. 
At UIHC, contact Dr. Hammond (office: 319-335-9595 or cell: 319-621-6110) as soon 
as you are aware that a sample for biomarkers will be collected/scheduled.  At Wake 
Forest, contact Dr. Christopher Peters (336-716-3452) as soon as you are aware 
that a sample for biomarkers will be collected/scheduled. 
Collection: 
• Draw two 3-ml samples of blood into light blue top citrate tubes, which contain 
3.2% citrate.    
• Immediately invert the tubes four times, and place on wet ice.   
• At UIHC, give to Dr. Hammond or her lab staff (who should be present).  At 
Wake Forest, samples are to be messengered to Dr. Peters’ laboratory in 
Hanes 2049.   
 
 
 
Processing: 
For each sample: 
• Centrifuge tubes at 2,000 g at 2-8°C for 5 min to separate plasma and red 
blood cells.  
• Aliquot 0.5 ml of plasma into a labeled cold cryovial, snap freeze, and store at 
-80°C.  Decant remaining plasma and discard.    
• Using a positive displacement pipette, aliquot 100 µL of the sedimented RBCs 
into a labelled chilled cryovial tube that contains 1 ml of cold 0.5 M perchloric 
acid.  Invert tube 4 times, then snap freeze, and store at -80°C until analysis. 
Samples must be kept on wet ice and  
processed within two hours of collection with no hemolysis 


Study Number  
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51 
 
Shipping:   
Biomarker samples collected at the University of Iowa will be processed by Dr. 
Hammond or her laboratory staff, stored in a -80 degree Celsius freezer at the 
University of Iowa, and shipped in batches of 200 or more by Dr. Hammond to 
Keystone Bioanalytical Laboratory for analysis.    
Biomarker samples collected at Wake Forest will be processed by Dr. Peters’ 
research staff, stored in a -80 degree Celsius freezer at Wake Forest, and shipped 
as a batch to Keystone Bioanalytics as directed by Dr. Hammond.    
One plasma sample and one RBC sample will be shipped on dry ice to Keystone 
Bioanalytical as directed by Dr. Hammond.  The other samples will be retained on 
site should the first samples be inadvertently destroyed. 
 
Allan Xu, Ph.D. 
Lab Director 
Keystone Bioanalytical,Inc. 
501 Dickerson Rd. 
North Wales, PA 19454 
215-699-8899 
axu@keystonebioanalytical.com 
 
Refer to Section 6.2.3 Pharmacokinetics 
Refer to Study Calendar -  Paclitaxel levels. 
Collection:  
• Two 5-ml blood samples will be collected, 30 ± 10 minutes AFTER the infusion of 
paclitaxel or between 15 and 30 minutes after the infusion of nab-paclitaxel, from 
the arm or port.   
• Collect the blood samples in a purple (EDTA) top tube and place on wet ice.    
• At UIHC, contact Dr. Hammond (319-335-9595 or 319-621-6110) once the 
sample is obtained.    
• At Wake Forest, contact Dr.Christopher Peters (336-716-3452) once the sample 
is obtained.     
 
Processing:   


Study Number  
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52 
• At UIHC, a person from Dr. Hammond’s lab will retrieve the samples on wet ice, 
centrifuge at 1,000 g at 2 to 8 degrees Celsius, and aspirate two 1-ml aliquots of 
plasma from each tube into two 1.8-ml polypropylene cryo tubes with inner 
threads.   
• All four samples will be labeled with the study ID and stored in a -80 degree 
Celsius freezer.  Avoid repeated freeze-thaw cycles. 
• At Wake-Forest, the samples will be messengered to Dr. Peters’ laboratory in 
Hanes 2049.  He will process the samples as described immediately above.   
Shipping:    
• One aliquot of each sample (total of two) collected at Wake Forest, will be 
shipped on dry ice to the Department of Pathology at University of Iowa to the 
attention of David Frederick.  An email will be sent to donna-
hammond@uiowa.edu and to matthew-krasowski@uiowa.edu with tracking 
information. The other samples will be retained on site should the first samples 
be inadvertently destroyed. 
 
Address Label: 
Attn: David Frederick 
Department of Pathology  
University of Iowa Hospitals and Clinics  
200 Hawkins Dr 6240 RCP 
Iowa City, IA 52242 
david-frederick@uiowa.edu 
319-353-7018 
 
On day of shipment, please send e-mail notification along with sample tracking 
information to: 
Donna L. Hammond, Ph.D. 
 
Phone: 319-335-9595 
Anesthesia Research 3000 ML 
 
Mobile: 319-621-6110 (contact 24/7) 
University of Iowa 
 
 
 
E-mail: donna-hammond@uiowa.edu 
200 Hawkins Drive 
Iowa City, IA  52242 
 
 
 


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APPENDIX D - List of Tables 
Title 
Schematic of NAD+ biosynthetic pathways 
 
 
 


Study Number  
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54 
APPENDIX E – FACT/GOG – NTX subscale 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
NTX 
1 
I have numbness or tingling in my hands........................... 
0 
1 
2 
3 
4 
NTX 
2 
I have numbness or tingling in my feet .............................. 
0 
1 
2 
3 
4 
NTX 
3 
I feel discomfort in my hands............................................. 
0 
1 
2 
3 
4 
NTX 
4 
I feel discomfort in my feet ................................................ 
0 
1 
2 
3 
4 
NTX 
5 
I have joint pain or muscle cramps .................................... 
0 
1 
2 
3 
4 
HI12 
I feel weak all over ............................................................. 
0 
1 
2 
3 
4 
NTX 
6 
I have trouble hearing......................................................... 
0 
1 
2 
3 
4 
NTX 
7 
I get a ringing or buzzing in my ears.................................. 
0 
1 
2 
3 
4 
NTX 
8 
I have trouble buttoning buttons ........................................ 
0 
1 
2 
3 
4 
NTX 
9 
I have trouble feeling the shape of small objects when 
they are in my hand ............................................................ 
0 
1 
2 
3 
4 
An6 
I have trouble walking........................................................ 
0 
1 
2 
3 
4 
 
 
 


Study Number  
March 24, 2021 
55 
APPENDIX F – Total Neuropathy Score – clinical version 
Scale 
Score 
0 
1 
2 
3 
4 
Sensory 
symptoms 
None 
Symptoms 
limited to 
fingers or 
toes 
Symptoms 
extend to 
ankle or 
wrist 
Symptoms 
extend to knee 
or elbow 
Symptoms 
above knee or 
elbow or 
functionally 
disabling 
Motor 
symptoms 
None 
Slight 
difficulty 
Moderate 
difficulty 
Require 
help/assistance 
Paralysis 
Autonomic 
symptoms, 
n 
0 
1 
2 
3 
4 or 5 
Pin 
sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up 
to 
wrist/ankle 
Reduced up to 
elbow/knee 
Reduced to 
above 
elbow/knee 
Vibration 
sensibility 
Normal 
Reduced in 
fingers/toes 
Reduced up 
to 
wrist/ankle 
Reduced up to 
elbow/knee 
Reduced to 
above 
elbow/knee 
Strength 
Normal 
Mild 
weakness 
(MRC 4) 
Moderate 
weakness 
(MRC 3) 
Severe 
weakness (MRC 
2) 
Paralysis 
(MRC 0–1) 
Deep 
tendon 
reflex 
Normal 
Ankle reflex 
reduced 
Ankle reflex 
absent 
Ankle reflex 
absent, others 
reduced 
All reflexes 
absent 
 
The Total Neuropathy Score – Clinical is a reduced version of the TNS that assesses 
only the signs and symptoms that are apparent during a clinical examination.  The 
questionnaire is copyrighted, and has to be purchased.  The table above is a 
summary of the key elements. 

ICF_004.pdf: 
NIAGEN® in Paclitaxel-induced  
Peripheral Neuropathy 
 
 
NCT03642990 
 
 
July 15, 2021 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 1 of 8 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
Nicotinamide riboside (NR) in Paclitaxel-induced Peripheral Neuropathy 
 
Principal Investigator: 
Donna Hammond, PhD 
 
Research Team Contact: 
Mary Schall, RN 
 
319-356-2778 
 
Other Research Team 
Members: 
Mark Karwal, MD; Sneha Phadke, DO; Michelle Arnold RN;
 
Praveen Vikas, MBBS; Michael Goodheart, MD; Emily Hill, 
MD; Megan McDonald, MD; Sharon Stockman, Jesus Gonzalez 
Bosquet, MD PhD  
 
 
 
This consent form describes the research study to help you decide if you want to participate.  This form 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights as a research subject.   
• If you have any questions about or do not understand something in this form, you should ask 
the research team for more information.   
• You should discuss your participation with anyone you choose such as family or friends.   
• Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study.  We are inviting you to participate in this research study because you have stage 
4 breast cancer, platinum-resistant recurrent ovarian, endometrial, peritoneal, or fallopian tube cancer, 
platinum-resistant recurrent or metastatic head and neck cancer, are being treated for your cancer with 
Paclitaxel (Taxol) or Nab-paclitaxel (Abraxane), and are experiencing peripheral neuropathy.  Nab-
paclitaxel is a different formulation of paclitaxel.  The symptoms of peripheral neuropathy include 
numbness or tingling, pricking sensations or muscle weakness, usually in the hands or feet.  However, 
peripheral neuropathy can also affect other areas of your body.     
 
The purpose of this research study is to find out if nicotinamide riboside (NR), a nutritional supplement 
and type of vitamin B3, can prevent the progression of peripheral neuropathy in people with breast, 
recurrent ovarian, endometrial, peritoneal, or fallopian tube cancer, or platinum-resistant recurrent or 
metastatic head and neck cancer being treated with Paclitaxel or nab-paclitaxel.   
 
Nicotinamide riboside is considered investigational, which means that it has not been approved by the 
U.S. Food and Drug Administration as it is being used in this research study.  Nicotinamide riboside is 
currently used to increase levels of NAD+, a substance in the blood which is important in converting 
blood glucose into energy.  Increased NAD+ levels may also play a part in delaying the effects of aging, 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 2 of 8 
obesity and disease.   
 
 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
A total of approximately 39 people will take part in this study conducted by investigators at the 
University of Iowa and Wake Forest University.   
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement will last approximately 9 months.  This includes 
up to 12 weeks of treatment with NR, with a visit on each occasion you receive chemotherapy during 
treatment, then follow-up visits at the following time points: 
 
• 7-14 days after the end of treatment 
• 30-37 days after the end of treatment (may be done by telephone) 
• 12-14 weeks after the end of treatment (may be done by clinic visit or telephone) 
• 24-26 weeks after the end of treatment (may be done by clinic visit or telephone) 
 
Each visit during treatment will last between 1-2 hours.  Each follow-up visit will also last between 1-2 
hours.   
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
Before you begin the study: 
If you choose to take part in this study, you will need to have the following procedures to find out if you 
can continue in the study.  Most of these procedures are part of your regular cancer care and would be 
done even if you do not join the study. 
 
• A complete physical examination, including assessment of vital signs (temperature, height, 
weight, heart rate, blood pressure, and respirations or breathing rate).  
• Blood tests (approximately 3-4 teaspoons of blood will be drawn and studied for kidney 
function, liver function, white cells, red cells, and platelets). 
• Pregnancy test for females of childbearing potential. 
• Questionnaire 1 – one page which asks 11 brief questions about how you’re feeling. 
• Questionnaire 2 – one page which asks 7 brief questions about the type of your neuropathy 
 
During study treatment: 
You will take the study drug, NR, by mouth twice a day while you’re receiving chemotherapy in this 
study. If the initial dose of NR is well-tolerated during the first week, the dose will be increased for all 
subsequent weeks.  You will take NR twice a day each day you are in the study.  You will stop taking 
NR one week after your last infusion of Paclitaxel or Nab-paclitaxel.   
Your physician will determine the dose and frequency of Paclitaxel or Nab-paclitaxel infusion that is 
standard of care for your disease.  Once you’ve started taking the study drug, NR, the following tests 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 3 of 8 
and procedures will be done at each visit: 
 
• Complete physical exam (only on weeks 3, 6 and 9 if you are receiving weekly chemotherapy). 
• Assessment of vital signs (temperature, weight, heart rate, blood pressure, and respirations or 
breathing rate).  
• Blood tests (approximately 3-4 teaspoons of blood will be drawn and studied for kidney 
function, liver function, white cells, red cells, and platelets). 
• Blood for research tests (approximately 3 teaspoons of blood will be drawn to check the level of 
Paclitaxel and NAD+ in your blood.)  If your chemotherapy drug levels get too high or too low 
from taking the study drug, you may be removed from this study. 
• Questionnaire 1 – one page which asks 11 brief questions about how you’re feeling.  
 
We will ask you to complete questionnaire 1 each time you visit.  This questionnaire will ask specific 
questions about how you’ve been feeling.  We will ask you to fill out a form each day about the amount 
and types of dairy products you eat (a dairy product diary).  We will also ask you to fill out a form to 
record when you took NR (a drug diary). We will provide you forms to keep track of the study drug that 
you take each day, and how much dairy you eat each day.  We will ask you to bring the dairy product 
diary, the drug diary, and any remaining pills with you to each visit.  Once a month, you will be asked to 
fill out questionnaire 2 about the type of neuropathy you are experiencing.   
 
After study treatment: 
After you’ve finished taking NR, you will have a follow-up visit 7-14 days after your last dose.  The 
following tests and procedures will be done:  
 
• A complete physical examination, including assessment of vital signs (temperature, weight, heart 
rate, blood pressure, and respirations or breathing rate).     
• Blood tests (approximately 3-4 teaspoons of blood will be drawn and studied for kidney 
function, liver function, white cells, red cells, and platelets). 
• Questionnaire – one page which asks 11 brief questions about how you’re feeling.  
 
You will also have follow-up scheduled at the time points listed below.  These may be done by a 
telephone call to see how you’re doing. 
 
• 30-37 days after the end of treatment. 
• 12-14 weeks after the end of treatment. 
• 24-26 weeks after the end of treatment. 
 
Follow-up Contact Plan: 
If we aren’t able to successfully contact you by telephone, we may send you a certified letter to your last 
known address, requesting a return receipt.   
 
WHAT ARE THE RISKS OF THIS STUDY? 
 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 4 of 8 
study.  
 
There is a risk that NR will increase or decrease the level of paclitaxel in the blood.  An increase in 
levels of paclitaxel could result in increased peripheral neuropathy and decreased levels of white blood 
cells and red blood cells.  A decrease in levels of paclitaxel could decrease the effectiveness of this 
chemotherapy.  Your levels will be monitored weekly.    
 
There is also a very small risk that NR will cause flushing.  You may also experience headache, nausea, 
vomiting, fatigue, dizziness, or loose stool. 
 
 
You will be required to take appropriate precautions to avoid pregnancy from screening through follow-
up because the effects of NR on the fetus are unknown.  Males must agree to take appropriate 
precautions to avoid fathering a child from screening through follow-up.  Any of the following methods 
have been determined to be more than 99% effective (<1% failure rate per year when used consistently 
and correctly) 
• Complete abstinence from sexual intercourse  
•  Double barrier methods: 
o  Condom with spermicide in conjunction with use of an intrauterine device 
o   Condom with spermicide in conjunction with use of a diaphragm 
• Surgical sterilization (bilateral removal of ovaries with or without hysterectomy, tubal ligation or 
vasectomy) at least 6 weeks prior to starting the study.    
• Non-hormonal intrauterine device (IUD)  
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
We don’t know if you will benefit from being in this study.  We hope that, in the future, other people 
might benefit from this study because of the information gained. The information gained might help to 
develop better treatments for peripheral neuropathy that occurs during chemotherapy. 
 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  Instead of being in this study, you could choose to have no treatment for your 
peripheral neuropathy, or choose to take part in a different research study, if one is available.   
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
You will not have any additional costs for being in this research study.  The study drug, nicotinamide 
riboside is being supplied by the maker of the drug, ChromaDex, Inc.  The cost of blood draws that are 
done for research only will not be the responsibility of you or your insurance company.   
   
You and/or your medical/hospital insurance carrier will remain responsible for your regular medical care 
expenses. 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 5 of 8 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study.   
 
WHO IS FUNDING THIS STUDY? 
 
  This study is being funded by discretionary funds available to the principal investigator. 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
• If you are injured or become ill from taking part in this study, medical treatment is available at the 
University of Iowa Hospitals and Clinics. 
• The University of Iowa does not plan to provide free medical care or payment for treatment of any 
illness or injury resulting from this study unless it is the direct result of proven negligence by a 
University employee.  
• If you experience a research-related illness or injury, you and/or your medical or hospital insurance 
carrier will be responsible for the cost of treatment. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
It is possible that other people such as those indicated below may become aware of your participation in 
this study and may inspect and copy records pertaining to this research.  Some of these records could 
contain information that personally identifies you.  
• federal government regulatory agencies,  
• the U.S. Food and Drug Administration  
• ChromaDex, Inc, the maker of the study drug may also inspect any part of your medical record 
for the purposes of auditing the conduct of the study. 
• auditing departments of the University of Iowa, and  
• the University of Iowa Institutional Review Board (a committee that reviews and approves 
research studies)  
  
To help protect your confidentiality, we will conduct research interventions in private rooms, limit data 
collection, and store research documents in locked offices and on password-protected computers.  Study 
data will not list your name, but will identify you by a code number. A Record of  Informed Consent 
document will be placed in your UIHC medical record to show that you have participated in this 
research study.  
 
If we write a report or article about this study or share the study data set with others, we will do so in 
such a way that you cannot be directly identified. 
 
To further protect your privacy, the researchers have obtained a Certificate of Confidentiality from the 
Department of Health and Human Services (DHHS).  This Certificate means that the researchers cannot 
be forced (for example by court subpoena) to disclose information that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other proceeding.  However, a Certificate of 
Confidentiality does not prohibit the researcher from disclosing information about you or your 
involvement in this research that you have agreed to disclose or make available.  For example, if you [if 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 6 of 8 
applicable: or your legally authorized representative] request in writing that information about you 
or your participation in the research be released to an insurance company, the researcher may not use the 
Certificate of Confidentiality to withhold this information.  This means that you and your family should 
actively protect your own privacy.  Finally, the researcher is not prevented from taking steps, including 
reporting to appropriate authorities, to prevent serious harm to yourself or others.  You may receive a 
copy of the Certificate of Confidentiality upon request. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will include 
a summary of the results.  You can search this website at any time. 
 
WILL MY HEALTH INFORMATION BE USED DURING THIS STUDY? 
 
The Federal Health Insurance Portability and Accountability Act (HIPAA) requires your health care 
provider to obtain your permission for the research team to access or create “protected health 
information” about you for purposes of this research study.  Protected health information is information 
that personally identifies you and relates to your past, present, or future physical or mental health 
condition or care.  We will access or create health information about you, as described in this document, 
for purposes of this research study and for your treatment.  Once your health care provider has disclosed 
your protected health information to us, it may no longer be protected by the Federal HIPAA privacy 
regulations, but we will continue to protect your confidentiality as described under “Confidentiality.” 
 
We may share your health information related to this study with other parties including federal 
government regulatory agencies, the University of Iowa Institutional Review Boards and support staff, 
the NIH, and ChromaDex, Inc., the maker of the study drug.  
 
You cannot participate in this study unless you permit us to use your protected health information.  If 
you choose not to allow us to use your protected health information, we will discuss any non-research 
alternatives available to you.  Your decision will not affect your right to medical care that is not 
research-related.  Your signature on this Consent Document authorizes your health care provider to give 
us permission to use or create health information about you. 
 
Although you may not be allowed to see study information until after this study is over, you may be 
given access to your health care records by contacting your health care provider. Your permission for us 
to access or create protected health information about you for purposes of this study has no expiration 
date. You may withdraw your permission for us to use your health information for this research study by 
sending a written notice to: 
 
Donna Hammond, PhD 
University of Iowa Hospitals and Clinics 
200 Hawkins Drive, 3000 ML 
Iowa City, IA  52242 
 
However, we may still use your health information that was collected before withdrawing your 
permission.  Also, if we have sent your health information to a third party, such as the study sponsor, or 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 7 of 8 
we have removed your identifying information, it may not be possible to prevent its future use.  You will 
receive a copy of this signed document. 
 
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time.  If you decide not to be in this 
study, or if you stop participating at any time, you won’t be penalized or lose any benefits for which you 
otherwise qualify. 
 
What if I Decide to Drop Out of the Study? 
If you decide to leave the study early, we will ask you to talk to the study doctor as soon as possible so 
that you can stop safely.  If you leave the study before the final planned study visit, the study doctor may 
ask you to complete the final visits.   
 
Will I Receive New Information About the Study while Participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can Someone Else End my Participation in this Study? 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned.  This might happen because in our judgment it would not be safe for you to 
continue, because your condition has become worse, because you are or became pregnant, or because 
funding for the research study has ended. This might also happen if your Paclitaxel levels go too high or 
too low.  
 
WHAT IF I HAVE QUESTIONS? 
 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact:  Donna Hammond, PhD at 319-335-9595.  If you experience a research-related injury, please 
contact:  Donna Hammond, PhD at 319-335-9595.   
 
If you have questions, concerns, or complaints about  your rights as a research subject or about research 
related injury, please contact the Human Subjects Office, 105 Hardin Library for the Health Sciences, 
600 Newton Rd, The University of Iowa, Iowa City, IA  52242-1098, (319) 335-6564, or e-mail 
irb@uiowa.edu.  General information about being a research subject can be found by clicking “Info for 
Public” on the Human Subjects Office web site, http://hso.research.uiowa.edu/. To offer input about 
your experiences as a research subject or to speak to someone other than the research staff, call the 
Human Subjects Office at the number above. 
 
 
This Informed Consent Document is not a contract. It is a written explanation of what will happen 
during the study if you decide to participate. You are not waiving any legal rights by signing this 
Informed Consent Document. Your signature indicates that this research study has been explained to 
you, that your questions have been answered, and that you agree to take part in this study.  You will 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201612723 
APPROVAL DATE: 07/15/21 
EXPIRATION DATE: 07/01/22 
 
Consent Version 19; Protocol dated 10.26.16 
 
Page 8 of 8 
receive a copy of this form. 
 
 
Subject's Name (printed):  __________________________________________________________ 
 
 
Do not sign this form if today’s date is on or after EXPIRATION DATE: 07/01/22. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Subject)  
 
 
 
 
(Date) 
 
 
 
 
Statement of Person Who Obtained Consent 
 
I have discussed the above points with the subject or, where appropriate, with the subject’s legally 
authorized representative.  It is my opinion that the subject understands the risks, benefits, and 
procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date)