Conditions: SARS-CoV-2 Infection Acute Kidney Injury
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
An interventional clinical trial using oral nicotinamide riboside (NR) in hospitalized patients with COVID-19 infection and acute kidney injury to determine the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels and to evaluate safety of the use of NR.

Detailed description:
The study team chose a treatment protocol with NR as a treatment for patients who will be admitted with COVID-19 related illness and develop AKI after admission. Treatment duration will be for 10 days and the primary study endpoint will be the change in whole blood NAD+ from baseline to end of treatment in NR group vs placebo group. The study team will evaluate whole blood NAD+ levels as a marker of efficacy and biological effect of NR.

Arms:
arm 1: Placebo capsules will be administered 2 capsules twice daily for 10 days arm 2: Nicotinamide riboside 250mg capsules will be administered 2 capsules twice daily for 10 days

Interventions: intervention 1: Placebo intervention 2: Nicotinamide riboside
Intervention descriptions: intervention 1: Placebo capsule containing inert ingredient intervention 2: 250 mg Nicotinamide riboside capsules

Protocol document:
ICF_000.pdf: 
 
FOR IRB USE ONLY 
IRB ID #: 202101169-1007 
APPROVAL DATE: 03/22/21 
RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
COVER PAGE FOR CONSENT FORM 
 
 
 
 
 
Official Study Title: Nicotinamide Riboside in SARS-CoV-2 (COVID-19) 
Patients for Renal Protection 
 
 
NCT number: NCT04818216 
 
IRB Approval Date: 03/22/2021 
 
Unique Protocol ID: HSC20200914H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
FOR IRB USE ONLY 
IRB ID #: 202101169-1007 
APPROVAL DATE: 03/22/21 
RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
Page 2 of 17 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
 
NIcotinamide Riboside in SARS-CoV-2 pAtients for reNAl protection 
(NIRVANA) 
 
Principal Investigator: 
  Kumar Sharma, MD 
 
Research Team Contact: 
 Subrata Debnath, MPH, Ph.D., 210-508-2889 
 
If you are the legally authorized representative of a person who is being invited to participate in this 
study, the word “you” in this document refers to the person you represent.  As the legally authorized 
representative, you will be asked to read and sign this document to give permission for the person you 
represent to participate in this research study.   
 
This consent form describes the research study and helps you decide if you want to participate.  It 
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 and responsibilities as a research participant. By signing this 
form you are agreeing to participate in this study. 
 
• You should read and understand the information in this document including the procedures, 
risks and potential benefits.  
• If you have questions about anything in this form, you should ask the research team for more 
information before you agree to participate.   
• You may also wish to talk to your family or friends about your participation in this study. 
• 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.  
 
The first section of this document contains some key points that the research team thought you would 
find important. The research study is described in more detail after this section. 
 
This is a research study conducted by Kumar Sharma, MD having to do with acute kidney injury (AKI) 
due to COVID-19 infection. AKI is very common in COVID patients and associated with increased 
deaths, complications, and poor health outcomes. Unfortunately, there is no approved medicine for AKI.   
The human body makes a chemical substance called NAD+ and this substance supports energy 
production. NAD+ levels in kidney and in blood may be low in patients with AKI. We will test if 
increasing NAD+ levels with nicotinamide riboside will speed up recovery from kidney injury. In this 
study we will be testing if a form of vitamin B3 called nicotinamide riboside (NR) is (1) safe in COVID 
patients with AKI, (2) it increases blood NAD+ levels, and (3) it improves or protects kidney function.  
 
HOW WILL THIS STUDY AFFECT ME? 
 
• The purpose of this study is to determine if nicotinamide riboside is safe and whether it increases 
blood NAD+ levels and improves or protects kidney function.   
 


 
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RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
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• During your stay in the hospital, this research study will take a limited amount of your time. 
After discharge, you will need to spend no more than 30 to 60 minutes for the remaining visits.  
 
• You were selected because you are diagnosed with COVID-19 infection and AKI.  
 
• You will take study medicine only for 10 days and then come to clinic for two follow-up visits at 
30 days and 90 days after taking your first dose of the study medicine 
o While in the hospital, you will take study medicine twice daily for 10 days and all 
other study procedures are standard of care; 
o If you are discharged from hospital before completing 10 days, at home you will 
take study medicine, collect a daily urine sample, and perform a fingerstick blood 
test to measure your kidney function daily for the remaining days.  
• The main risks to you are an upset stomach, muscle soreness, itching, and your blood 
hemoglobin and blood cell count may drop. More detail about risks is provided below. 
 
• You will not be paid for participating in this study. You will not have costs for participating in 
the study. Study medicine and research procedures will be paid by the research team.  
 
• If you withdraw from the study, the research team may continue to use information already 
collected about you prior to your withdrawal.  
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study.  We invite you to participate in this research study because you were admitted 
to hospital with a diagnosis of COVID-19 infection and your kidneys are affected with declining kidney 
function known as acute kidney injury or AKI. AKI is associated with high rates of death and poorer 
health outcomes compared to someone without AKI. Currently, there is no specific medicine to treat 
AKI and it is not known if available medicines or therapies for COVID-19 may help prevent or treat 
AKI.   
 
 The purpose of this research study is to test if nicotinamide riboside (NR, a form of vitamin B3 present 
in several foods such as milk) is safe in COVID patients who are hospitalized and developed AKI. The 
study also examines if taking NR increases blood NAD+ levels.  
 
Nicotinamide riboside or NR (Niagen®) is a commercially available nutritional supplement. However, 
for this study, NR is considered investigational, which means that it has not been approved by the U.S. 
Food and Drug Administration for treatment of AKI in COVID patients. The safety and effects of 
Niagen on blood NAD+ levels will be compared against a placebo. A placebo is an inactive, harmless 
substance that looks like the other study drug.  
 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 


 
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You will be asked to complete up to 12 visits with the research team. The study procedures for first 10 
days (10 visits) may be completed during your hospital stay. Most of the study procedures will coincide 
with some standard of care or procedures and a few are research only. If you are discharged from the 
hospital before completing the first 10 days, you will receive all necessary information and materials to 
complete the procedures for the remaining days at home. Then you will need to return to clinic to see 
your study doctor t approximately at day 30 and day 90 from when you first started taking study drug 
The last two visits are research-only visits. 
 
Baseline visit and Randomization (Treatment Visit 1): 
After your eligibility is determined the study team will discuss the study with you. After obtaining 
consent from you, a baseline visit will be performed which will include a review and collection of 
following information from your medical records: medications during hospital stay, home medications, 
all concomitant medicines including dietary or nutritional supplements and over-the-counter 
medications, vitals and physical examinations including temperature, pulse rate, respiratory rate, and 
blood pressure, other clinical information to assess the severity of your condition, information of fluid 
intake and output, and routine laboratory test results. Some urine (about a cup) and blood (about 1 
tablespoon) will be collected.  
 
Note that a pregnancy test will be performed for women with childbearing potential after obtaining 
consent to the study. Positive pregnancy test will disqualify participation to this study.  
 
After completing the above procedures, you will be assigned by chance (like flipping a coin) in a 1:1 
ratio (or 50% chance) to one of two study groups:  
 
• Placebo tablet 500 mg orally twice daily (Placebo)  
or  
• Niagen 500 mg orally twice daily (Niagen) 
 
Neither you nor the study doctor will know whether you are receiving Niagen or placebo. However, in 
the event of an emergency, there is a way for your study doctor to find out which one you are receiving. 
 
If you are intubated (the insertion of a tube into your windpipe) and unable to take the study medicine 
orally, the pharmacist will provide the medicine via nasogastric tube (insertion of a plastic tube through 
the nose down into your stomach) if deemed safe by your hospital COVID care team.   
Regardless of your assignment to either a placebo or Niagen, you will receive all the standard treatment 
for your health conditions including COVID-19 based on recommendations by your hospital COVID 
care team. 
 
About half a teaspoon of blood will be collected from you at 3 hours and again at 6 hours after taking 
the first study pills. 
 
Treatment Visits 2 to 10 (Day 2 to Day 10) while you are hospitalized: 
 
You will be assessed daily by the study team for a total of 9 additional days while hospitalized. We will 
review your medical record daily to collect data about your vital signs, medications, treatments, and 
clinical course and the results of routinely performed laboratory tests. All these data will be collected 


 
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RELEASED DATE: 03/22/21 
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Page 5 of 17 
from the medical record and will not require additional time from you. You will continue to receive all 
standard of care for your health conditions.  
 
You will be asked to provide the following on each day from days 2 to 10 
• First morning void urine collection  
• About one tablespoon of blood 
 
Treatment Visits 2 to 10 (Day 2 to Day 10) if your hospital stay is less than 10 days from Visit 1:   
 
If you are discharged from hospital to home before completing a total of 10 days of study medicine 
dosing, you will receive study medicine for the remaining days with instructions how to take the 
medicine and record taking the medicine on a paper form. In addition, you will also receive a device 
called StatSensor® XpressTM to measure your kidney function. All necessary items will be provided to 
use the device – instructions, strips, alcohol swabs, lancets, and a biohazard waste container. The 
following information will be collected daily from you or your caregiver or family member using a 
phone visit:  
• Any changes to your medications and treatment from previous day 
• Any health complaints including changes to your health from previous day 
• Your body weight, temperature, pulse rate, respiratory rate, and blood pressure (if available) 
• Study drug administration and accountability log 
• Your kidney function test results using the StatSensor® device 
 
Each day you will collect first morning void urine in the provided container, which will be picked up 
daily until Day 9 by a courier service for delivery to the hospital laboratory. On Day 10 a study team 
member will visit your home to collect one tablespoon of blood, urine, the StatSensor® device, 
biohazard waste container, and any other left-over study items. All these procedures will be collected 
with all safety precautions in place.  
 
Follow-up Visits 11 and 12 (Day 30 ± 3 and Day 90 ±3): 
 
Two follow-up visits will be performed at the outpatient clinic with your study doctor. A study team 
member will call you well-ahead of the visit with instructions and clinic location. The following 
procedures will be performed at each follow-up visit at the clinic: 
• Assess your overall health 
• Collect any health complaints including new health issues or changes to your health from the last 
visit 
• Record your current medications and treatment  
• Collect body weight, temperature, pulse rate, respiratory rate, and blood pressure 
• Perform physical examination 
• Collect first morning void or random urine 
• Draw about one tablespoon of blood 
 
If a clinic visit is not possible for any valid reason, a phone visit will be conducted in conjunction with 
review of your medical records to complete the applicable procedures listed above. In addition, a 


 
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RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
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phlebotomist will visit your home to collect blood and urine with all safety measures in place.   
 
If you do not or are unable to complete any of the visits described above after hospital discharge, the 
study team will take following measures: 
• First, your family member who is listed in study file or in your medical records will be contacted 
via phone and e-mail daily for 3 consecutive days or weekly for 3 consecutive weeks (for each 
follow-up visit); 
• Second, the study team will review your medical records to collect as much data as possible for 
each missed visit; 
• Third, the study team will search public records and database to document your vital status.    
 
Genetic Research 
Genes are a unique combination of molecules (called DNA) that we inherit from our parents.  There are 
millions of tiny differences in our genes.  These differences may make us more or less likely to develop 
certain diseases or conditions or to have certain characteristics.  Genetic research involves studying the 
differences in genes and DNA between individuals. This type of testing creates information that is as 
unique to you as your fingerprint. 
   
As part of this study, we are obtaining urine and blood samples from you. These may be used for 
commercial profit (even if we remove your identifiable information).  There are no plans to provide 
financial compensation to you should this occur.  By allowing us to use your information including urine 
and blood data you give up any property rights you may have in the urine and blood.  
 
Will you save my research information and/or biospecimens to use in future research studies? 
 
We would like to use the urine and blood data we are obtaining in this study for studies going on right 
now as well as studies that are conducted in the future.  These studies may provide additional 
information that will be helpful in understanding AKI and its short- and long-term complications or 
prognosis, or other diseases or conditions, including research to develop investigational tests, treatments, 
drugs or devices that are not yet approved by the U.S. Food and Drug Administration.  It is unlikely that 
what we learn from these studies will have a direct benefit to you.  There are no plans to provide 
financial compensation to you should this occur.  By allowing us to use your information including urine 
and blood data you give up any property rights you may have in the urine and blood data. 
 
Some biosamples will or might be used to analyze your genetic information. You can think of genetic 
information as a large instruction book that your body reads to understand how it should be built and 
function. All humans have the same instruction book in their body but some words or letters may be 
different from one person to the other. Some of those differences have no effect on your health but 
others can influence the likelihood of developing a disease or affect how medicine to treat a disease will 
work. If genetic analyses are done, they may involve all or part of your genetic information, which will 
only be used for study/scientific research. There are no plans to provide this information to you or your 
physician. 
 
We will share your information including urine and blood data with other researchers. They may be 
doing research in areas similar to this research or in other unrelated areas.  These researchers may be at 
UT Health San Antonio and University Health, at other research centers and institutions, or industry 


 
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EXPIRATION DATE: 03/08/22 
 
 
Page 7 of 17 
sponsors of research.  We may also share your research data with large data repositories (a repository is 
a database of information) for broad sharing with the research community.  If your individual research 
data is placed in one of these repositories only qualified researchers, who have received prior approval 
from individuals that monitor the use of the data, will be able to look at your information.   
 
If you change your mind and do not want us to store and use your information including urine and blood 
data for future research you should contact the research team members identified at the top of this 
document.  The information including urine and blood data will no longer be used for research purposes. 
However, if some research with your information including urine and blood data has already been 
completed, the information from that research may still be used. Also, if the information including urine 
and blood data has been shared with other researchers it might not be possible to withdraw the 
information including urine and blood data to the extent it has been shared. 
  
Please place your initials in the blank next to Yes or No for each of the questions below: 
 
My information including data and samples may be stored and used for future research as 
described above. 
 
_____ Yes 
_____ No 
Initials  
Initials 
 
My information including data and samples may be shared with other researchers and used by 
these researchers for the future research as described above. 
 
_____ Yes  
_____ No 
Initials  
Initials 
 
Unless you agree to future use as described above, your private information including data/ blood 
collected as part of this study will not be used or distributed for future research studies, even if 
identifiers are removed. 
  
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 60 people will take part in this study conducted by investigators at UT Health San 
Antonio and University Health.  A total of about 100 participants are expected to participate nationwide 
in this multi-center study.   
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement will last for:   
• A total of 12 visits 
o Daily for 10 days 
o Two follow-up visits: at day 30 ± 3 and day 90 ± 3   
• Duration for each daily visit for the first 10 visits depends on your hospital stay  
o If you are in the hospital for 10 consecutive days, then a small amount of time is needed from 
you because most of the study procedures listed above are review of your medical records. 


 
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RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
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The study team may contact you or your treating physician or family member to collect 
information which is not available in the medical records and or to collect additional 
information for accuracy and completeness  
o If your hospital stay is less than 10 days after receiving the first study medicine, you will 
spend approximately 30 to 45 minutes each day for up to 9 days to complete the visit 
procedures listed above including the phone visit.   
• Duration for each follow-up visit will require about 60 to 90 minutes.  
 
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.  
 
Some risks described in this consent document, if severe, may cause death.  
 
Nicotinamide riboside may produce drug interactions. Please inform the study team if you are taking any 
prescription or over-the-counter medications, including other nutritional or herbal supplements 
 
Likely / Common  
 
Mild 
• Gastrointestinal disorders: nausea, heart burn (e.g., indigestion, gas, upper abdominal discomfort, 
and bloating), diarrhea, transient changes in stool; 
• Musculoskeletal disorders: back soreness, muscle soreness; 
• Skin disorders: pruritus (itching), flushing, hives; 
• Other disorders: leg cramps, increased bruising, excessive sweating; 
Less Likely / Less Common 
 
Serious 
• Allergic reaction or hypersensitivity  
 
Mild 
• Abnormal liver function tests 
• Drop in blood hemoglobin and platelet (a type of blood cell) counts  
 
Blood Collection 
The physical risks that could arise from this study are related to finger prick to collect blood drop and 
blood draws. The risks for finger prick are bleeding and mild pain. The risks of a blood draw are 
minimal and may include pain, bruise at the site of the draw, and a rare risk of infection and fainting.   
 
 
If you are a woman capable of becoming pregnant, we will ask you to have a pregnancy test before 
beginning this study.  You must use effective birth control methods and try not to become pregnant 
while participating in this study.  If you become pregnant, there may be unknown risks to your unborn 


 
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Page 9 of 17 
child, or risks to your unborn child that we did not anticipate.  There may be long-term effects of the 
treatment being studied that could increase the risk of harm to an unborn child.  You must tell the doctor 
if your birth control method fails while you are on the study. If you believe or know you have become 
pregnant while participating in this research study, please contact the research team member identified at 
the top of this document as soon as possible.  Please discuss with the research team how long you need 
to wait before becoming pregnant after completing the treatment or procedures on this study. 
 
Risks of Genetic Research 
There may be information obtained from the genetic testing that indicates that you, or potentially a 
family member (since we inherit genes from our parents, and pass genes on to our children) are at risk 
for a particular disease or condition.  For example, genetic sequencing may indicate that an individual is 
more prone to develop certain types of cancer or other types of diseases, (e.g. Alzheimer’s or other 
inherited diseases).   
 
If made available to persons or agencies outside of our research group, information about genetic test 
results could affect your employment or insurance.  For instance, employers, insurers, or others may use 
this information when making decisions about you or your family members regarding employment, 
insurance, or other benefits. 
 
Re-Identification from Genetic Sample 
While the data developed for this study is being stored without traditional identifiers (stored only with 
coded ID numbers, no names), there may be ways of linking the genetic materials back to you.  Because 
your DNA is unique to you, it is possible that someone could look at the information in the DNA 
database and compare it to information in another database, and use that to identify you.  This is difficult 
to do and is very unlikely to happen. 
 
Genetic Research 
There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this 
law makes it illegal for health insurance companies, group health plans and employers with greater than 
15 employees to discriminate against you based on your genetic information. However, it does not 
protect you against discrimination by companies that sell life insurance, disability insurance or long 
term-care insurance.  
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
You may or may not benefit from being in this study.   
 
However, we hope that, in the future, other people might benefit from this study because the study 
results may lead to additional research to gain better understanding if Niagen is beneficial to protect the 
kidneys and to minimize severity of AKI. 
 


 
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Page 10 of 17 
WHAT OTHER TREATMENT OPTIONS ARE THERE? 
 
Before you decide whether or not to be in this study, your doctor will discuss other treatment options 
that are available to you.  Instead of being in this study, you could be on currently available management 
or standard of care for AKI or or you may wish to purchase Niagen on your own, since it is a 
commercially available nutritional supplement. 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
As part of this study you will receive tests and procedures that are similar to what you would receive 
during routine clinical care of your condition.  Your health plan/insurance company will be billed for 
some or all of these costs, and you will be responsible for any co-pays and deductibles that are normally 
required by your health plan/insurance.  Not all insurance plans cover the costs associated with being in 
a study. Even if they do, you may be responsible for more out-of-pocket expenses, such as co-pays and 
deductibles, when there are more tests and procedures or more expensive tests and procedures involved 
in the study than if you were to receive routine clinical care outside the study.   
If you wish to know whether there are more tests and procedures or more expensive tests and procedures 
in the study, you should ask your study doctor.   
 
If you wish to know whether your insurance will pay, you should contact them directly, or speak with 
the study team about obtaining a financial pre-certification prior to enrolling in the study. 
 
The study is providing Niagen, the device to measure kidney function at home, and items necessary to 
complete visit procedures at home at no cost to you. 
 
You will not have any additional costs for being in this research study. 
 
.WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study.   
           
WHO IS FUNDING THIS STUDY? 
 
The National Institutes of Health (NIH) is funding this research study.  This means that UT Health San 
Antonio and University Health is receiving payments from the NIH to support the activities that are 
required to conduct the study.  No one on the research team will receive a direct payment or increase in 
salary from the NIH for conducting this study. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
The researchers have taken steps to minimize the known or expected risks.  However, you may still 
experience problems or side effects, even though the researchers are careful to avoid them.  In the event 
of a research-related injury or if you experience an adverse reaction, please immediately contact your 
study doctor Kumar Sharma, MD, Phone # (210) 567-4706 and/or the Human Research Protection 
Office at 1-(800)-438-0445. You may also need to tell your regular doctors. 


 
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If you are injured or made sick from taking part in this research study, medical care will be provided. 
This care may be billed to you or your insurance. Depending on the circumstances, this care may be 
provided at no cost to you. We have no plans to give you money if you are injured. The investigator can 
provide you with more information. 
 
If you sign this form, you do not give up your right to seek additional compensation if you are harmed as 
a result of being in this study. 
 
The federal government has issued a declaration under a law known as the Public Readiness and 
Emergency Preparedness (PREP) Act to address the coronavirus (COVID-19) public health emergency. 
If you are injured or harmed as a result of participating in this study, that federal government declaration 
may limit your ability to obtain damages by filing a lawsuit against the study's researchers, health care 
providers, study site, study sponsor, and/or manufacturer or distributer of the drug. However, if you are 
injured or harmed as a result of participating in this study, the federal government has established a 
program that may provide compensation to you or your family. To find out more about this program, 
known as the "Countermeasures Injury Compensation Program" (CICP), go 
to https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-2427. The CICP is the payer of last 
resort, meaning that the CICP would generally only reimburse or pay for items or services to the extent 
such items or services are not covered by other third-party payers, such as your health insurance or 
workers' compensation you receive. 
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
 
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.  
• Government representatives (including the Office for Human Research Protections) to complete 
federal or state responsibilities 
• The U.S. Food and Drug Administration 
• The National Institutes of Health and its delegated body such as the National Institute of 
Diabetes and Digestive and Kidney Diseases (NIDDK) and the entities that they use to monitor, 
administer, or conduct the research   
• Your primary care physician and or your treating physician team at the hospital if a medical 
condition that needs urgent attention is discovered 
• Local or federal public health agencies to complete public health reporting requirements. 
• Information about your participation in this study may be documented in your health care records 
and will be available to anyone with access to your health care record, including your health 
insurance company.  This information may also be released as part of a release of information 
request. 
• Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study.  
• The safety adjudication committee (SAC) and the data coordinating center of the NIRVANA 
Study 


 
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Page 12 of 17 
• The Institutional Review Board and the Compliance Office of UT Health San Antonio, and other 
groups that oversee how research studies are carried out; and 
• The Research offices at UT Health San Antonio and University Health. 
• Any report or article that we write will not include information that can directly identify you.  
The journals that publish these reports or articles require that we share your information that was 
collected for this study with others to make sure the results of this study are correct and help 
develop new ideas for research. Your information will be shared in a way that cannot directly 
identify you. 
 
To help protect your confidentiality, we will use code numbers instead of your name, to identify your 
health information.  Initials and numbers will be used on any photocopies of your study records, and 
other study materials containing health information that are sent outside of the NIRVANA study sites 
for review or testing.  If the results of this study are reported in medical journals or at meetings, you will 
not be identified.  
 
To further protect your privacy, this research is covered by a Certificate of Confidentiality from the 
federal government. This means that the researchers can refuse to disclose information that may identify 
you in any legal or court proceeding or to anyone who is not connected with the research except if:  
• there is a law that requires disclosure, such as to report child abuse and neglect, or harm to self or 
others;  
• 
you give permission to disclose your information, including as described in this consent form; or 
• it is used for other scientific research allowed by federal law. 
You have the right to share your information or involvement in this study with anyone at any time. You 
may also give the research team permission to disclose your information to a third party or any other 
person not connected with the research.  
 
If information about you or your involvement in this research is placed in your medical record the 
information may no longer be protected under the Certificate. However, information in your medical 
records is protected in other ways.    
   
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?” 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
The research team will only use and share your information as talked about in this form or as permitted or 
required by law.  When possible, the research team will make sure information cannot be linked to you 


 
FOR IRB USE ONLY 
IRB ID #: 202101169-1007 
APPROVAL DATE: 03/22/21 
RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
Page 13 of 17 
(de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact UT Health San Antonio’s Compliance Officer at 210-567-2066.  
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
• your treatment or the care given by your health provider. 
• your insurance payment or enrollment in any health plans.   
• any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
• You authorize the use of your PHI for this research 
• This authorization does not expire. 
• You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
• To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
 The research team may only use and share information already collected for 
the study. 
 Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons. 
 You will not be allowed to continue to participate in the study. 
 
 
Can we contact you by email? 
We would like to contact you by email for the purposes listed below.  Some of these emails may contain 
health information that identifies you. 
• appointment scheduling containing PHI. 
 
Only the research team will have access to your email communications.  We will only communicate by 
email to send you the information listed above.  If you have any questions or need to contact us for an 
urgent or emergent situation, please contact the research team member identified at the top of this 
document. 
 
You should be aware that there are risks associated with sending your health information via email.   
• There is always a risk that the message could be intercepted or sent to the wrong email 
address.  To avoid sending messages to the wrong email address, the first email we send you 
will be a test message to ensure we have the correct email address. 


 
FOR IRB USE ONLY 
IRB ID #: 202101169-1007 
APPROVAL DATE: 03/22/21 
RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
Page 14 of 17 
• When using any computer you should be careful to protect your username and password.  
Make sure you log-out before getting up from the computer.   
• If you share a home computer with other family members, and do not want them to know you 
are participating in this study make sure you provide an email address that only you can 
access.  
• Your employer will have access to any email communications sent or received on any 
electronic devices used for work or through a work server. 
  
Do you agree to allow us to send your health information via email?   
 
_____ Yes  
_____ No 
Initials  
Initials 
 
If you agree to allow us to contact you by email, we will ask that you sign a separate Email 
Authorization Agreement. 
 
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. Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed.   
 
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 withdraw from the study? 
 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study. 
 
If you withdraw from the study we will ask your permission to continue to collect information from your 
health care records. Should this occur we will ask you to sign a separate consent form before collecting 
this information.  
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 investigator might decide to end your participation in this research 
study earlier than planned.  This might happen for no reason or because in our judgment it would not be 
safe for you to continue. 


 
FOR IRB USE ONLY 
IRB ID #: 202101169-1007 
APPROVAL DATE: 03/22/21 
RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
Page 15 of 17 
 
WHAT IF I HAVE QUESTIONS? 
 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Kumar Sharma, MD, Phone # (210) 567-4706. If you experience a research-related injury, 
please contact: Kumar Sharma, MD, Phone # (210) 567-4706.  
 
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office 1-(800)-438-0445, or email hrpo@wustl.edu.   General 
information about being a research participant can be found on the Human Research Protection Office 
web site, http://hrpo.wustl.edu.  To offer input about your experiences as a research participant or to 
speak to someone other than the research staff, call the Human Research Protection Office at the number 
above. 
 
The University of Texas Health Science Center at San Antonio (UT Health San Antonio) is the local 
Institutional Review Board committee that reviews research on human subjects (Institutional Review 
Board) and can also answer any questions about your rights as a research subject, and take any concerns, 
comments or complaints you may wish to offer.  You can contact the IRB by calling 210-567-8250, or 
by mail to IRB, UTHSCSA, Mail Code 7830, 7703 Floyd Curl Drive, San Antonio, TX  78229-3900. 
 
 
This consent form 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 agreeing to participate in this study. 
As a participant you have rights and responsibilities as described in this document and including: 
• To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
• To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
• To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
• To give the research team accurate and complete information. 
• To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 
 
 
 
 
 
 
 
 
 
 
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 receive a signed and dated copy 


 
FOR IRB USE ONLY 
IRB ID #: 202101169-1007 
APPROVAL DATE: 03/22/21 
RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
Page 16 of 17 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 03/08/22. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
Legally Authorized Representative’s Name and Relationship to Participant: 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 03/08/22. 
 
 
______________________________ 
(Participant’s name – printed) 
 
 
__________________________________________ 
_______________________________ 
(Signature of Legally Authorized Representative) 
 
(Date) 
 
 
__________________________________________ 
_______________________________ 
(Name of Legally Authorized Representative - printed) 
(Relationship to Participant – printed) 
 
 
Who should sign as the Legally Authorized Representative (LAR)? 
If the participant has a legal guardian or attorney-in-fact this individual must sign as the LAR.    
 
If there is no legal guardian or attorney-in-fact the individuals listed below may sign in order of priority.  
 
(1) Spouse unless the participant has no spouse, or is separated, or the spouse is physically or mentally 
incapable of giving consent, or the spouse's whereabouts is unknown or the spouse is overseas;  
(2) Adult child;  
(3) Parent;  
(4) Brother or sister;  
(5) Relative by blood or marriage.  
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 


 
FOR IRB USE ONLY 
IRB ID #: 202101169-1007 
APPROVAL DATE: 03/22/21 
RELEASED DATE: 03/22/21 
EXPIRATION DATE: 03/08/22 
 
 
Page 17 of 17 
participant’s legally authorized representative.  The participant has indicated that they understand the 
risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed) 
 
 
Witness to the subject’s Signature 
 
The witness should be someone not affiliated with the research: neither investigator nor study personnel. 
“Study personnel” means persons involved in carrying out the particular research protocol for which the 
subject is signing the consent. It is preferred that the witness not be associated with the subject. 
However, a family member or friend may serve as a witness if an impartial witness is not available. 
 
__________________________________________ 
_______________________________ 
(Signature of Witness) 
 
 
(Date) 
 
 
___________________________________________ 
(Name of Witness - printed) 
 

Prot_SAP_002.pdf: 
 
 
 
 
COVER PAGE 
 
 
 
 
Official Study Title: NIRVANA: NIcotinamide Riboside in SARS-
CoV-2 pAtients for reNAl protection 
 
NCT Number: NCT04818216 
 
IRB Approval Date: 03.09.2021 
 
Protocol Number: HSC20200914H 
 
 
 
 
 
 
 
 
 
 


 
 
 
NIRVANA: NIcotinamide Riboside in SARS-CoV-2 pAtients for 
reNAl protection  
 
Protocol Number: Pending 
National Clinical Trial (NCT) Identified Number:  Pending Registration 
Principal Investigator: Kumar Sharma, MD 
IND Sponsor: Kumar Sharma, MD 
IND Number: 152024 
Funded by: The National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), the National Institutes of Health (NIH)  
Version Number:  v.1.0  
December 16, 2020 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
 
 
 
 
 
 


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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 3 
1 
PROTOCOL SUMMARY ............................................................................................................................... 4 
1.1 
Synopsis ................................................................................................................................................ 4 
1.2 
Schema ................................................................................................................................................. 6 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background......................................................................................................................................... 10 
2.3 
Risk/Benefit Assessment .................................................................................................................. 11 
2.3.1 
Known Potential Risks ................................................................................................... 11 
2.3.2 
Known Potential Benefits .............................................................................................. 15 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 15 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 16 
4 
STUDY DESIGN ........................................................................................................................................... 18 
4.1 
Overall Design .................................................................................................................................... 18 
4.2 
Scientific Rationale for Study Design.............................................................................................. 18 
4.3 
Justification for Dose ......................................................................................................................... 19 
4.4 
End of Study Definition ..................................................................................................................... 20 
5 
STUDY POPULATION ................................................................................................................................ 20 
5.1 
Inclusion Criteria ................................................................................................................................ 20 
5.2 
Exclusion Criteria ............................................................................................................................... 21 
5.3 
Lifestyle Considerations .................................................................................................................... 22 
5.4 
Screen Failures .................................................................................................................................. 22 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 23 
6 
STUDY INTERVENTION ............................................................................................................................ 25 
6.1 
Study Intervention(s) Administration ............................................................................................... 25 
6.1.1 
Study Intervention Description ..................................................................................... 25 
6.1.2 
Dosing and Administration ............................................................................................ 28 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 28 
6.2.1 
Acquisition and accountability ...................................................................................... 28 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 29 
6.2.3 
Product Storage and Stability ....................................................................................... 29 
6.2.4 
Preparation ...................................................................................................................... 30 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 30 
6.4 
Study Intervention Compliance ........................................................................................................ 31 
6.5 
Concomitant Therapy ........................................................................................................................ 31 
6.5.1 
Rescue Medicine ............................................................................................................ 31 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 31 
7.1 
Discontinuation of Study Intervention ............................................................................................. 31 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 32 
7.3 
Lost to Follow-Up ............................................................................................................................... 33 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 34 
8.1 
Efficacy Assessments ....................................................................................................................... 34 
8.2 
Safety and Other Assessments ....................................................................................................... 38 


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8.3 
Adverse Events and Serious Adverse Events ............................................................................... 41 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 41 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 42 
8.3.3 
Classification of an Adverse Event .............................................................................. 43 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 44 
8.3.5 
Adverse Event Reporting .............................................................................................. 45 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 45 
8.3.7 
Event Adjudication Process .......................................................................................... 47 
8.3.8 
Reporting Events to Participants ................................................................................. 48 
8.3.9 
Events of Special Interest ............................................................................................. 48 
8.3.10 
Reporting of Pregnancy ................................................................................................ 48 
8.4 
Unanticipated Problems .................................................................................................................... 48 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 48 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 48 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 49 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 49 
9.1 
Statistical Hypotheses ....................................................................................................................... 49 
9.2 
Sample Size Determination .............................................................................................................. 49 
9.3 
Populations for Analyses .................................................................................................................. 50 
9.4 
Statistical Analyses............................................................................................................................ 50 
9.4.1 
General Approach .......................................................................................................... 50 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 51 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 52 
9.4.4 
Safety Analyses .............................................................................................................. 54 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 54 
9.4.6 
Planned Interim Analyses ............................................................................................. 55 
9.4.7 
Sub-Group Analyses ..................................................................................................... 55 
9.4.8 
Tabulation of Individual participant Data .................................................................... 55 
9.4.9 
Exploratory Analyses ..................................................................................................... 55 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 55 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 55 
10.1.1 
Informed Consent Process ........................................................................................... 56 
10.1.2 
Study Discontinuation and Closure ............................................................................. 58 
10.1.3 
Confidentiality and Privacy ........................................................................................... 59 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 60 
10.1.5 
Key Roles and Study Governance .............................................................................. 60 
10.1.6 
Safety Oversight ............................................................................................................. 60 
10.1.7 
Clinical Monitoring .......................................................................................................... 61 
10.1.8 
Data Handling and Record Keeping ............................................................................ 62 
10.1.9 
Protocol Deviations ........................................................................................................ 65 
10.1.10 
Publication and Data Sharing Policy ........................................................................... 66 
10.1.11 
Conflict of Interest Policy .............................................................................................. 66 
10.2 
Additional Considerations ................................................................................................................. 66 
10.3 
Abbreviations ...................................................................................................................................... 67 
10.4 
Protocol Amendment History ........................................................................................................... 68 
11 
REFERENCES ............................................................................................................................................. 69 


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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title 
NIcotinamide Riboside in SARS-CoV-2 pAtients for reNAl protection 
(NIRVANA) 
Study 
Description 
A pilot, double-blind, placebo-controlled, multicenter, interventional clinical 
trial with oral nicotinamide riboside (NR) 500 mg (versus placebo) twice 
daily for a total of 10 days in hospitalized participants with COVID-19. 
Objectives 
 
Primary 
• To determine the effect of nicotinamide riboside (NR) on whole blood 
NAD+ levels in hospitalized patients with COVID-19 infection and AKI 
during the 10-day intervention period; 
• To evaluate the safety of NR in patients with COVID-19 infection and 
AKI during the 10-day intervention period; 
Secondary 
• To determine the effect of NR on changes in  area under curve (AUC) 
serum creatinine from baseline during the 10-day intervention; 
• To determine the effects of NR on serum creatinine AUC, dialysis, and 
death with an ordinal categorical outcome having four categories 
(labeled 1, 2, 3, 4), defined as, in order from least to most severe disease, 
1. Serum creatinine AUC < median, 2. Serum creatinine AUC ≥ median, 
3. Dialysis, 4. Death during the 90d period post randomization;   
• To determine the effect of NR on MAKE (Major Adverse Kidney Events;  
composite criteria defined as development or progression of chronic 
kidney disease, the initiation of long-term dialysis, or death from any 
cause) at 30d and 90d post randomization; 
• To determine the effect of NR on degree of kidney impairment defined 
with  estimated glomerular filtration rate (eGFR) and proteinuria at 30d 
and 90d post randomization; 
Exploratory 
• To determine the relationship of whole blood NAD+ levels with AUC 
creatinine and surrogate markers of AKI such as kidney injury molecule-
1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL); 
Endpoints 
Primary 
• Rates of change in whole blood NAD+ level from baseline to day 10 in 
NR compared to Placebo. 
• Safety of NR in hospitalized patients with COVID-19 and AKI (defined as 
the occurrence of at least one serious adverse event of grade 3 or higher 
or the occurrence of thrombocytopenia (>25% decline in blood platelet 
count from baseline value). 
 
 
 


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Secondary 
• Rates of change in AUC serum creatinine benchmarked to baseline 
from baseline to day 10 in NR compared to Placebo; 
• An ordinal categorical outcome with four categories (labeled 1, 2, 3, 
4), defined as, in order from least to most severe disease, 1. Serum 
creatinine AUC < median, 2. Serum creatinine AUC ≥ median, 3. 
Dialysis, 4. Death; 
• Time to first occurrence of MAKE (doubling of serum creatinine, the 
initiation of long-term dialysis, or death from any cause) at 30 d and 
90 d post randomization; 
• Kidney function defined by eGFR and proteinuria at 30d and 90d 
post randomization. 
 
Exploratory 
• Correlations between whole blood NAD+, AUC serum creatinine, and 
AKI surrogate markers of AKI such as KIM-1 and NGAL; 
Study 
Population: 
Participants will be >18 years old and admitted to hospital with a 
laboratory diagnosis of COVID-19 infection and AKI 
Phase: 
Phase 2 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
The study is a multicenter study with University of Texas Health San Antonio 
(UTHSA) as the coordinating site. The three recruiting sites are: University 
Hospital affiliated with UTHSA, Icahn School of Medicine at Mount Sinai, 
New York, NY and Harborview Medical Center/University of Washington, 
Seattle, WA 
Description of 
Study 
Intervention: 
The intervention for this clinical trial is Niagen®, a nicotinamide riboside, 
an over the counter nutritional supplement 
Study Duration 
Estimated 2 years 
Participant 
Duration: 
The estimated time required for this study will be up to 90 days after 
consenting to study protocol. A total of up to 10 visits will occur during the 
initial 10 days with two follow-up visits – 30 days and 90 days from 
enrollment date.  


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1.2 
SCHEMA 
 
Flow diagram of the NIRVANA Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID, Corona virus disease; EHR, Electronic health records; NR, Nicotinamide Riboside 
    
 
 
 
Total N=100:  Using EHRs screen potential participants by 
inclusion/exclusion criteria; obtain informed consent with COVID safety in 
place, document medical history. 
• Perform baseline assessments: 
⸰ Obtain vitals and physical examination data from EHRs 
⸰ Collect blood and urine 
• Administer initial study intervention: NR vs Placebo. 
• Administer study intervention: NR vs Placebo. 
• Collect and assess study endpoints and safety data 
• Collect blood and urine 
⸰ Perform laboratory safety assessments  
⸰ Perform whole blood NAD+ measurement  
Placebo n=50 
NR n=50 
Randomize 
Prior to  
Enrollment 
Baseline 
visit: Day 1  
Treatment 
visits:  
Day 1-10 
(Daily) 
Follow-up 
visits:  
Day 30, 90 
• Perform follow-up assessments: 
⸰ Vitals and physical examination at d30 and d90 
• Collect urine and blood at d30 and d90 
• 
Collect and assess study endpoints and safety data 


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1.3 
 SCHEDULE OF ACTIVITIES (SOA) 
 APACHE-II, Acute physiology and chronic health evaluation II; AE, adverse events; ICU, Intensive care unit; 
* Baseline (Day 1) assessments should be performed prior to study drug administration; 
1 Includes all inhospital and home medications (standard of care treatment, prescription, over-the-counter, 
supplements);  
2Dosing of the first study drug will be administered as soon as possible (within 6 hours of obtaining consent and 
negative pregnancy test for women with childbearing potential);  
3 Participants who will be discharged or leave hospital before Day 10 intervention will be provided with study pills 
for the remaining days.  
4 Respiratory rate, FiO2, O2 saturation, ventilator parameters, if applicable and participant is hospitalized; 
5 Urine output data based on medical records or from first morning urine collections if discharged from hospital; 
6Any laboratory tests performed as part of routine clinical care within the specified visit day may be used for safety 
laboratory testing by extracting values from the EHR; 
Table 1. Schedules of activities 
Study Period  
Scree
ning 
Treatment Period 
 
Follow-up  
 
 
Visit Encounter  
Visit 
0/ 
Day 
 0 
 Visit 
1/ 
Day 
1  
(Base
line)* 
Visit 
2/ 
Day 
2 
Visit 
3/ 
Day 
3 
Visit 
4/ 
Day 
4 
Visit 
5/ 
Day 
5 
Visit 
6/ 
Day 
6 
Visit 
7/ 
Day 
7 
Visit 
8/ 
Day 
8 
Visit 
9/ 
Day 
9 
Visit 
10/ 
Day 
10 
Visit 
11/ 
Day 
30 ± 
3 
Visit 
12/ 
Day 
90 
±3 
Procedure 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
STUDY INTERVENTION 
Randomization2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
STUDY PROCEDURES 
APACHE-II 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Endpoint 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Respiratory 
parameters4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Mortality, ICU 
transfer, length of 
stay 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine output5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CLINICAL LABORATORY 
Blood analysis6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X⁋ 
X⁋ 
SAFETY LABORATORY 
Blood analysis7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
RESEARCH LABORATORY and REPOSITORY 
Blood and urine8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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7 Creatine phosphokinase and liver function tests will be performed on Day 5 (see Table 4) 
8 Whole blood NAD+ and serum creatinine will be collected daily before study medication dosing; Blood will be 
collected at 3-hour and 6-hour post-randomization for future pharmacokinetics; Blood and urine for biomarkers 
will be collected at Baseline and daily during the intervention period, at day 30 ± 3 and day 90 ± 3; 
⁋If the participant is still hospitalized then inpatient safety laboratory test results will be collected from EHR 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Impaired mitochondrial function has been recently recognized as a major mechanism for acute 
kidney injury (AKI) in septic shock and ischemia-reperfusion injury [1-5]. A major feature that 
limits mitochondrial function is the reduction of electron donors to the mitochondria in the form 
of nicotinamide adenine dinucleotide (NAD+). Reduced levels of NAD+ have been implicated in 
both animal models and humans with AKI, and stimulation of pathways that lead to 
enhancement of NAD+ appears to be beneficial [3, 4, 6]. Recent studies using oral nicotinamide 
(NAM) and nicotinamide riboside (NR) as NAD+ donors have found these agents to be safe, 
well-tolerated, and upregulate NAD+ pathways in a dose-dependent manner [7, 8]. NR provided 
after organ injury was found to be protective in pre-clinical studies [9, 10]. It has been 
demonstrated that NR is more orally bioavailable than NAM, safe in obese participants, and 
beneficial in many pre-clinical models of organ dysfunction [7, 8, 11-14]. NAM use during the 
perioperative period in participants undergoing cardiothoracic surgery showed reduced incidence 
of AKI in a pilot study [5]. NR use (in combination with pterostilbene, PT; NRPT) was found to 
increase NAD+ levels in patients with AKI as compared to the placebo group [15]. 
 
The kidneys are highly active metabolically, contain a high density of mitochondria, and 
consume the highest amount of oxygen after the heart. Mitochondrial energy (adenosine 
triphosphate or ATP) production requires the universal cofactor nicotinamide adenine 
dinucleotide (NAD). This essential metabolite serves as a key cofactor in a plethora of 
mitochondrial metabolic processes that facilitate energy production as well as several other 
important cellular functions [16]. Consistent with these key roles of NAD+, various stressors 
have been associated with decreased NAD+ levels [15], contributing to disease pathogenesis. 
 
Rationale for Study Design: 
We chose a treatment protocol with NR as a treatment for patients who will be admitted with 
COVID-19 related illness and develop AKI after admission. Treatment duration will be for 10 
days and the primary study endpoint will be the change in whole blood NAD+ from baseline (to 
10d, 2d, AUC) in NR group vs placebo group. We will evaluate whole blood NAD+ levels as a 
marker of efficacy and biological effect of  NR based on two recent publications [8, 15]. We 
evaluated using a marker of efficacy for NR with the whole blood NAD+ based on two recent 
publications [8, 15]. In a study of healthy overweight subjects 40-60 years of age, Conze et al. 


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[8] found a 21 µg/ml mean NAD+ difference between patients randomized to 1000 mg 
NIAGEN® versus those randomized to placebo at day 7 (NIAGEN 42 µg/ml, Placebo 21 µg/ml) 
with a standard deviation of 10 µg/ml and approximately equal baseline means (NIAGEN 21 
µg/ml, Placebo 24 µg/ml).  Simic et al. [15] assessed a combination of NR with pterostilbene 
(NRPT) vs placebo in hospitalized patients of age ≥ 18 years with AKI and found an 18% 
increase in whole blood NAD+ within 48h post treatment in the NRPT group, and a 50% 
reduction from baseline in the placebo group with AKI. With reference to Conze et al. [8] al., 
this study will achieve >99.9% power for testing Ho:RNR = RPlacebo versus Ho: RNR≠RPlacebo with 
alpha=0.05, autocorrelation ()=0.5, and n=40 per arm where RNR and RPlacebo are the rates of 
change from baseline to day 10 in the NR and Placebo arms, if the effects observed in this study 
are the same as those observed by Conze et al. with regard to NAD+.  In this setting the effect 
size is 2.1 [=(42-21)/10] and the minimally detectable effect size is 0.63.   
Safety of NR will also be assessed as a primary endpoint in this study. Although NR is generally 
recognized as safe or GRAS [17] and has been demonstrated to be well-tolerated with mild, if 
any side effects, reported using variables doses from 100 mg/day up to 2000 mg/day [8, 11, 12] it 
will be informative to assure that serious adverse events (SAEs) are not increased with NR in 
patients with COVID-19 infection and AKI.  
 
We also plan to assess the AUC of serum creatinine benchmarked to baseline and other clinical 
outcomes as secondary endpoints to determine if there are trends indicating that NR may be a 
promising treatment for hospitalized COVID-19 infected patients who develop AKI. We will 
also correlate whole blood NAD+ levels with AUC creatinine with well described surrogate 
markers of AKI (KIM-1, NGAL) as an exploratory outcome measure. If we demonstrate that NR 
increases whole blood NAD+ in COVID-19 positive patients with AKI and is safe, this result 
would be a compelling finding to support further clinical trials with NR in this population. 
Further support for future studies would be obtained from our secondary endpoints and will of 
great value in establishing power calculations for future definitive studies [9, 10]. 
 
Upon completion of the NRIVANA study, we plan to pursue a Phase IIb or Phase III study based 
on the following scenarios:    
 
1. Demonstrate significant increase in whole blood NAD+ level in the NR group compared 
to placebo (p<0.05), no significant increase in harm with NR treatment and a positive 
trend or improvement in any one of the secondary outcomes (p<0.2) would warrant a 
future Phase III study. 
2. Demonstrate significant increase in whole blood NAD+ level in the NR group compared 
to placebo (p<0.05) and no significant increase in harm with NR treatment would warrant 
a Phase IIb study. 
3. Demonstrate significant improvement in any one of the secondary outcomes with NR 
compared to placebo (p<0.2) and no significant increase in harm with NR treatment 
would warrant a Phase IIb study.  


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In a future Phase III clinical trial, we envision the primary endpoint would be the MAKE (Major 
Adverse Kidney Events) – the proportion of subjects who develop any of the components of 
MAKE at d90 post randomization. In the NIRVANA study MAKE is one of the secondary 
endpoints.     
 
2.2 
BACKGROUND  
 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the 
novel coronavirus 2019 disease (COVID-19), is responsible for the global pandemic which is 
taking a tremendous toll in the form of human morbidity and mortality. SARS-CoV-2 infection 
is unpredictable in its course as it may be asymptomatic in some patients but rapidly develop 
life-threatening complications in others leading to multisystem organ failure [18-21]. Kidney 
involvement is prominent in admitted patients with COVID-19 pneumonia with 75% exhibiting 
proteinuria, hematuria, or AKI [22]. In a comprehensive analysis of 5,449 patients admitted with 
COVID-19, AKI developed in 1,993 patients for an incidence rate of 37% [23]. The incidence of 
AKI is even higher (68%) in COVID-19 patients admitted to the intensive care unit (ICU) as 
reported from New York City [24]. Moreover, up to 86% of deaths in COVID-19 patients were 
associated with AKI [22]. The overall mortality in hospitalized COVID-19 infected patients was 
originally found to be 25.6% however more recent studies find the mortality rate to be now at 
about 7.6% [25]. The basis for AKI with COVID-19 is not known. The N3C database, as of 18 
November 2020, indicated that of 1213 hospitalized COVID-19 patients with AKI satisfying our 
entry criteria and not satisfying our exclusion criteria, a total of 120 (9.9%) died. The actual 
dates of death are not known. 
 
The pathophysiology of AKI is multifactorial, and, in many cases, the precise mechanism of AKI 
is unclear [26, 27]. Currently there is scarcity of data with regard to the underlying pathogenesis 
of AKI in SARS-CoV-2 patients. However, the “cytokine storm” appears to be the primary 
contributing factor to AKI and disease severity in patients with COVID-19 [28, 29]. Based on 
clinical observations, AKI occurs in critically ill patients with COVID-19 that are under severe 
metabolic stress originating from maladaptive systemic inflammatory immune response, 
hypoxemia, ischemia, microthrombi, sepsis, and toxins (e.g., rhabdomyolysis) [28]. The kidneys 
may also be the site for direct invasion of SARS-CoV-2 due to the high expression of ACE2 in 
renal tubular epithelial [30, 31]. Therefore, it is possible that inflammatory events and/or direct 
SARS-CoV-2 infection of renal cells lead to a metabolic derangement affecting the NAD+ 
metabolome and consequent mitochondrial dysfunction leading to AKI. At the present time there 
is no targeted treatment for AKI. Given the role of mitochondrial function and NAD+ in other 
models of AKI and multi-organ failure associated with infection and inflammation, we postulate 
that a similar process of reduced NAD+ and reduced mitochondrial function may underlie AKI 
with COVID-19 infection.  
 


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NR and NAD restoration in animal studies of organ injury 
Mice receiving intraperitoneal administration of NR at 185 mg/kg for 6 days had about 100-fold 
increase in nicotinic acid adenine dinucleotide in the heart [32]. Another study also demonstrated 
that mice with NR administration of 400 mg compound/kg body weight per day caused increase 
of NAD+ levels in muscle and liver [33]. Interventional studies also showed beneficial effects of 
NR on specific organ injury. NR significantly reduced non-fasting and fasting blood glucose, 
weight gain and hepatic steatosis and protected neuropathy in diabetic mice supplemented with 3 
g of NR per kg of their diet [32]. A study in rats of intestinal ischemia-reperfusion found that 
administration of NR (50 mg/kg) at end of ischemia period and early reperfusion led to 
endothelial protection and intestinal wall protection from reperfusion injury [9]. NR 
supplementation to murine models of dilated cardiomyopathy or heart failure restores myocardial 
NAD levels and preserves cardiac function via induction of the nicotinamide riboside kinase 2 
(NMRK2) pathway for NAD+ synthesis [10]. Others also demonstrated that NR can prevent 
alcohol or non-alcohol induced liver injuries via replenishing NAD+, reducing oxidative stress, 
activating SIRT1-PGC-1α-mitochondrial biosynthesis or sirtuin (SIRT)1- and SIRT3-dependent 
mitochondrial unfolded protein response [34-36]. 
 
Therefore, a therapeutic to safely restore mitochondrial function in patients with recent onset 
AKI may be of major benefit to reduce the severity of AKI in newly admitted patients with 
COVID-19. We specifically hypothesize that supplementation with NR will reduce the severity 
of AKI in newly admitted SARS-CoV-2 patients. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
   
2.3.1 KNOWN POTENTIAL RISKS  
 
The study drug NR may not prevent or treat the disease, or the condition of the participant or 
disease may worsen, but there is currently no accepted standard of care to prevent or treat AKI. 
As with any research study, there is a potential for side effects to occur with the administration of 
the study drug. All participants will be closely monitored on a daily basis for adverse events 
(AEs) defined as changes in health condition and laboratory parameters from baseline (Day 1). 
Few side effects have been identified for the use of NR, but the side effects that have been 
reported such as nausea, back soreness and muscle soreness have been typically mild [8].  
 
NR is a formal precursor of NAD+ and naturally present in certain foods including milk. After 
absorption, NR enters the cell, and is metabolized into nicotinamide mononucleotide (NMN) by 
a phosphorylation step catalyzed by the nicotinamide riboside kinases (NRKs). NMN is 
subsequently converted to NAD by nicotinamide nucleotide adenylyltransferases (NMNAT1-3). 
However, the quantities in foods are quite low, and probably do not exceed the low micromolar 
range [37]. In the USA, NR is considered as GRAS or Generally Recognized as Safe for use in 
food products which supports its rapid implementation as a drug-like therapy [17].  


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NR has been demonstrated to be well-tolerated with mild, if any side effects reported using 
variables doses from 100 mg/day up to 2000 mg/day [8, 11, 12]. The current study intervention 
is 1000 mg/day administered as 500 mg twice a day.  
 
NR was recently evaluated in a single center, double blind, placebo-controlled, and crossover 
study in which 12 elderly participants received 500 mg NR twice a day for 21 days. In this study 
NR was well tolerated without any SAE including no changes in hematological and clinical 
biochemistry safety parameters – i.e., renal, liver, and thyroid functions [14].  The reported 
symptoms included nausea, flushing, leg cramps and increased bruising in the NR group and 
headache, skin rash, flushing, fainting and drowsiness in the placebo group [7].  
 
A dose escalation study was performed in 8 healthy subjects in a non-randomized, open-label 
pharmacokinetics (PK) study with 250 mg NR orally administered on days 1 and 2, then 
uptitrated to peak dose of 1000 mg twice daily on days 7 and 8. No clinically significant changes 
were seen at NR dose up to 1000 mg orally twice daily in any of the five pre-specified safety 
endpoints, i.e., potassium, creatine phosphokinase (CPK), glucose, uric acid and alanine 
aminotransferase. Serum potassium decreased by an average of 0.4 mEq/L, which was 
statistically significant (p = 0.015) but the individual levels remain in normal range. There was a 
slight though statistically significant decrease for hematocrit (mean difference = −2%, p = 
0.005), hemoglobin (-0.4 g/dL, p = 0.04), and platelet count (-20,000/μL, p = 0.03). There were 
no significant changes in blood pressure, body temperature, body weight, white blood cell count, 
lactate dehydrogenase or aspartate aminotransferase. In addition, there were no significant 
changes in serum levels of sodium, chloride, urea nitrogen, creatinine, or in white blood cell 
differential [38].  
 
In an investigator-initiated randomized, placebo-controlled, double-blinded study of 40 healthy 
men with BMI> 30 kg/m2 NR was administered at a dose of 1000mg twice daily for 12 weeks 
[39]. Adverse events (AEs) were reported in 4 subjects in the NR group which included pruritis, 
excessive sweating, bloating and transient changes in stool. There were two AEs in the placebo 
group which were acid reflux and loose stools. The severity was mild in all cases. Laboratory 
analysis for blood counts and chemistries at 6 weeks revealed no abnormalities in the NR group. 
 
A recent report evaluated a combination of NR with an anti-oxidant pterostilbene (PT; NRPT) in 
24 hospitalized patients with AKI with a single dose ranging from 250mg NR, 500mg NR, 
750mg NR to 1000mg NR twice a day [15]. Compared to the baseline timepoint, NRPT dose 500 
mg/100 mg twice a day increased whole blood NAD+ levels 47% at 48 h, (p = 0.04). Whole 
blood NAD+ levels in patients with AKI receiving placebo decreased by 50% at 48 h (p = 0.05). 
Compared to placebo, there was no significant difference in creatinine, estimated glomerular 
filtration rate (eGFR), electrolytes (sodium, potassium), liver enzymes (ALT, AST, ALP), 
hemoglobin, white blood count or platelet count in patients treated with NRPT at 48 h. NRPT 


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was safe at all doses in patients with AKI with only minor side effects (bloating and gas, upper 
abdominal discomfort) reported that resolved without intervention. There were no side effects in 
placebo group. There was no SAE in either group [15]. 
 
Safety of NRPT (up to 500mg NR + 100mg PT/day) has also been evaluated in a randomized, 
placebo-controlled, double-blind study in a population of 120 healthy adults between the ages of 
60 and 80 years for 8 weeks [40]. There was a total of six AEs – nausea, fatigue, headache, 
dyspepsia, abdominal discomfort, and diarrhea with mild to moderate intensity.  
  
In the largest study to date, 140 healthy male and female participants (40-60 years of age) 
underwent a randomized, placebo-controlled study with 4 groups: placebo (n=35), 100 mg group 
(n=35), 300mg/d (n=35) and 1000mg/d (n=35) and supplementation was provided for 56 d [8]. 
One subject in placebo group dropped out due to nausea, one subject was withdrawn from 300 
mg group due to non-compliance, two subjects in the 100 mg and two in the 1000 mg group 
withdrew consent and one subject in the 1000 mg group was lost to follow-up. Compliance 
ranged from 97.1%-99% across all groups. There were no serious adverse events (SAEs) and the 
type, incidence and severity of the AEs were similar across all groups – 17 participants in 
placebo group, 16 in 100 mg/d group, 14 in 300mg/d group and 14 in 1000mg/d group. There 
were a total of 22 AEs in the 1000mg NR group with 3 being reported as possibly related to 
study drug: sore back, muscle soreness, and nausea with mild in intensity. Hematological and 
chemistry profiles were similar in all groups. The effects of NR on muscle metabolism has been 
studied [14, 33]; however, these studies did not measure serum cystatin C or CPK. 
 
There are paucity of data regarding the safety profile of NR in patients with CKD. Two clinical 
trials of NR in patients with eGFR 20-60 mL/min/1.73m2 are ongoing [41, 42]. Forms of vitamin 
B3 nicotinic acid (pyridine-3-carboxylic acid or niacin) and its circulating amide derivative 
nicotinamide (pyridine-3-carboxamide, NAM)  have been tested in advanced CKD patients 
undergoing hemo- and peritoneal dialysis patients [43]. One randomized, placebo-controlled 
clinical trial tested NAM (750 mg twice daily) alone and in combination with lanthanum 
carbonate among individuals with eGFR 20–45 ml/min per 1.73 m2 for 12 months [44]. This 
study reported severe nausea, severe diarrhea, flushing, hives, bruising and bleeding in the NAM 
group (n=51) which were not significantly different than that reported in the placebo group with 
the exception of hives. It is important to note that this particular study did not find any evidence 
of thrombocytopenia (platelet count <100,000/mm2), liver function abnormalities, and elevated 
CPK (>800 U/L) in the NAM group compared to the placebo group [44]. In patients with 
hemodialysis, the documented safety profile of NAM included primarily flushing, pruritus, 
hypotension, hepatotoxicity, and gastrointestinal upset. Most studies reported NAM associated 
transient thrombocytopenia without any bleeding events in hemodialysis patients which returned 
to normal range within weeks of discontinuation of intervention [43, 45, 46]. In contrast, studies 
conducted in peritoneal dialysis patients did not report such hematologic changes associated with 


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NAM [47]. It should be noted that NR does not induce prostaglandin-mediated flushing or 
vasodilatory responses [48]. One study tested NAM 100 mg twice daily for 6 months in pediatric 
population (age 7-17 yrs) with hyperphosphatemia undergoing maintenance hemodialysis [49]. 
NAM group reported diarrhea, nausea, vomiting, and flushing which were not significantly 
different from the control group and did not result in withdrawal from the study. Despite a 
significant decline in mean platelet count from the baseline in the NAM group, the platelet level 
remained within the normal range and none of the participants experienced any bleeding 
disorder.      
 
N-methyl-2-pyridone-5-carboxamide or 2PY, a major metabolite of NAM, is considered a 
uremic toxic in patients with impaired renal function [50, 51]. While serum 2PY level may 
increase significantly with NAM supplementation [46], the intracellular concentration may not 
rise compared to baseline in hemodialysis patients [52]. In general, available data conclude that 
NAM is safe and tolerable in adults at doses of below 3 g/day [53]. Taken together the available 
safety data of niacin and NAM indicate that in patients with impaired renal function both agents 
are tolerable [54-56]. The prominent side effects of NAM at therapeutic doses (i.e., 1000 
mg/day) are gastrointestinal symptoms (mainly diarrhea) that generally resolve on treatment 
withdrawal or discontinuation. Develeopement of hetatoxicity require massive dose of NAM – 9 
g/day and prolong therapy for months may cause thromobocytopenia [55, 56]. 
Based on the available data, the known potential risks of NR can be divided into those that are 
likely and those that are rare. 
 
Likely  
These risks are expected to occur in 5-15 participants or less out of 100 participants. 
• Gastrointestinal disorders: nausea, heart burn (e.g., indigestion, gas, upper abdominal 
discomfort, and bloating), diarrhea, transient changes in stool; 
• Musculoskeletal disorders: back soreness, muscle soreness; 
• Skin disorders: pruritus, flushing, hives; 
• Other disorders: leg cramps, increased bruising, excessive sweating; 
• Laboratory findings: liver function abnormalities; decrease in blood urea nitrogen;  
 
Rare  
The following risk may occur at an unknown rate:   
• Hematologic profile – e.g., <10% reduction in hemoglobin and platelet counts  
• Allergic reaction or hypersensitivity  
 
There is no available data on potential interactions between NR and standard treatment for 
comorbidities (concurrent medications) or any investigational agents for the treatment of 
COVID-19. Administering NR concurrently with other agents may lead to antagonism or 
synergy or may have no effect.  


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2.3.2 KNOWN POTENTIAL BENEFITS  
 
The benefits of nicotinamide riboside (NR) administration in COVID-19 participants to prevent 
or treat acute kidney injury are not currently known. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
This trial protocol incorporates numerous design elements to minimize risk to participants to 
meet human participant protection requirement. The dose of NR in this trial is comparable to the 
dose used in other published and ongoing clinical trials to increase blood NAD+ levels and have 
shown minimal to mild side effects.  The duration of treatment in this trial of 10 days is 
significantly shorter than that of many published clinical trials with NR to reduce risk but likely 
sufficient to observe benefit. To further mitigate risk, we will exclude participants with 
concomitant niacin, nicotinamide, or NR supplementation.  
 
The safety profile of NR has been reported in several small-scale randomized and non-
randomized clinical trials involving heathy volunteers. Most of these reported risks are mild in a 
grading scale (see section 2.3.1). Based on prior data in healthy populations, obese participants 
and in those with AKI, there have been no reported major adverse events. Minor adverse events 
include gastrointestinal side effects, muscle and back pains. It remains possible that NR in 
patients with COVID-19 could have unexpected effects or make COVID-19 complications 
worse. The potential benefit would be less kidney injury and preservation of kidney function to 
reduce the degree of CKD in patients with COVID-19 infection. Taking into account the 
preliminary data available on the possible benefit of NR to boost NAD+ levels for kidney 
protection along with the relative lack of therapeutic options for AKI incidence and severity it 
appears to reasonably balance potential risks with possible benefit that may outweigh such risks. 
By appropriate daily clinical evaluation, laboratory monitoring, soliciting of symptoms and 
incident reporting by participants during the study, the risk to participants will be minimized. 
 
Participants will receive the usual standard of care during hospitalization and during the 10-day 
active intervention period. The standard of care includes a daily review of health status, 
participant’s report of any new symptoms and complaints, targeted physical exam and routine 
laboratory tests. Adverse events data will be retrieved from the electronic health records (EHR) 
and entered into the case report form for evaluation and comparison using the baseline values. 
For any missing data in the EHR and to collect additional information, the study team will obtain 
data from the primary care team and the participant. If participants are discharged from the 
hospital during the course of the study, they will be contacted by video visit or phone daily 
during period of intervention (first 10 days after enrollment) by a member of the study team to 
assess for any new symptoms or any intercurrent medical events and changes in symptoms 
severity from the previous day. After the 10-day interventional period, participants will  have a 
study visit at Day 30 and Day 90 and will be asked about intercurrent events. 


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All collected AEs will be initially reviewed and evaluated by the site investigators. All AEs will 
be electronically captured into the study database. The site investigators will also make initial 
assessment of severity and causality. Unexpected AEs and SAEs will be submitted to an 
independent Safety Adjudication Committee (SAC) for further evaluation. The SAC will be 
composed by a team of medical monitors, one from each study site and independent of the study 
investigators, who will review unexpected AE /SAE data on a weekly basis during the active 
phase of the study. The SAC chair will meet weekly during the course of the study and be 
chaired by one of the independent SAC members. If a SAC member identifies a pattern of 
unexpected AEs or SAEs that is out of proportion to the current understanding of the natural 
history of the disease, the DSMB will be asked to review unblinded safety data in an ad hoc 
meeting. The DSMB will be appointed by the NIDDK.  
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may 
reasonably be expected to result.” Based on the preceding assessment of risks and potential 
benefits, the risks to participants are reasonable in relation to anticipated benefits. 
3 
OBJECTIVES AND ENDPOINTS 
 
Table 2: Study objectives, endpoints, and justification for endpoints 
 
OBJECTIVES   
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
• To determine the effect of 
nicotinamide riboside (NR) on 
whole blood NAD+ levels in 
hospitalized patients with 
COVID-19 infection and AKI 
during the 10-day intervention 
period; 
• To evaluate the safety of NR 
in patients with COVID-19 
infection and AKI during the 
10-day intervention period. 
• The primary endpoint is the 
rate of change in whole 
blood NAD+ level over the 
10 day period from 
baseline to day 10. 
• Safety of NR in 
hospitalized patients with 
COVID-19 and AKI 
(defined as the occurrence 
of at least one serious 
adverse event of grade 3 or 
higher or the occurrence of 
thrombocytopenia defned 
as >25% decline in blood 
platelet count from 
baseline.   
• Recent clinical data indicate 
a reduction of blood NAD+ 
level in AKI patients and an 
increase in NAD+ in 48 hrs 
with NR treatment;   
• The safety of NR in 
COVID-19 patients is not 
known 
Secondary 
• To determine the effect of 
NR on changes in AUC 
• The rate of change in  AUC 
serum creatinine 
benchmarked to baseline; 
• The recovery of AKI, as 
assessed by AUC serum 


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serum creatinine from 
baseline during the 10-day 
intervention;  
• To determine the effect of 
NR on serum AUC, dialysis, 
and death with an ordinal 
categorical outcome with 
four categories (labeled 1, 2, 
3, 4), defined as, in order 
from least to most severe 
disease, 1. Serum creatinine 
AUC < median, 2. Serum 
creatinine AUC ≥ median, 3. 
Dialysis, 4. Death; 
• To evaluate the effect of NR 
on on MAKE (composite 
criteria defined as 
development or progression 
of chronic kidney disease), 
the initiation of long-term 
dialysis, or death from any 
cause) at 30d and 90d post 
randomization. 
• To determine the effect of 
NR on kidney function 
defined by eGFR and 
proteinuria at 30d and 90d 
post randomization. 
• An ordinal categorical 
outcome with four 
categories (labeled 1, 2, 3, 
4), defined as, in order 
from least to most severe 
disease, 1. Serum 
creatinine AUC in the first 
tertile, 2. Serum creatinine 
AUC in the second tertile, 
3. Serum creatinine AUC 
in the third tertile, 4. Death; 
• Time to first occurrence of 
MAKE defined as 
doubling of serum 
creatinine, the initiation of 
long-term dialysis, or 
death from any cause at 30 
day and 90 day post 
randomization; 
• Kidney function defined 
by estimated glomerular 
filtration rate (eGFR) and 
proteinuria at 30d and 90d 
post randomization. 
creatinine during the 10 
days of intervention and 
benchmarked to baseline, 
has been linked to reduced 
progression of chronic 
kidney disease (CKD). 
• The ordinal categories 
address the hierarchy of 
increase in severity as has 
been used in recent 
COVID-19 studies as per 
the World Health 
Organization clinical 
progression scale [57, 58]  
• AKI may progress to CKD 
which is associated with 
need for dialysis and 
increased mortality. 
 
 
Exploratory 
• To determine the 
relationship of whole 
blood NAD+ levels with 
AUC creatinine and 
surrogate markers of AKI 
such as kidney injury 
molecule-1 (KIM-1) and 
neutrophil gelatinase-
associated lipocalin 
(NGAL); 
• Correlations between   
whole blood NAD+, AUC 
serum creatinine, and 
surrogate markers of AKI 
such KIM1 and NGAL; 
 
• AUC of serum creatinine is 
a direct assessment of the 
duration and severity of 
AKI; KIM-1 and NGAL are 
promising surrogate urinary 
biomarkers of AKI 
however, their clinical 
utility in COVID-19 patients 
with AKI is not known; 
 
 
 
 


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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
The overall study design is depicted in Figure 1. 
 
                                                                                           No AKI within 10 days      
 
 
                                                                    
                                                                   Meets KDIGO AKI stage    
 
                                                                                     
 
 
10 days from adm to meet AKI Stage I-III                         Intervention Period 1-10 days D30    D90       
                                                                                                   In-hospital Rx (study days)    
 
 
                                                                                                                       In-hospital Rx & early D/C <SD10 
                                                                                                                                    Daily home fingerstick blood Cr until D10 
                                                                                                                                    Serum Cr on D10  
  
Figure 1. Study flow – screening and enrollment  
 
 
• Phase 2 Study 
• This is a prospective, pilot, double-blind, placebo-controlled, multicenter, clinical 
interventional trial 
• Intervention: 2 arms – study drug (Nicotinamide riboside, NR) and placebo for 10 days  
• Two follow up visits: at day 30 and day 90 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The NIRVANA Protocol describes a trial design to provide pilot data on the potential efficacy of 
nicotinamide riboside (NR) for the treatment of incident AKI or AKI severity in patients with 
COVID-19 infection admitted to the hospital while receiving available or usual standard of care. 
 
AKI in patients with SARS-CoV-2 is being increasingly recognized as a major risk factor of 
morbidity and mortality. The incidence of patients with AKI ranged between 22% to 46% in 
independent analyses of inpatients with SARS-CoV-2 in NYC [24]. Recently, data from the 
Northwell Health System, NYC reported that 90% of COVID-19 patients on mechanical 
ventilation developed AKI [23]. The Mount Sinai Health System [24], also from NYC, 
documented a 3 times higher incidence of Stage 3 AKI vs Stages 1 or 2. In addition to these 
COVID-19 hospital admission 
without AKI 
Monitor daily serum creatinine 
(Scr)  
Screening 
Randomize 
NR 
Placebo 
Follow-
up Period 
Expected 
scenario 
Participants with 
early discharge <10 
study days 
Exclude 


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extremely high morbidity indices for AKI, data from a single center in Wuhan, China reported a 
mortality hazard ratio of 4.7 in Stage 3 AKI patients [59]. Similar findings were found by Mount 
Sinai with a 52% mortality rate in patients with AKI, compared to mortality of only 9% in those 
without AKI admitted to the ICU. Surprisingly, 44% of SARS- COVID-19 patients with AKI did 
not fully recover kidney function by the time of discharge from the hospital [24]. Recent data 
suggest that mortality is lower in hospitalized patients with COVID-19 [25]. Therefore, strategies 
to identify and treat patients with impending AKI will be of major value to reduce mortality, 
hospital length of stay, hospital costs and potential progression to CKD. 
 
To date, no standard treatment is available for SARS-CoV-2 infection. Since “cytokine storm” is 
considered a primary contributing factor to AKI and disease severity in patients with COVID-19 
[28, 29], convective-based clearance may be a useful modality for removal of large-sized 
cytokines [60, 61]. However, this invasive approach may not be feasible as initial treatment for 
all COVID-19 patients at the time of hospital admission. Patients with severe COVID-19 
infection often present with high levels of cytokines in the plasma, such as IL-6 [62, 63]. Clinical 
trials using anti-IL6 receptor (Sarilumab and Tocilizumab) are underway in hospitalized patients 
with COVID-19 [64]. Human recombinant soluble ACE2 (hrsACE2) has been touted as a 
competitive interceptor of SARS-CoV-2 by preventing binding of the viral particle to host 
tissues [65]. Although tolerable, the efficacy of hrsACE2 to prevent AKI is unknown [66, 67].  
Treatment to inhibit viral replication with Remdesivir may reduce hospital stay but does not 
confer any benefit in reducing AKI incidence in COVID-19 patients compared to placebo [68]. 
Another approach is to focus on the cellular target of the virus. Cyclosporine, an 
immunosuppressor, has the potential to suppress the CD147-cyclophilin axis targeting ACE2. 
However, due to the potential high-risk of cyclosporine to cause AKI, it’s use in AKI would be 
difficult to manage [69].  
 
It is likely that the overall burden of AKI in COVID-19 is underestimated due to the fact that 
serum creatinine values at admission might not reflect true pre-admission baseline kidney 
function and pre-admission serum creatinine values might not be readily available. A key 
challenge for breakthrough treatments will be to establish paradigms for implementing precision 
medicine to prevent and mitigate progression of AKI in newly admitted patients with COVID-
19. There are no known treatments for AKI including AKI due to COVID-19. The current 
proposal will address several major unmet needs by assessing a novel therapeutic approach for 
AKI with NR  in patients admitted with COVID-19. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
NR (500 mg orally twice a day) or placebo will be administered for a period of 10 days. NR or 
matching placebo will be given via nasogastric tube in those participants who are intubated or 
felt to be at aspiration risk. [70] NR is more orally bioavailable than nicotinamide or niacin [38]. 
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obesity, diabetes, CKD and hypertension. One study [38] with healthy volunteers that 
administered NR in escalating dose regimen for 9 days reported that following the Day 9 dose, 
blood NR concentration peaked (Cmax) at t = 3 hours. The study did not evaluate PK after initial 
dose [38]. The NR dosing interval in the proposed study derives from the average steady-state 
blood concentration based on the area under the blood concentration-time curve over the 12-hour 
dosing interval [38]. In a 90-day toxicology study, the lowest observed adverse effect level 
(LOAEL) for NR was 1000 mg/kg/day [8].  
 
Nicotinamide riboside is a dietary supplement, which is commercially available and designated 
as a “Generally Recognized as Safe” by the Food and Drug Administration (FDA) at oral doses 
of up to 1000mg (four 250 mg capsules) daily for adults [17]. The dietary supplement NR has 
been demonstrated to be well-tolerated with mild, if any side effects reported. There are several 
clinical trials currently underway employing variable dosages, including 1000 mg/day proposed 
in the current protocol, for numerous different conditions, both biomedical and behavioral [71]. 
The dose of 500 mg bid for 10 days was chosen as 1000 mg/d was found to give peak NAD+ 
levels in blood at 7 and14 days after starting oral administration of NR [8] with no further 
increase up to 56 days of treatment. The frequency of adverse effects in symptoms, vital signs or 
routine lab tests (chemistries and complete blood counts) in the 1000 mg/d of NR (group) was 
not different from the placebo group. Plasma and urine levels of the NAD+ metabolites were 
found to increase significantly in participants given the dose of 1000 mg/d of NR [8]. 
 
4.4 
END OF STUDY DEFINITION 
 
The study intervention period is for 10 days with follow-up visits at Day 30 and Day 90. 
 
5 
STUDY POPULATION 
  
5.1 
INCLUSION CRITERIA 
 
Inclusion and Exclusion Criteria must be confirmed by a clinician listed on the delegation log. If 
there is any uncertainty, the site principal investigator will make the decision on whether a 
potential participant is eligible for study enrollment. 
 
In order to be eligible to participate in this study, an individual must meet all of the following 
inclusion criteria: 
1. Provision of signed and dated informed consent form from a participant or legally 
authorized representative (LAR); 
2. Male or female, >18 years old; 
3. Admitted to hospital with a laboratory diagnosis of COVID-19 infection and COVID-19 
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Improving Global Outcomes (KDIGO) guidelines during the first 10 days following 
admission (Table 3); 
4. Willing to adhere to the study intervention regimen; 
 
Rationale: Persistent AKI Stage 1 will be defined as absence of recovery from the AKI stage 
within 24 hrs after receiving standard of care  management by the primary provider team. The 
NIRVANA study team will monitor serum creatinine daily and participants with sustained AKI 
will proceed to randomization. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Hypersensitivity to nicotinamide riboside (NR); 
2. Pregnant or lactating women confirmed with positive laboratory pregnancy tests as 
per local requirements; 
3. eGFR <15 mL/min/1.73 m2 as per the Chronic Kidney Disease Epidemiology 
Collaboration equation at admission lab;  
4. Maintenance renal replacement therapy or initiation of renal replacement therapy 
before randomization 
5. Currently on NR or nicotinamide or vitamin B3 (niacin) supplementation 
(multivitamins are allowed); 
6. Concomitant cirrhosis of liver or acute liver failure; 
7. Any medical history or condition that might, in the opinion of the attending 
physician, put the participant at significant risk if he/she were to participate in the 
trial; 
8. Individuals with kidney transplant; 
9. Individuals with blood platelet count <100,000/microL; 
 
Rationale: The exclusion criteria are primarily designed for patient safety. In addition, these 
exclusion criteria address some uncertainties in the COVID-19 severity and effects of 
concomitant medications on disease progression. For example, the incidence of AKI in kidney 
transplant recipients with COVID-19 is not well studied [73]. Moreover, kidney transplant 
recipients are on maintenance immunosuppressive therapy with deleterious effects on infection 
Table 3: Staging of AKI by the Kidney Disease: Improving Global Outcomes [72]  
AKI Stage 
Serum Creatinine 
Urine output 
1 
1.5 – 1.9 x baseline  
<0.5 mL/kg/h for 6-12 h 
2 
2.0 – 2.9 x baseline 
<0.5 mL/kg/h for ≥12 h 
3 
3.0 times baseline OR increase in serum 
creatinine ≥4.0 x baseline OR initiation of 
renal replacement therapy 
<0.3 mL/kg/h for ≥24 h OR 
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outcomes. An optimal management of immunosuppressive agents in this patient group with 
COVID-19 is not clear [74]. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not-applicable. 
 
5.4 
SCREEN FAILURES 
 
Pre-Screening 
The site investigator or delegate will pre-screen hospitalized patients with laboratory confirmed 
COVID-19 (a positive laboratory test for SARS-CoV-2) for eligibility. After a COVID-19 
patient is admitted to the hospital with a positive laboratory diagnosis of COVID-19, the study 
team will be notified by the COVID Admitting Team. In addition, the study team will identify 
eligible participants from the hospital COVID-19 database which is periodically updated every 6 
to 8 hours.   
 
Screening – Assessment of Eligibility and Exclusion Tracking 
Eligibility screening will be performed by the study team, under IRB-approved HIPAA waiver, 
using the EHR. Certain screening visit laboratory assessments will be performed to determine 
eligibility after obtaining consent – blood draw for serum creatinine (if no routine value available 
within 24 hours prior to consenting) and pregnancy test for women with childbearing potential.    
 
For participants who appear to meet inclusion criteria during screening, an electronic case report 
form will be completed to determine eligibility and track exclusions. All potential participants 
for which EHR screening is performed will be entered in a de-identified manner on the site 
screening log. At the time of entry into the screening database the participants will be assigned a 
screening number. The screening log will be maintained in the study REDCap database and will 
capture inclusion and exclusion criteria leading to a determination of “eligible” or “ineligible”. 
Additionally, the screening log will cover the period between screening and enrollment. As such, 
the screening log will also document the reason(s) “eligible” potential participants were not 
enrolled. The screening log will not contain identifiable health information.  
 
The complete eligibility determination process may be suspended prior to complete screening 
procedures at any time if an exclusion criterion is identified by the study team. Only the reason 
for ineligibility will be collected on screen failures. For women with child-bearing potential, 
screening failure will be determined by pregnancy test performed after obtaining consent. 
Participants who are found to be ineligible will be told the reason for ineligibility and de-
identified variables will be retained including month and year when participant was evaluated for 
study, age, sex, ethnicity, and reason(s) why the participant was excluded. Participants who fail 
screening will receive standard management for COVID-19 and comorbidities. Participants are 


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eligible to enter this study only once during the accrual duration. Screen failed participants will 
not be allowed to re-screen.  
 
A participant already enrolled in an observational study or an open-label randomized clinical 
trial (RCT) would be eligible to participate in the NIRVANA study, provided eligibility criteria 
are met. With respect to double-blind RCT, the steering committee will determine trial by trial if 
a participant is eligible to enroll in the NIRVANA study.  
 
If a participant appears to meet all eligibility criteria, the site investigator or delegate will 
approach the treating clinician to ask permission to approach the participant or LAR to confirm 
eligibility, discuss potential study recruitment, and proceed with informed consent. 
 
Process of Obtaining Informed Consent (also see section 10.1.1.2) 
Informed consent will be obtained from the participant or LARy. In most instances, bringing a 
paper consent form and pen to the bedside of a participant with known COVID-19 and then 
taking these out of the room would violate infection control principles and policies. Given the 
infectious risk from COVID-19 and potential shortages of personal protective equipment (PPE), 
there is a moral and practical imperative to minimize face-to-face contact between participants 
and non-clinical personnel. The current pandemic also presents unique challenges to obtaining 
consent from participant’s LAR. To minimize infectious risk, many institutions are not allowing 
visitors to enter the hospital. Furthermore, the LAR is likely to have been exposed to the 
participant and may therefore be under self-quarantine at the time of the informed consent 
discussion. Therefore, in addition to the traditional approach of an in-person consent discussion 
and signed paper informed consent, we will allow use of “no-touch” consent procedures. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants will be recruited from three participating sites: the University of Texas Health San 
Antonio (UTHSA), Icahn School of Medicine at Mount Sinai, New York, NY, and University of 
Washington (UW), Seattle, WA. The single IRB (sIRB) at the Washington University in St. 
Louis (FWA00002284) will serve as the Central IRB for all three participating sites. We will 
recruit and consent eligible participants and will advance them into the Treatment Period. A total 
of 100 participants will be randomized. 
 
Each participating site and the coordinating site (UTHSA) will contribute to recruitment of study 
participants. Recruitment methods will focus primarily on the selection of eligible participants 
via identifying patients admitted to the respective hospitals with a diagnosis of COVID-19. Lead 
investigators at each site are physician scientists who will have direct access to eligible 
participants. For efficient recruitment, each site will employ the following approaches. After a 
COVID-19 patient is admitted to the hospital with a new positive laboratory diagnosis of 
COVID-19, the study team members will be notified by the COVID-19 Admitting Team. All 


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three participating sites also maintain a COVID-19 database which is updated every 6-8 hours 
and a designated study member will review the COVID-19 database twice a day. Each study 
team will have access to the respective hospital COVID-19 admission logs and EHR enabling 
them to review several eligibility criteria. The study investigators or clinical coordinators will 
approach the potentially eligible participants or LAR (when appropriate) and inform them of the 
study protocol. All participants will provide written consent for participation in the study. Sites 
have the ability to use one of the FDA approved options for obtaining written signature during a 
pandemic, based on their institutional requirements. 
 
 
During consenting process, each participant will receive clear and detailed information about the 
NIRVANA study with an emphasis on risks, benefits, and alternative to enrollment. Participants 
will be given opportunities and time to learn about ongoing clinical trials for COVID-19 and 
their eligibility to enroll in another competing study. Voluntary participation will be discussed 
and participants will be allowed to withdraw from the current study at any time point after 
providing consent.  
 
At present, all COVID-19 clinical trials in all three participating institutions are reviewed by a 
COVID-19 clinical trials committee or a COVID-19 task force. As stated, the committee or task 
force reviews all new studies prior to approval. In addition, the group evaluates current resources 
and standard of care when determining whether a study can proceed once approved. 
The anticipated duration of the study recruitment period is approximately 15 months. The 
proposed study intervention is 10 days. At least 80% adherence with study intervention is 
expected because of short (10-day) intervention with minimal burden for study participants. NR 
is a safe nutritional supplement and poses only a few side effects which are mild in nature. It is 
likely, however, that 15% of enrolled participants may withdraw from the current study and 
enroll to another COVID-19 trial. We expect an additional attrition rate of 5% during the follow-
up period due to extended isolation, travel restrictions, or relocation. Statistical methods will be 
based on the Intent-to-Treat Principle that every randomized subject will be assumed treated as 
randomized and all randomized patients will be included in the analysis regardless of 
noncompliance, protocol violations or withdrawals. 
 
The data coordinating center (DCC) at UTHSA will email weekly recruitment reports showing 
study-wide weekly and cumulative enrollment in baseline and randomization. The reports will 
also include each site’s current baseline goal, achievement of baseline goal, randomization goal, 
and achievement of randomization goal. Clinical site investigators will meet weekly with their 
study teams to discuss progress on weekly goals, identify barriers and problems, and revise 
recruitment plans as necessary. The investigators at three participating sites will meet by 
conference call at regular scheduled intervals to review each site’s recruitment progress, share 
problems and successes, and revise recruitment plans as necessary. 
 


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The enrollment will be tracked and paused after 50 participants until the DSMB reviews primary 
outcome data from all 50 participants; a decision to continue enrollment will be made by the 
NIDDK after reviewing DSMB recommendations while the investigators remain blinded. 
 
Participant retention is paramount to the success of this study. The following approaches will be 
included to minimize loss of data and to maximize the retention especially for the follow-up 
visits: participants will be reminded about the upcoming visits at least a week before; asking a 
participant for the name and contact number of a family member or friend who can be contacted 
to reach the participant; and use of email contact (with care to maintain confidential medical 
information over nonsecure email). As COVID-19 infection results in prolonged isolation 
periods, the study team will be trained in compassionate and emotionally positive interactions 
with participants via virtual visits. If a participant is unable to attend clinic visit for any logistical 
issues, they will be offered a phone or video call to collect vital status followed by a home visit. 
The home visit will be limited to blood and urine collections with all safety precautions in place. 
Each site has an existing post-COVID care program composed of clinicians, social workers, and 
researchers. The study site will coordinate with the post-COVID care program to enhance 
retention of our participants for the duration of this study. For any missing visit/contact or 
missing data, the reason for the missing visit/contact and/or data will be recorded in the REDCap 
case report form (eCRF). 
 
Replacement of Participants: 
Randomized participants who are randomized but do not receive study intervention (NR or 
placebo) may be replaced to maintain the stipulated cohort sizes. This would include participants 
who are randomized and then withdrew consent before receipt of the intervention. Participants 
who are discontinued from further dosing or follow-up procedures or withdraw their informed 
consent to all follow-up study procedures may be replaced, if deemed necessary by site 
investigator, to ensure that data are collected from a sufficient number of participants. The SAC 
will be notified within 48 hours if a participant permanently discontinues study drug or 
withdraws consent to all follow-up visit procedures. A determination whether to replace the 
subject will be made jointly between the site investigator and SAC. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
   
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Baseline Visit (Day 1) 
After obtaining consent, baseline visit procedures will be performed as listed in Table 1 
(Schedules of Activities in Section 1.3). Participants will be randomized after abstracting the 
following data from the EHR: sociodemographic, contact information, medical/surgical history, 


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comorbidities, and routine medications on admission, standard of care at hospital, home 
medications, all concomitant medicines including dietary or nutritional supplements and over-
the-counter medications, vitals and physical examinations, routine laboratory test results.  
 
Randomization will be accomplished through the use of an online randomization service. 
Participants will be randomly allocated to 1:1 ratio to receive either nicotinamide riboside (NR) 
or placebo. Only the study statisticians (Drs Michalek and Zelnick) and the local hospital 
Research Pharmacists will have access to the randomized assignment for the purpose of tracking 
randomization and study drug dispensing, respectively. Study investigators and study 
participants will be blinded to the intervention assignments. Neither the statisticians nor the 
pharmacist will have direct contact with the study participants. 
 
Eligible study participants enter intervention phase after consenting to the study protocol: 
• Nicotinamide riboside (NR, Niagen🄬) or placebo will be administered orally (or via 
nasogastric tube) 500 mg twice a day for 10 days during hospitalization or prescribed 
for at home administration if discharged before 10 days from the hospital. 
• Placebo capsule manufactured by ChromaDex to match NR or Niagen🄬 
 
TREATMENT PERIOD  
All measures related to study treatment visits are harmonized to standard of care to minimize 
care interruption and disruption to hospital staff workflow. Most of the treatment procedures are 
standard of care or routine procedures for COVID-19 participants in an acute care setting. These 
data will be obtained from the EHR. If any treatment procedure is not available through the 
EHR, the study team will obtain these data from the primary care team or directly from the 
participant. Where multiple results are present in the EHR, they will all be recorded in the study 
database so that all relevant values are captured. A summary of the trial’s schedule of event is 
included in Table 1 (Section 1.3). 
 
Treatment Visits 1 to 10 (Day 1 to Day 10) for participants with hospital duration of at 
least 10 days 
Participants will be assessed daily while hospitalized during the intervention period. The 
following clinical and laboratory data will be collected daily from the EHR during the Visits 1 to 
10 while hospitalized: 
1. Review of current medications and treatment  
2. Adverse events 
3. Vital Signs, including temperature, pulse rate, respiratory rate, and systolic and diastolic 
blood pressure  
4. Study drug administration and accountability  
5. Evaluation of APACHE-II (Acute physiology and chronic health evaluation II) 
6. Assessment of fluid intake, if applicable 


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7. Assessment of urine output, if applicable 
8. Respiratory parameters  
9. Ascertainment of endpoint assessment (serum creatinine and urine volume), mortality, 
intensive care unit (ICU) transfer rate, and length of hospital stay 
10. First morning void urine collection (optional and if indicated by primary care team) 
11. Blood collection 
 
The list of daily laboratory tests is provided in Table 4.  
 
Treatment Visits 1 to 10 (Day 1 to Day 10) for participants with hospital duration of <10 
days 
During each daily virtual phone visit, following information will be collected from each 
participant and/or family caregivers: 
1. Review of current medications and treatment 
2. Any new health issues or changes from previous day 
3. Vital Signs, including temperature, pulse rate, respiratory rate, and systolic and diastolic 
blood pressure (if available) 
4. Respiratory parameters (if available)  
5. Study drug administration and accountability (virtual review of compliance log) 
6. Endpoint assessment (fingerstick creatinine using StatSensor Xpress®) 
7. Ascertainment of mortality or hospitalization  
 
Each day participants will collect first morning void urine which will be picked up daily until 
Day 9 by the courier service (FedEx same day delivery service) for delivery to the hospital 
laboratory. Urine specimens will be aliquoted and stored at the hospital laboratory by the 
hospital staff and will be picked up by the study team for storage in the COVID designated 
biorepository.   
 
To monitor clinical measures necessary for primary outcome, a phlebotomist and a study team 
member will visit participant’s home for the day 10 collection of blood with safety precautions in 
place including necessary PPE. At this home visit, study staff will collect the POC device and 
urine specimen from the participant.  Both blood and urine specimens will be delivered to the 
hospital laboratory by research staff. The biosamples will be aliquoted and stored at the hospital 
laboratory by the hospital staff. The research aliquots will then be picked up by the study team 
for storage in the COVID designated biorepository.   
 
FOLLOW-UP PERIOD:  
There are two follow-up visits.  
 
 


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Follow-up Visits 11 and 12 (Day 30 ± 3 and Day 90 ±3) 
The Day 30 ± 3 and Day 90 ± 3 follow-up visits will be performed at the outpatient clinic. 
However, restrictions due to local infection control measures may limit some participants from 
leaving their residences and returning to the clinic for the follow-up visit. In that circumstance 
follow-up by phone visit will be conducted in conjunction with review of medical records to 
complete the applicable procedures listed below. A phlebotomist will visit the participant at 
home to collect blood and urine if participant cannot or is unwilling to come to the clinic. For 
participants who are allowed and willing to come to clinic, the following assessments will be 
performed at the clinic: 
1. Review of current medications and treatment  
2. Vital Signs, including temperature, pulse rate, respiratory rate, and systolic and diastolic 
blood pressure 
3. Physical examination 
4. Endpoint assessment 
5. Adverse events – collection of health status based on participants reported and review of 
EHR 
6. Ascertainment of mortality or hospitalization 
7. First morning void or random urine collection 
8. Blood collection 
6.1.2 DOSING AND ADMINISTRATION 
 
Participants, randomized to the study drug nicotinamide riboside (NR) group, will receive a total 
daily dose of 1000 mg (four 250 mg capsules) NR administered orally or via nasogastric tube as 
500 mg (2 capsules) every 12 hours for up to 10 days during hospitalization.  
 
Participants, randomized to the placebo group, will receive matching placebo, two capsules 
orally every 12 hours for up to 10 days during hospitalization. 
 
Participants with hospital stay of <10 days will be provided with study drug in a pill box for the 
remaining days to maximize compliance at the time of discharge. Verbal and oral instructions 
will be provided for oral intake of study drug every 12h and daily virtual visits will record timing 
of administrations. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
   
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
NR and matching placebo will be obtained from ChromaDex, Irvine, CA. NR is manufactured in 
a Good Manufacturing Practice (GMP)-compliant facility according to ISO/IEC 18025:2005 
standards. 


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For all study drugs (NR and placebo), a system of numbering in accordance with all 
requirements of Good Clinical Practice (GCP) will be used, ensuring that each dose of study 
drug can be traced back to the respective batch of the ingredients. Lists linking all numbering 
levels will be maintained by the PI. A complete record of batch numbers and expiry dates of all 
study treatment as well as the labels will be maintained in the study file.  
 
Following randomization of a participant, a computer-generated system will generate 
randomization number, medication numbers, and treatment code. During the hospital stay the 
hospital nursing staff will administer drug to a participant as prescribed: 2 capsules of each 250 
mg orally every 12 hours and document the administration in compliance log. The local hospital 
research pharmacist will prepare study drug for nasogastric tube administration as per guidelines 
from ChromaDex.  
 
Participants with hospital stay of <10 days will be provided with study drug in a pill box at the 
time of discharge to maximize compliance for the remaining days. These participants will 
receive clear verbal and written instructions on administering of and compliance with study drug.   
 
All expired and unused products will be returned to supplier ChromaDex for destruction. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
NR is supplied as capsule white in color and each capsule contains active ingredient 
nicotinamide riboside chloride 250 mg. Placebo capsules will be identical in appearance (size, 
shape, color).  The study drug will be labeled as required by law: Caution: New Drug. Limited 
by Federal Law to Investigational Use. 
 
Preparation of NR or matching placebo for administration via nasogastric tubing will be prepared 
daily, as needed, in an aqueous suspension in 100 ml of water and will be made by each local 
hospital research pharmacist. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
All study drugs will be stored at the respective site hospital Research Pharmacy and will follow 
GCP and GMP requirements. Study drugs will be inaccessible to unauthorized personnel. Both 
NR and placebo are stable at room temperature. Storage conditions (minimum and maximum 
temperatures) and a complete record of batch numbers and expiry dates will be maintained in the 
study file.  
 
Participants discharged before completing 10-day in-hospital intervention will store study drug at 
home in a cool dark place at temperature below 25⸰C preferably in a refrigerator. 
 


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6.2.4 PREPARATION 
 
If participants require nasogastric tube administration, NR will be available in a powder form 
and the NR and placebo will be prepared by pharmacist so that both solutions are not visually 
distinguishable. 
 
Both NR and placebo will be available in capsule form for oral administration. NR or matching 
placebo will be administered via nasogastric tube to those participants who are intubated or felt 
to be at aspiration risk. Hospital research pharmacist will prepare the nasogastric preparation for 
both NR and matching placebo. The pharmacist will weigh out and prepare the bulk NR or 
matching placebo powder in purified water immediately before administration. Powder NR 
yields slight yellowish-brown color when dissolved in water. To mask this, pharmacist will 
dissolve brown sugar in water. For example, to match 1 gram of Niagen in 50 mLs of purified 
water, placebo will be prepared by dissolving ~75 mgs of brown sugar in 50 mLs of purified 
water for administration via NG tube.   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Eligible participants who provide voluntary consent will advance to randomization. In order to 
minimize bias, the set inclusion and exclusion criteria offer broader participation from a wider 
range of participants who may be eligible in three geographically diverse study centers. The set 
of inclusion and exclusion criteria do not compromise the scientific integrity.   
 
The study drug (NR or placebo) packaging and labeling will be designed to maintain the blinding 
of the investigator’s team and the participants. The study drug allocation will remain blinded to 
the study participants and study investigators according to standard operating procedures. The 
randomization and blinding procedures will be described in a corresponding manual of operation 
(MOP).  
 
If participants require nasogastric tube administration, NR will be available in a powder form 
and the NR and placebo will be prepared by pharmacist so that both solutions are not visually 
distinguishable. Using a dark opaque sterile draping the participant will not visually perceive the 
NG administration of study drug. The hospital nurse will administer the nasogastric feeding and 
use an opaque sterile draping so participant and study personnel will not visually perceive the 
drug administration of study drug. 
  
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. However, the treatment blind may be broken to provide 
unblinded information to the study site only if specific emergency treatment/course of action 
would be dictated by knowing the treatment status of the participant. In the event of an 
emergency or any finding that requires unblinding, the investigator may break the blind for an 


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individual participant. This will allow the investigator, or other responsible person, to identify 
the study drug if there is an emergency, without jeopardizing the double-blind integrity of the 
remainder of the study. The code can be broken by the investigator, or other responsible person, 
when knowledge of the participant’s treatment is required for the clinical management of the 
participant. If it becomes necessary to know the individual treatment during the study and thus to 
break the code for that participant, the date and reason for unblinding are to be recorded on the 
relevant source document and in the REDCap eCRF. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Each dose of study product will be administered by hospital nursing staff to randomized 
participants while they are in the hospital. Study drug administration will be documented in the 
site medication administration record or research record according to local procedures. A 
compliance log will be maintained in the eCRF containing participant ID, bottle number and 
batch number, route, and date and time of administration. Problems with participant medication 
adherence during hospitalization is not anticipated as the medications will be managed by 
hospital nursing staff. Upon discharge, if this occurs before 10 days of hospitalization, 
participants will receive study drug for the remaining days to complete a total duration of 10 
days. These participants will receive verbal and written instructions on administering study drug. 
Participants will be asked to keep a written log as to when they self-administered study drug with 
dates and times recorded. If a care provider (i.e., family member) is present in the participant’s 
home, daily pill counts will also be performed during the virtual phone or video visit. 
 
6.5 
CONCOMITANT THERAPY 
 
All standardized treatment and management for any comorbidity and concomitant condition are 
permitted. Concomitant therapy with niacin, nicotinamide, NR and their derivatives are prohibited 
during the duration of the study.  
 
6.5.1 RESCUE MEDICINE 
   
To our knowledge there is no specific rescue medicine for NR as there is no known toxicity 
associated with this compound. If a rescue medicine is being considered for a participant for 
underlying COVID-19 or other intercurrent illness, this may be a reason that warrants stopping 
study drug. Any such decision will be made by the primary care team and the participant and the 
study team will be informed. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 


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Discontinuation from study intervention does not mean discontinuation from the study (i.e., 
withdrawal of consent), and remaining study procedures will be completed as indicated by the 
study protocol. Randomized participants who wish to discontinue study medications will be 
encouraged by the site PI and study coordinator to continue with the visits, laboratory tests, and 
data collection so data will be available for intent to treat analysis of the trial. The site PI will 
encourage passive data collection such as hospitalization documentation and EHR for 
participants who no longer want to attend visits. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request, for any 
reason, and without any consequence. Participants should be listed as having withdrawn consent 
only when they no longer wish to participate in the study and no longer authorize the 
investigators to make efforts to continue to obtain data. A participant has a right to withdraw 
from the current study and enroll in a different research study at any time point. However, 
participants will remain in the current study and all data will be collected as per the Schedule of 
Activities (section 1.3), Table 1 unless participants withdraw consent.      
 
The study investigators have the right to discontinue the study drug at any time, which may be 
due but not limited to the following reasons:  
• For an individual participant, a suspected drug-related event of hypersensitivity Grade 2 or 
higher; 
• The investigator believes that for safety (e.g., SAE) or tolerability reasons it is essential for 
the participant to stop treatment; 
• The investigator formally unblinds the participant’s treatment allocation for safety reasons; 
• The participant requires renal replacement therapy or dialysis of any type (Note: The 
requirement for dialysis is the only endpoint for which treatment with double-blind study 
drug should be discontinued; 
• The participant takes prohibited NR supplements (multivitamins are allowed); 
• Newly reported results of parallel clinical studies and/or animal studies indicating toxicity, 
teratogenicity, carcinogenicity or reproduction toxicity of NR at similar doses administered 
in this study; 
 
Participants who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments unless consent is withdrawn from further study 
participation, or the participant is lost to follow-up.  
 
In the event of a study drug discontinuation due to safety and tolerability, participants will 
continue to receive available and/or standard management for COVID-19 and comorbidities as 


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clinically indicated. Participants who discontinue study drug will continue subsequent study visit 
procedures (including biosample collections) to assess safety and worsening or progression of 
any health issues that might be attributable or plausibly related to study drug. As the study is an 
intent to treat analysis, all participant data will be obtained and processed in the same manner 
regardless of study drug discontinuation for any reason. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
REDCap eCRF. Withdrawal of consent prior to receipt of study drug will constitute a screen-
failure and will be recorded. Participants who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced. Participants who sign the 
informed consent form, and are randomized and receive the study intervention, and subsequently 
withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
 
Data recorded up to the point of withdrawal will be included in the trial analysis, unless consent 
to use data has also been withdrawn. Withdrawal of consent after randomization and 
administration of one or more doses of study drug will lead to discontinuation of study 
interventions but study site will request access to EHR for data related to the trial. 
 
Criteria for Stopping Study Drug 
Administration of the blinded study drug may be stopped temporarily or permanently for  
(1) adverse events, (2) clinical deterioration, or (3) evidence of an alternative cause to the 
participant’s symptoms. Study intervention will also be discontinued permanently when a 
participant:  
a) receives dialysis treatment for the management of AKI;  
b) develops thrombocytopenia defined as <75,000/microL in blood platelet count; 
c) is found to have abnormal liver function test (AST, ALT, total bilirubin, or 
alkaline phosphatase) >4 times the upper limit of normal without other 
identifiable cause; 
d) is found to have abnormal serum CPK levels >4 times the upper limit of normal 
without other identifiable cause.    
 
If a participant experiences an AE that the patient (or LAR), the treating clinicians, or 
investigators feel merits temporarily or permanently stopping the study drug, the study drug will 
be stopped. The explanation for stopping the study drug will be recorded in the REDCap eCRF, 
and the AE will be recorded and reported according to the AE reporting guidelines. Participants 
will stop study drug, but data collection will continue as usual. 
 
7.3 
LOST TO FOLLOW-UP 
The following actions will be taken if a participant is not able to be contacted or fails to return to 
the clinic for the required follow-up study visits: 


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• The study team will attempt to contact the participant and/or relative(s) in file and to 
reschedule the missed visit as soon as participant is available after the protocol-specific 
time window or perform a remote phone visit at the least. 
• Before a participant is deemed lost to follow-up, a study team member will make every 
effort to regain contact with the participant and/or relative(s) in file (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). 
 
Should the participant continue to be unreachable, EHR will be reviewed to document 
participant’s vital status, and he or she will be considered to have withdrawn from the study with 
a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Given the infectious risk from COVID-19 and potential shortages of PPE, we will minimize 
face-to-face contact between participants and non-clinical staff. Additionally, minimizing 
research activities and conducting the trial in a pragmatic manner will increase the ability to 
complete the trial in the face of strained clinical and research resources during the COVID-19 
pandemic. We will emphasize data that can be collected from the EHR, laboratory values as part 
of routine clinical care, and assessments that can be completed over the telephone as needed.  
 
Medical History 
A complete medical history will be obtained from the EHR at the Screening Visit (Day 0) and 
any changes (i.e., adverse events) from the Baseline visit (Day 1) will be documented at every 
visit thereafter. The information will be recorded on the  REDCap eCRF.  
 
Physical Examination 
A complete physical examination will not be performed if there is a documented physical 
examination by a physician or nurse practitioner provider in the EHR within 24 hours prior to 
consenting. The findings of the examination will be recorded on the eCRF and serve as baseline 
findings. 
 
Vital Signs 
Temperature, heart rate, oxygen saturation, respiratory rate including respiratory parameters, and 
blood pressure will be obtained at the screening visit and during every visit from the EHR. The 
results will be recorded on the REDCap eCRF. 
 
 


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Review of Concomitant Medications 
All concomitant medications and treatments will be captured at the Baseline and all subsequent 
visits in the REDCap eCRF. These data collection will include routine medications on 
admission, inhospital standard of care treatment, concomitant medications for th management of 
comorbidities, any prophylactic medications, dietary or nutritional supplements, and over-the-
counter medications. In addition, EHR will be reviewed on daily basis to update REDCap eCRF 
to capture changes in standard of care and clinical management for COVID-19 in a dynamic 
landscape. Study team will inquire and record any home medications 7 days prior to enrollment. 
At the Screening visit, concomitant medication list will be solicited from the participant or LAR.  
 
For the baseline visit, treatment intervention, and the follow-up visits, the following assessments 
will be completed: 
 
Baseline variable collections: 
• Presence or absence of inclusion and exclusion criteria 
• Date and time of admission 
• Demographics (age, sex, race, and ethnicity) 
• Vitals and respiratory parameters 
• Physical examination 
• Comorbidities 
• Acute signs and symptoms 
• Parameters to assess severity-of-disease using the Acute Physiologic and Chronic Health 
Evaluation (APACHE) II classification, as applicable 
• Current use of home and inhospital medications including over-the-counter   
• Receipt of open label study medication 
• Receipt of invasive procedures 
• Blood and urine collections and analyses (see Table 4) 
• Other procedures as per the Schedule of Events (see Section 1.3 Table 1) 
 
Study intervention period (daily): 
• Date and time of randomization 
• Drug administration and accountability 
• Vitals and respiratory parameters 
• Physical examination 
• Comorbidities 
• Acute signs and symptoms 
• Review of current medications 
• Receipt of invasive procedures 
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• Collect hospital data to complete APACHE-II  
• Blood and urine collections and analyses (see Table 4) 
• Other procedures as per the Schedule of Events (see Section 1.3 Table 1) 
 
Assessments following Hospital Discharge: Early discharge (before completing 10-day 
intervention) and Follow-up visits 
 
Early discharge: Using daily phone call or videoconferencing, following data will be collected 
• Drug accountability 
• Vitals and respiratory parameters 
• Comorbidities 
• Acute symptoms 
• Review current medications 
• Query about adverse events, endpoints, and outcomes 
• Review EHR for additional data, if applicable  
• Fingerstick blood creatinine using the POC device will be performed by the 
participant/care provider until Day 10 (see Table 4) 
• Daily urine collections for biorepository (see Table 4) 
• Blood collection will be done on Day 10 for research laboratory analysis and 
biorepository (see Table 4) 
• Other procedures as per the Schedule of Events (see Section 1.3 Table 1)  
 
Assessments for participants with early hospital discharge  
 
It is reasonable to expect that a percentage of participants may be discharged home prior to 
completing 10-day in hospital intervention. In the event that participants will be discharged prior 
to the 10-day study intervention days of study drug administration, the study drug will be 
provided to participants in a pill box with written and verbal instructions to take twice daily for 
the remaining days to complete a 10-day course. To monitor compliance, at the time of discharge 
each participant will receive study drug administration and accountability log with instructions.  
 
In addition, to monitor pattern of fingerstick creatinine, each participant will be provided with a 
StatSensor Xpress®, a home fingerstick point of care (POC) device for fingerstick creatinine 
measurement. The device is similar to a glucose meter that utilizes a test strip and a small drop of 
blood from finger stick. Participant and accompanying family member will receive a 
demonstration on how to use this device at the time of discharge along with lancets, alcohol 
swabs, test strips, and safe disposal biohazard waste containers. Using all safety measures, the 
study team will use the POC device using participant’s fingerstick blood. The POC device 
generated fingerstick creatinine value will be documented and compared with the discharge day 
routine serum creatinine value. Participants will use POC fingerstick creatinine device daily for 


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the duration of the 10-day intervention period. Participants will receive daily virtual visit from 
the study staff to collect health status, provide study drug reminder and compliance, and collect 
POC device result. There will be a home visit at Day 10 to collect urine and blood in compliance 
with all local and applicable COVID-19 safety measures. 
 
Follow up visits: At each follow-up visit (Day 30 and Day 90), the following assessments may 
occur at clinic or at home or by phone or videoconferencing and procedures will vary: 
• Review of current medications  
• Comorbidities 
• Record vital signs and physical examination 
• Collect data on adverse events, endpoints, and outcomes 
• Collect blood and urine for research laboratory analyses and biorepository (see Table 4) 
• Other procedures as per the Schedule of Events (see Section 1.3 Table 1) 
 
Biospecimens Collections and Measurements 
 
Primary and secondary endpoints from routine daily laboratory tests and clinical care: 
 
Daily serum creatinine: Blood will be collected daily for the measurement of serum creatinine 
and documented for the study starting Day 1 and up to 10 days of hospitalization for participants 
who remain hospitalized or via StatSensor Xpress® for creatinine and outpatient serum creatinine 
measurement for participants who will be discharged prior to the 10-day intervention period. 
There will be a serum creatinine measured on the 10th day for discharged participants, in addition 
to the StatSensor Xpress® fingerstick creatinine measurement. AUC will be computed 
cumulatively across days for each patient. 
 
Daily urine output: Daily urine output will be reported as part of routine clinical care and 
documented for the study starting Day 1 and up to 10 days of hospitalization. Daily urine outputs 
will not be obtained for participants who will be discharged prior to 10-day intervention period. 
 
Onset of dialysis: Timing of onset of dialysis will be reported as part of routine clinical care and 
documented for the study starting Day 1 and up to 10 days of hospitalization. 
 
Research Laboratory Biospecimens Collections for future Biomarkers Analysis:  
Blood and urine will be collected at Visit 1 and then every visit thereafter for secondary or sub-
study analyses. Baseline (Day 1) blood and urine collections will be performed before 
participants receive first study drug dosing and after obtaining consent. There will be additional 
blood and urine collections on Day 1 at hour 3 and hour 6 after first drug administration for 
pharmacokinetics and analyses of biomarkers. Day 1 to Day 10 blood and urine collections will 
coincide with routine collection by the hospital staff. Hospital laboratory will aliquot and store 


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the specimens and they will be picked up by the study team for storage in a COVID-19  
designated biorepository. Each day, participants will collect first morning void urine into a 
provided container which will be kept refrigerated and picked up daily (until Day 9) by the 
courier service for delivery to the hospital laboratory. At Day 10, the study team will visit the 
participant at home to collect blood and first morning void urine and will deliver to the hospital 
laboratory. Both blood and urine biospecimens will be aliquoted and stored at the hospital 
laboratory by the hospital staff and will be picked up by the study team for storage in the 
COVID-19 designated biorepository at UTHSA. The list of research laboratory tests is provided 
in Table 4. 
 
Blood and urine collections on Day 30 ± 3 and Day 90 ± 3 will take place when participants 
return to clinic or when the study team visits participants at home for follow-up visits. 
Collection, handling, and processing of all biospecimens will be performed in Biosafety 
Laboratory (BSL) 2 environment as per current US Centers for Disease Control and Prevention 
(CDC) guidance. Blood and urine biospecimens for analysis of biomarkers will be shipped to 
UTHSA and stored in a COVID-19 designated biorepository.   
 
All blood and urine biospecimens will be tracked in the REDCap study database. Biosamples 
will be reconciled with the study schedule of events to assure that all expected biosamples are 
accounted for. Study biosamples in the UTHSA COVID-19 designated biorepository will retain 
association with the clinical data. 
 
All assessments will be detailed in the MOP. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Assuring participant safety is an essential component of this protocol. NR is considered GRAS 
(Generally Recognized as Safe) as filed for designation to FDA. Use of NR for the prevention 
and or treatment of AKI in COVID-19 positive participants, however, raises unique safety 
considerations. This protocol addresses these considerations through: 
• Exclusion criteria designed to prevent potential overdose effects by excluding participants 
with concomitant intakes of niacin, nicotinamide, and NR; 
• Daily assessment of participants health status;  
• Systematic collection of safety outcomes; 
• Structured reporting of adverse events; 
• Appointment of independent safety adjudication committee (SAC) 
 
Study procedures and evaluations to be done as part of the study to monitor safety and support 
the understanding of the study intervention’s safety. For all visits starting from baseline until the 
last follow-up visits, the following assessments will be completed:  


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• Physical examination: A physical examination at the baseline visit or a record of routine 
physical examination performed within 24 hours prior to consenting, and at Day 30, and Day 
90 follow-up visits.  
• During the 10-day intervention period, participant’s health status will be obtained on a daily 
basis from the participant and from EHR. Health status of participants will be collected by 
the study team at Day 30, and Day 90 follow-up visits. Participants will be specifically asked 
for any new symptoms on a daily basis.  
• The safety clinical laboratory parameters will be performed at each visit while hospitalized. 
Any laboratory tests performed as part of routine clinical care (Clinical Laboratory Tests) 
within the specified visit window will be used for safety laboratory testing (see Table 4). 
 
Research laboratory tests: 
Blood for the first whole blood NAD+ level will be drawn within 6 hours prior to the first study 
drug dosing (i.e., baseline NAD+ level, Day 1). Whole blood NAD+ level will be measured daily 
for a total of 10 days while hospitalized starting at the baseline.  
 
Safety laboratory from routine daily laboratory tests: 
Safety laboratory will be performed at Visit 1 and then every visit thereafter for hospitalized 
participants. Clinical laboratory tests performed as part of routine clinical care in the 24 hours 
prior to first study drug dose will be accepted for the baseline (Day 1) safety laboratory tests. 
Any clinical laboratory tests (see Table 4) performed as part of routine clinical care within the 
specified visit can be used for safety laboratory testing within the period of hospitalization up to 
10 days prior to starting the study drug.  
 
Rationale for specific safety laboratory tests: 
Several case studies reported that COVID-19 patients may present with mild symptoms such as 
muscle weakness with elevated CPK and laboratory confirmation of rhabdomyolysis [75-77]. 
Although, the incidence of rhabdomyolysis in COVID-19 is not known, several case reports 
indicate an association between rhabdomyolysis and AKI in COVID-19 patients [78-80]. One 
study reported elevated levels of CPK in about 14% of patients [21], suggesting involvement of 
muscle injury.  
 
NR has been evaluated on the development of aging-induced non-alcoholic fatty liver disease in 
mice [81]. It was found that AST (aspartate transaminase) level was significantly reduced by NR 
supplementation while the alanine transaminase (ALT) level decreased without significance 
compared to baseline [81]. One human study demonstrated that NR significantly reduced AST 
level at day 56 from baseline [8]. It is likely that COVID-19 patients will be receiving different 
medications for comorbidities and as per the FDA guidance [82], liver function tests will be 
performed as listed in the Table 4. 
 


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Table 4: Blood and urine tests for research laboratory, safety, and repository  
 
Research laboratory tests 
Safety laboratory tests 
Repository 
Daily during Study Day 1 to Study Day 10  
Blood (daily): 
1. Whole blood NAD+  
2. Serum creatinine 
(performed if 
routine test is 
missed or not 
available) 
 
Urine (daily):  
1. Urinalysis  
2. Urine creatinine  
3. UACR and UPCR 
4. Urine glucose 
5. Lactate 
6. Urine phosphate 
7. Urine NAD+ 
metabolome 
 
Blood:  
1. CPK on day 5  
2. Liver function tests on day 5 
3. Daily CBC and platelets 
(performed if routine test is 
missed or not available) 
 
Blood: 
• Future biomarkers  
• Genetic analysis 
 
Urine: 
• Future biomarkers 
 
Note: additional collections at 
hour 3 and hour 6 post-
randomization study drug for 
PK analysis 
Day 30 and Day 90 
Blood:  
1. Serum creatinine 
2. Whole blood NAD+ 
3. Serum electrolytes 
(Na, Cl, K) 
4. Bicarbonate 
5. Calcium and 
phosphate 
6. Blood glucose 
7. CBC with platelets  
 
Urine:  
1. Urinalysis  
2. Urine creatinine  
3. UACR and UPCR 
4. Urine glucose 
5. Lactate 
6. Urine phosphate 
7. Urine NAD+ 
metabolome 
 
 
Blood: 
• Future biomarkers  
• Genetic analysis 
 
Urine: 
• Future biomarkers 
 
 
 


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Due to limited direct interactions with the participants, safety assessments will be performed by 
collection of EHR data, participant interviews, vital sign measurements, physical examination, 
and laboratory tests, including complete blood count and comprehensive metabolic panel, and 
diagnostic tests or procedures. Participants’ reported symptoms or complaints recorded in the 
medical record will be reviewed and recorded in the appropriate eCRF. In addition, information 
will be solicited from the participants and designated staff physicians to supplement accurate and 
complete safety assessment.  
 
Each participating investigator will have primary responsibility for the safety of the individual 
participants under his or her care. The investigators will determine daily if any adverse events 
occur during the period from enrollment through study intervention and will determine if such 
adverse events are reportable. Thereafter, adverse events will not be required to be reported 
unless the investigator feels the adverse event was related to the study drug or study procedures. 
 
The site investigator will (i) provide a verbatim term (a diagnosis where possible) for detected 
and reportable AE, (ii) each AE will also be described in terms of duration (start and stop date), 
severity, association with the study product, action(s) taken, and outcome, (iii) classify and 
assign a grade to each detected and reportable adverse event using the CTCAE v. 5.0 
classification system, and (iv) rate the likelihood that the event was related to the study drug. 
 
A team of medical monitors (Safety Adjudication Committee, SAC), composed of three 
clinicians with expertise in infectious disease or acute care management, one from each study 
site, independent of the study investigators will review the medical charts for unexpected AE 
/SAE data weekly during the study intervention period. The senior SAC member will serve as 
SAC Chair. The SAC will confirm the verbatim term (a diagnosis where possible) for detected 
and reportable adverse event with knowledge of the study site physician’s rating and then 
classify and assign a grade to each detected and reportable adverse event using the CTCAE v. 5.0 
classification system. Disagreements between the study site investigator and the SAC member 
will be adjudicated weekly on a call facilitated by the SAC Chair.  
 
All AEs will be recorded on the AE eCRF. Verbatim terms for AEs will be coded to the current 
version of the MedDRA coding dictionary at the DCC. Verbatim terms will be coded at the 
Lower Level Term (LLT) where possible and to the Preferred Term (PT) otherwise. Accurate 
mapping to CTCAE will be confirmed during the coding review process. AEs and SAEs will be 
aggregated and reported for the DSMB at the PT level. If the SAC identifies an unexpected SAE, 
sIRB and FDA expedited reporting procedures will be followed and the DSMB will be notified.  
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
   
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 


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Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, (which may cause worsening of a pre-existing medical condition), 
whether or not it is considered intervention-related [FDA (21 CFR 312.32 (a))].  
 
Any medical condition that is present at the time participant provided consent to the protocol will 
be considered as baseline and not reported as an AE. However, if the severity of any pre-existing 
medical condition increases after consenting, it will be recorded as an AE. 
 
Given the nature of severity and unpredictable clinical course and outcomes of the underlying 
illness, participants will have many symptoms and abnormalities in health or vital status and 
laboratory findings. All Grade 3 and 4 AEs will be captured as AEs in this trial. These grades are 
according to the CTCAE (Common Terminology Criteria for Adverse Events, Version 5.0, 
November 27, 2017. U.S. Department of Health and Human Services, National Institutes of 
Health). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An SAE is defined as “An AE or suspected adverse reaction is considered serious if, in the view 
of either the investigator or the sponsor, it results in any of the following outcomes: 
 
• A life-threatening AE; 
• New hospitalization or prolongation of existing hospitalization; 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, 
• Death, 
• Any other event requiring medical or surgical treatment to prevent one of the outcomes 
above 
 
All SAEs, as with any AE, will be assessed for severity and relationship to study intervention. 
All SAEs will be recorded on the appropriate SAE eCRF. All SAEs will be followed through 
resolution or stabilization by a licensed study physician (for IND studies, a physician listed on 
the Form FDA 1572 as the site PI or Sub-Investigator). 
 
In this protocol, other safety events will be defined as follows: 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both 
unexpected (not consistent with risks outlined in the study protocol), serious, and meets the 
definition of a suspected adverse reaction. A Serious Unexpected Serious Adverse Reactions 
(SUSAR) is any SAE where a causal relationship with the study product NR is at least 
reasonably possible but has not been documented in currently available published reports or data. 
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cause (for example, COVID-19 itself or some other pre-existing conditions or comorbidities 
preceding randomization), the timing of the event with respect to study treatment and the 
response to withdrawal of the study treatment. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 
In the protocol, the following guidelines will be used to describe severity of adverse events:  
• Mild (Grade 1): Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• Moderate (Grade 2):  Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Severe (Grade 3):  Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. Of note, the term “severe” does not necessarily equate to 
“serious”. 
• Severe (Grade 4): Events that are potentially life threatening. 
• Death (Grade 5) 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
Study investigators will grade the strength of the relationship of an adverse event to study drug 
or study procedures as follows:  
• Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the participant’s 
clinical state or other therapies; and c) Evaluation of the participants’ clinical state 
indicates to the investigator that the experience is definitely related to study procedures. 
• Probably or Possibly Related: The event should be assessed following the same criteria 
for “Definitely Associated”. If in the investigator’s opinion at least one or more of the 
criteria are not present, then “probably” or “possibly” associated should be selected. 
• Probably Not Related: The event occurred while the participant was on the study but can 
reasonably be explained by the known characteristics of the participant’s clinical state or 
other therapies. 
• Definitely Not Related: The event is definitely produced by the participant’s clinical state 
or by other modes of therapy administered to the participant. 
• Uncertain Relationship: The event does not meet any of the criteria previously outlined. 
 
 
 


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8.3.3.3 EXPECTEDNESS  
 
The study investigators will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention 
and hospital course. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The study investigators will assess and record all events with start dates occurring any time after 
informed consent is obtained until Day 90 – the last visit. The study investigator will review 
EHR daily to collect and assess all AEs (including SAEs) from the time participants provided 
consent to the study until Day 10  and again during Day 30 and Day 90 follow-up visits 
regardless of its relationship to study drug. At each visit, the investigator will inquire about the 
occurrence of any new and the prognosis of already documented AE/SAEs since the last visit. 
All AEs will be captured in detail and followed to satisfactory resolution or stabilization, until 
the investigator deems the event chronic or not clinically significant and until the participant is 
considered to be stable. The participants will receive standard of care for the events. Site 
investigators will consult with treating physician to monitor the event progression. Study 
investigators will also assess if there is a reasonable possibility that the study drug or procedure 
caused the event. Investigators will also consider if the event is explained by the participant’s 
underlying medical conditions, anticipated clinical course, previous medical conditions, and 
concomitant medications. 
 
Routine and safety laboratory values from the respective hospital laboratories will be reported by 
each site investigator to the SAC as soon as the results are available to the study database. 
Participants will receive standard of care for the event and followed to satisfactory resolution or 
stabilization, The DCC will review laboratory results for completeness. Any abnormal laboratory 
test results (clinical chemistry, hematology, or urinalysis) or other safety assessment (e.g., CPK), 
including those that worsen from the baseline, felt to be clinically significant in the medical and 
scientific judgement of the investigator, will be recorded as AEs. The SAC will review AEs 
weekly and SAEs on a daily basis and any events that the clinical centers categorize as requiring 
treatment discontinuation for safety reasons. 
  
The following laboratory results will be flagged as expected study AEs in this trial: 
• Thrombocytopenia: Platelet count >25% reduction from the baseline; 
• Liver function test abnormalities: AST, ALT, total bilirubin, alkaline phosphatase > 4 
times the upper limit of normal; 
• Creatinine phosphokinase (CPK): > 4 times upper limit of normal; 
 
 


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The following symptoms will be flagged as expected study AEs in this trial: 
• Bruising 
• Bleeding 
• Severe diarrhea 
• Severe nausea 
• Flushing 
• Hives 
• Heartburn. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
Information on all AEs will be recorded on the appropriate eCRF. All related and relevant signs, 
symptoms, and results of diagnostic procedures performed because of an AE will be grouped 
together and recorded as a single diagnosis. AEs and SAEs related to COVID-19 outcomes or 
expected AEs with NR or study procedures will not be reported to sIRB and not adjudicated by 
SAC. Any baseline medical condition and laboratory results that are present at the time that the 
participant consented to the study but do not deteriorate will not be reported as an AE. However, 
if the medical condition deteriorates and any laboratory results become abnormal at any time 
during the study, these will be reported as AEs. Unexpected AEs and their relatedness to study 
drug or procedure will be reported. 
Aggregate analyses of adverse events observed from the NIRAVA trial will detail new 
information regarding the investigational product NR (i.e. new side effects or increasing 
frequency of side effects) will be reported to SAC on weekly basis. Significant non-clinical 
findings will also be reported to SAC if they are suggestive of increased risk for study patricians. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study investigators will report all unexpected serious adverse events and their relatedness to 
study drug or procedure to the DCC within 24 hours of awareness or initial assessment. The 
DCC will then notify the sIRB and NIDDK. These reporting will follow the criteria outlined in 
21 CFR 312.32(c). The SAC will be blinded to the randomization code and will determine if the 
event is unexpected and define the relationship to NR based on section 8.3.3.2. An adverse event 
is considered “unexpected” if it is not listed in the study protocol (21 CFR 312.32(a)). If a 
determination is made that a serious adverse event which is not exempt and has a reasonable 
possibility of having been caused by a study procedure or the study drug, it will be classified as a 
suspected adverse reaction. If the suspected adverse reaction is unexpected, it will be classified 
as a SUSAR. 
 
The DCC will report all unexpected deaths, serious and treatment related adverse events, and 
SUSARs to the DSMB and NIDDK within 7 working days after receipt of the report from a 


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clinical site. A written report will be sent to the DSMB, FDA, local IRB, and the sIRB within 15 
calendar days. The DSMB will also review all reported adverse events and clinical outcomes 
during scheduled DSMB meetings. The DCC will distribute the written summary of the DSMB’s 
periodic review of reported adverse events to the local IRB and sIRB in accordance with NIH 
guidelines (http://grants.nih.gov/grants/guide/notice-files/not99-107.html).  
 
In addition, (1) serious, unexpected suspected adverse reactions, (2) findings 
from other clinical, animal, or in-vitro studies that suggest significant human risk, 
and (3) a clinically important increase in the rate of a serious suspected adverse 
reaction will be reported to all investigators, sIRB, local IRB, the FDA, and the DSMB no later 
than 15 calendar days after determining that the information qualifies for reporting [21 CFR 
312.32(c)(1)]. 
 
Clinical Outcomes that will be Exempt from Serious Adverse Event Reporting 
 
Pre-specified laboratory safety endpoints will be designated to evaluate possible laboratory 
abnormalities that might be seen with NR based on previous studies with NR (i.e., <10% 
reduction in hemoglobin and >25% reduction in platelet counts from baseline). 
 
Study-specific outcomes of COVID-19 infection and critical illness will be systematically 
collected for all participants in both study group and are exempt from adverse event reporting 
unless the investigator considers the event to be Definitely or Possibly Related (or of an 
Uncertain Relationship – section 8.3.3.2) to the study drug or study procedures. Examples of 
study-specific clinical outcomes include: 
• Death not related to the study procedures 
• Cardiovascular events 
o Receipt of vasopressors 
o Atrial or ventricular arrhythmia 
o Cardiac arrest 
o Respiratory events  
o Hypoxemia requiring supplemental oxygen 
o Acute respiratory distress syndrome 
o Receipt of mechanical ventilation 
o Receipt of extra-corporeal membrane oxygenation 
• Gastrointestinal events 
o Elevation of aspartate aminotransferase or alanine aminotransferase 
o Acute pancreatitis 
o Severe diarrhea  
• Hematological events 
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o Thrombocytopenia 
 
Note: A study-specific clinical outcome may also qualify as a reportable adverse event. 
 
8.3.7 EVENT ADJUDICATION PROCESS  
 
Unexpected AEs and SAEs occurring from the time the informed consent signed through the 
Day 90 visit will be documented, recorded, and reported. Upon entry into REDCap eCRF, a 
notification will be generated to the independent site SAC member that unexpected AEs are 
ready for review. SAC members will be expected to review unexpected AEs within one week of 
notification. (Unexpected SAEs will have different language in the text and will require same 
day review by the SAC member.) SAC review will be separate from the expedited SAE reporting 
process and incomplete SAC assessment will in no way delay expedited SAE reporting.  
 
Adjudicators will be blinded to the study treatment actually given to each patient and will use 
subject matter knowledge to render opinions regarding, for example, relatedness to treatment.  
The database will be configured so that certain baseline data will be viewable, including age, 
race, gender, BMI, diabetic status (diabetic, not diabetic), and current smoking status (smoker, 
not a smoker). 
 
The REDCap adjudication module will compare the site investigator’s AE grade and relatedness 
with that of the independent site SAC Physician. Where they agree, no further action will be 
needed and the AE will be submitted to statistician for reports to DSMB. Where the independent 
site SAC Physician disagrees with site investigator’s AE grade and relatedness, the site 
investigator will be notified to review the report. Where the site investigator and independent 
SAC member agree, AEs that are not also other reportable events will be considered complete. 
AEs meeting the definition of other reportable events such as SAEs will trigger those processes 
with automated system notifications. Where the site investigator and independent SAC member 
disagree, the AE will be labeled as needing adjudications. Weekly adjudication meetings will be 
held if there are unexpected AEs needing adjudication. The study investigator will work 
collaboratively with the SAC on adjudication calls to make a final determination if an adverse 
event or reaction has a reasonable possibility of having been caused by the study drug or 
procedure as outlined in 21 CFR 312.32(a)(1). The protocol for handling of unexpected AEs and 
SAEs which are not uniformly adjudicated will be established.  Any change to an adjudicated AE 
by a site investigator or SAC member will trigger review by the safety desk for impact on the 
adjudication. Where changes impact the adjudication decision, the event will be triggered for re-
adjudication by the safety desk. The Adjudication process will be tracked and managed by DCC 
staff filling the Safety Desk role. AEs will be summarized for the DSMB as described in the 
DSMB plan. 
 
 


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8.3.8 REPORTING EVENTS TO PARTICIPANTS  
 
Information regarding this clinical trial will be available on ClinicalTrials.gov. The study 
investigators will notify SAC, sIRB, DSMB, and FDA if new safety information regarding the 
nutritional supplement becomes available from ChromaDex and any published literature during 
the implementation of the study within three calendar days of obtaining the information. Study 
investigators will follow DSMB recommendation regarding how quickly the information is to be 
disseminated to participants. 
 
8.3.9 EVENTS OF SPECIAL INTEREST  
 
Not-applicable. 
 
8.3.10 REPORTING OF PREGNANCY  
 
Not-applicable. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
An Unanticipated Problem (UP) is any event, incident, experience, or outcome that meets the 
following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• Related to participation in the research (meaning there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
All unanticipated problems will be collected and defined as per the Unanticipated Problems 
Involving Risks & Adverse Events Guidance (2007) – HHS regulations at 46.103(b)(5). 
 
To satisfy the requirement for prompt reporting, UP will be reported 
using the following timeline: 


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• UPs that are SAEs will be reported to the sIRB, local IRB, and the SAC within 24 hours of 
the investigator becoming aware of the event per the SAE reporting process described above. 
• Any other UP will be reported to the sIRB, local IRB, and the SAC within 3 days of the 
investigator becoming aware of the problem. 
 
As per the FDA guidelines [21 CFR 312.32(c)(2)], any unexpected fatal or life-threatening 
suspected adverse reactions to study active agent will be reported to the sIRB, local IRB, FDA, 
and DSMB no later than 7 calendar days after initial receipt of the information. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not-applicable. 
 
9 
STATISTICAL CONSIDERATIONS  
  
9.1 
STATISTICAL HYPOTHESES 
 
The primary analysis will perform a two-sided α = 0.05 test of the null hypothesis of no 
difference in mean whole blood NAD+ level changes from the baseline and day 10 between the 
two arms, versus the alternative that participants randomized to the intervention arm have a 
different mean change than those randomized to placebo..  
 
9.2 
SAMPLE SIZE DETERMINATION 
 
We evaluated using a marker of efficacy for NR with the whole blood NAD+ based on two 
recent publications [8, 15]. In a study of healthy overweight subjects 40-60 years of age, Conze 
et al. [8] found a 21 µg/ml mean NAD+ difference between patients randomized to 1000 mg 
NIAGEN versus those randomized to placebo at day 7 (NIAGEN 42 µg/ml, Placebo 21 µg/ml) 
with a standard deviation of 10 µg/ml and approximately equal baseline means (NIAGEN 21 
µg/ml, Placebo 24 µg/ml).  Simic et al. [15] assessed a combination of NR with pterostilbene 
(NRPT) vs placebo in hospitalized patients of age ≥ 18 years with AKI and found an 18% 
increase in whole blood NAD+ within 48h post treatment in the NRPT group, and a 50% 
reduction from baseline in the placebo group with AKI. With reference to Conze et al. [8] al., 
this study will achieve >99.9% power for testing Ho:RNR = RPlacebo versus Ho: RNR≠RPlacebo with 
alpha=0.05, autocorrelation ()=0.5, and n=40 per arm where RNR and RPlacebo are the rates of 
change from baseline to day 10 in the NR and Placebo arms, if the effects observed in this study 
are the same as those observed by Conze et al. with regard to NAD+.  In this setting the effect 
size is 2.1 [=(42-21)/10] and the minimally detectable effect size is 0.63. 
 
 
 


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9.3 
POPULATIONS FOR ANALYSES 
 
We will summarize the number of participants that are screened, enrolled, and randomized, 
including reasons for exclusion at each step. In accordance with the intention-to-treat principle, 
the primary analytic population will consist of all randomized participants, who will be evaluated 
according to their randomly assigned treatment arm and regardless of whether they adhere to 
study protocol or complete the study. We will further analyze the safety population of all 
randomized participants who receive any amount of study drug, analyzed according to the study 
drug received rather than the assigned intervention.. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
In general, continuously distributed data will be summarized with the sample size, mean, 
standard deviation, median, minimum, and maximum. Categorical and binary data will be 
summarized with frequencies and percentages. Raw data storage, documentation, and security 
will be effectively served with the REDCap platform. Participants will be randomized to 
treatments in randomly permuted blocks of size 2 and 4 stratified by clinical site.   
 
The number of participants screened, the number of screen failures by reason, and the number 
eligible for randomization, the number randomized, and, by treatment (Placebo, NR), the number 
withdrawing from the study for any reason, lost to follow-up by reason, unable to receive at least 
one dose and replaced, and the number completing the study per protocol will be tabulated and 
summarized with a CONSORT Diagram. We will also describe adherence to treatment over the 
course of the study, overall and by treatment arm.   
 
Randomized controlled trials often suffer from two major complications, i.e., noncompliance and 
missing outcomes. One potential solution to this problem is a statistical concept called intention-
to-treat (ITT) analysis, to be used in this trial. ITT analysis includes every subject who is 
randomized according to randomized treatment assignment. It ignores noncompliance, protocol 
deviations, withdrawal, and anything that happens after randomization. ITT analysis maintains 
prognostic balance generated from the original random treatment allocation. In ITT analysis, 
estimate of treatment effect is generally conservative [83]. 
 
Missing data can threaten the inferences made about study questions. The study team will make 
every effort to minimize the impact of missing data, including attempting to obtain final 
information on participants even if adherence to study procedures is poor or they do not follow 
the randomized treatment. In cases where missing data is unavoidable, we will use multiple 
imputation using chained equations to impute outcomes and relevant covariates to mitigate the 
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the variability in the imputation procedure [84]. Any data point that appears erroneous or 
inexplicable based on clinical judgement will be investigated by study staff. If data points are 
considered to be outliers then sensitivity analyses will be carried out with and without the 
suspected outlier. Under the missing at random (MAR) assumption the estimates provided by our 
planned repeated measures statistical models using maximum likelihood estimation will be 
asymptotically unbiased [85].  
 
All data will be summarized by treatment and clinical site in all randomized participants.  
Statistical estimates of treatment effects (with 95% confidence intervals, where appropriate), and 
p-values will be tabulated. All statistical tests will be two-sided with a significance level of 5%.  
R and/or SAS will be used throughout. Due to the overall exploratory nature of this study 
corrections for multiple comparisons will not be applied. 
  
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
PRIMARY END POINT: Blood NAD+ level  
 
The null hypothesis to be tested is Ho:RNR=RPlacebo, where RNR and RPlacebo are the rates of change 
from baseline to day 10 in the NR and Placebo arms.  We expect that the rate of change in 
NAD+ from baseline to day10 with NR treatment will be increased relative to Placebo.  Whole 
blood NAD+ will be measured daily in each patient during the first 10 days upon randomization. 
NAD+ level changes from the baseline will be graphically summarized with overlaid line and 
whisker plots of the mean trajectory for each arm with the whiskers being of length equal to one 
standard error of the mean. The significance of treatmement group differences with regard to the 
rate of change of NAD+ will be assessed using the methods of Schluchter et al [86] to address 
informative censoring, due for example to dialysis and death, with a random subject effect to 
account for the correlation among repeated measures within an individual. The model will 
include treatment and day.  The day by treatment interaction will be of interest and will be 
addressed with the coefficient of the day by treatment interaction term to be added to the 
unadjusted model. Adjusted analyses will be carried out with age, race, clinical site, baseline 
serum creatinine, treatment and day included in the model. The unadjusted and adjusted models 
will be summarized with the coefficients, standard errors, 95% confidence intervals and p-
values. A day by treatment interaction term, treatment by day, and treatment by clinical site 
interactions will be considered and reported and described if found significant (p<0.10). We will 
examine potential treatment interactions among subgroups of interest such as age, and sex. 
Consistent with the power calculation (Section 9.2), these models will be used to provide 
treatment group contrasts on the mean rate of change (estimated by the coefficient of day in the 
model, also known as the slope parameter), summarized with the model-based mean rates of 
changs, mean differences in rates of change and 95% confidence intervals and p-values.  
Spaghetti plots and plots of the mean NAD+ trajectories by treatment group, and mean rates of 
change, will be reported. 


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Potential participants who may have severe AKI or advanced CKD will be considered with a 
binary independent variable in the models addressing this condition with corresponding displays 
of the line and whisker plots by treatment group and summary tables of coefficients, standard 
errors and p-values. Interactions between this binary variable and treatment will be of interest 
and will be described. 
 
Capture and tabulation of concomitant medications, dialysis, co-enrollment in another COVID-
19 clinical trial, any new standard of care, pre-existing CKD, and treatments by study arm (NR, 
Placebo) may be used to define other potential adjustments with binary or categorical variables 
to be defined post hoc in exploratory analyses. Such models may motivate extended 
interpretations of any treatment effects found. 
 
PRIMARY END POINT: Safety 
 
All reportable AEs will be listed by Preferred Term by subject, treatment, clinical site, grade, 
relation to treatment, severity, and seriousness. All unanticipated events will be listed by 
treatment and clinical site with a detailed description of each event, incident, experience or 
outcome.  An unblinded statistician will summarize safety data periodically for the DSMB. 
 
AEs will be tabulated by treatment and clinical site, displaying, for each event, the number and 
percentage of participants experiencing at least one Grade 3 or 4 occurrence and he null 
hypothesis to be tested is Ho: pNR=pPlacebo where pNR and pPlacebo are the probabilities of 
experiencing at leat one Grade 3 or Grade 3 event in the NR and Placebo groups.  Ho will be 
tested with Fisher’s Exact test, overall and by clinical site.  Additionally, treatment groups will 
be contrasted on the occurrence at least once of each event with Fisher’s exact test. All statistical 
testing will be two-sided with a significance level of 5%. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
SECONDARY END POINT:  AUC Serum creatinine over 10 days adjusted for baseline 
serum creatinine 
 
We expect that rate of change in AUC serum creatine will be decreased in the NR group relative 
to the Placebo group.  The null hypothesis to be tested is Ho:RNR=RPlacebo, where RNR and RPlacebo 
are the rates of change in serum creatinine from baseline to day 10 in the NR and Placebo arms. 
Serum creatinine will be measured daily in each patient during the first 10 days upon 
randomization. Serum creatinine AUC will be graphically summarized with spaghetti plots and 
overlaid line and whisker plots of the mean trajectory for each arm with the whiskers being of 
length equal to one standard error of the mean.  To address non-ignorable missingness due to 
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censoring, the statistical method will be the same as that specified for NAD+.  Potential 
participants who may have severe AKI or advanced CKD will considered with a binary 
independent variable in the models addressing this condition with corresponding displays of the 
line and whisker plots by treatment group and summary tables of coefficients, standard errors 
and p-values. Interactions between this binary variable and treatment will be of interest and will 
be described. 
 
SECONDARY END POINT: Serum creatinine AUC and ordinal categorical outcome with 
four categories including dialysis and death 
 
Serum creatinine AUC will be computed using the trapezoidal rule within each patient starting 
from randomization to day 10, and will be assigned to Category 1 if AUC < median AUC, to 
Category 2 if AUC ≥ median AUC in those who do not experience dialysis and who do not die 
during the first 10 days of hospitalization. Patients who experience dialysis at any time during 
the 10 day period will be assigned to the Category 3 and those who die during the first 10 days of 
hospitalization will be assigned to Category 4.  The null hypothesis is Ho: OR1=OR2=OR3=1, 
where OR1, OR2, and OR3 are the odds ratios for Categories 1, 2, 3, and 4.  If the proportional 
odds model holds the null hypothsis is Ho:OR=1 where OR is the single odds ratio summarizing 
the treatment effect.  With NR treatment we expect that the odds of Category 1 will be increased, 
the  odds of Category 2, 3, and 4 will be decreased. 
 
The primary analysis will be based on a cumulative logit model for ordinal data of the primary 
outcome with terms for treatment, age, gender, clinical site, and baseline serum creatinine. The 
proportional odds assumption will be tested with a score statistic and empirical logit plots. If the 
proportional odds assumption is violated then the analysis will be conducted under a partial 
proportional odds assumption. Under a partial proportional odds assumption, three odds ratios 
will be estimated; if evidence suggests that the proportional odds assumption holds, a single odds 
ratio will summarize the treatment effect. In either case, the odds ratio estimate(s), 95% 
confidence interval(s), and p-value(s) will be reported. Further study will be indicated if the p-
value for any treatment effect suggesting benefit in the NR arm is less than or equal to 0.05. 
 
SECONDARY END POINT:  Major Adverse Kidney Events (MAKE) 
 
The null hypothesis is Ho:HR=1 where HR is the ratio of the hazard of MAKE with NR 
treatment to the hazard of MAKE with Placebo treatment.  We expect that HR will be less than 
1.  MAKE is defined as Yes if a doubling of serum creatinine (from baseline), the initiation of 
long-term dialysis, or death from any cause is observed, and No otherwise. Treatment arms will 
be compared with regard to the time to the first occurrence of MAKE over the entire duration of 
the study from baseline to 90 days post-randomization with proportional hazard models of time 
to MAKE in terms of treatment without and with adjustment for age, race, clinical site, baseline 


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serum creatine. The coefficients, standard errors and 95% confidence intervals and 
corresponding hazard ratios will be reported without and with adjustment for covariates. The 
proportional hazards assumption will be assessed with Schoenfeld residuals and log survival 
plots. The unadjusted model will be graphically summarized with overlaid Kaplan Meier curves 
and the p-value for the corresponding log rank test. Covariate interactions with treatment will be 
of interest and will be explored.  
 
SECONDARY END POINT: Kidney impairment as indicated by eGFR and proteinuria at 
30 and 90 days 
 
The null hypothesis to be tested is Ho: RNR=RPlacebo, where RNR and RPlacebo are the mean rates of 
change of eGFR in patients randomized to NR or to Placebo respectively from baseline to day 30 
and day 90.  We expect the eGFR rate of change to be increased with NR relative to Placebo.  
The same hypothesis will be tested for proteinuria, using log-transformed urinary albumin-to-
creatinine ratio, where we expect the mean proteinuria rate of change to be decreased with NR 
relative to Placebo.   
 
We will quantify kidney dysfunction at 30 days and 90 days post-randomization, measured by 
eGFR calculated by the CKD-EPI (the Chronic Kidney Disease Epidemiology Collaboration) 
equation [87] and the urine protein/creatinine ratio (PCR). To address non-ignorable missingness 
due to dialysis, death, or withdrawal of consent, all of which may be considered as informative 
censoring, the statistical method will be the same as that specified for NAD+. 
 
eGFR will be evaluated untransformed, while urine PCR will be log-transformed to evaluate 
percent change because urine PCR is highly skewed and relative changes in urine PCR are 
proportional to risk of adverse renal and cardiovascular outcomes. We will include time, 
treatment, and interactions of treatment with time as independent variables in a mixed effects 
linear model. We will focus on the coefficient for the interaction of treatment with time as the 
primary measure of treatment effect. We will consider a p-value <0.05 for this interaction term to 
indicate a significant treatment effect. These analyses will be further adjusted for baseline 
characteristics that are prognostic of the outcome, including age, sex, clinical site, and stage of 
AKI at randomization. Adjustment will be accomplished by adding covariates and interactions of 
covariates with time. 
 
9.4.4 SAFETY ANALYSES 
 
Please see section 9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 


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Treatments groups will be summarized overall and by clinical site at baseline with regard to 
demographic characteristics (age, race, ethnicity, and gender), and clinical, laboratory and 
questionnaire measurements of efficacy (Section 8.1). 
 
9.4.6 PLANNED INTERIM ANALYSES  
An O'Brien-Fleming procedure will be used to conduct an interim analysis for safety when 50% 
of the patients complete the study. A statistical basis for stopping the study at the first look will 
be achieved if the test statistic for the primary safety endpoint (the occurrence of at least one 
serious adverse event of grade 3 or higher or the occurrence of thrombocytopenia less than 
50,000 per microliter) indicates harm in the NR arm at p≤0.003. If the test statistic does not reach 
p≤0.003 at the first look then the trial will proceed to the final analysis. The statisticians (Drs. 
Joel Michalek and Leila Zelnick) will inform the principal investigator if the interim analysis 
crosses the boundary in the direction of harm is observed (p≤0.003). A treatment effect will be 
declared harmful at the final analysis if the test statistic indicates harm and p≤0.047. The safety 
data will be summarized at interim analysis. The statisticians will inform the DSMB if there are 
any safety concerns at the interim analysis. Any decision on stopping the study based on safety 
will be made in coordination with NIDDK and the DSMB. 
9.4.7 SUB-GROUP ANALYSES 
 
Not applicable.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable.  
 
9.4.9 EXPLORATORY ANALYSES 
 
EXPLORATORY END POINTS:    
Correlations between whole blood NAD+, AUC serum creatinine, and surrogate markers of 
AKI (such as KIM-1 and NGAL) will be quantified with Pearson or Spearman correlation 
coefficients, 95% confidence intervals and p-values and visualize with scatter plots and 
overlaid least square lines.  Relationships between these variables by treatment group will 
tabulated and summarized graphically with scatter plots and overlaid line specific to each 
treatment.  Principal component analyses may be used.  Data may be log transformed prior to 
analysis and graphics. 
    
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 


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10.1.1 INFORMED CONSENT PROCESS 
  
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
This study will be conducted in conformity with the principles set forth in The Belmont Report: 
Ethical Principles and Guidelines for the Protection of Human Participants of Research (US 
National Commission for the Protection of Human Participants of Biomedical and Behavioral 
Research; April 18, 1979), and the federal policy for the Protection of Human Participants 
codified in 45 CFR Part 46, 21 CFR Part 50 (Protection of Human Participants), and the ICH E6 
(R2). 
 
Each institution engaged in this research will hold an OHRP-approved FWA. sIRB will review 
and approve this protocol, associated informed consent documents, recruitment material, and 
handouts or surveys intended for the participants, prior to the recruitment, screening, and 
enrollment of participants. The sIRB review shall be in accordance with 45 CFR 46 and 21 CFR 
50, 21 CFR 56 (IRBs), and other federal, state, and local regulations and policies, as applicable. 
Local site IRBs may have additional national and local regulations. 
 
Any amendments to the protocol or consent materials will be approved by the DSMB and 
followed by sIRB before they are implemented. sIRB review and approval will occur at least 
annually throughout the duration of the study. The investigator will notify the sIRB of any 
deviations from the protocol and SAEs, as applicable to the sIRB policy. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Consent forms describing in detail about the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to 
starting intervention/administering study intervention. Informed consent is a process that is 
initiated prior to an individual agreeing to participate in a trial and continuing throughout the 
individual’s trial participation. Investigators or designated research staff will obtain a 
participant’s informed consent in accordance with the requirements of 45 CFR 46, 21 CFR 50 
and 21 CFR 56 for FDA-regulated studies, state and local regulations and policy, and ICH E6 
GCP before any study procedures or data collection are performed. All consent forms will 
receive prior approvals from sIRB followed by institutional/hospital IRBs with the 
incorporations of any local guidelines or requirements.  
 
Typically, participants or their LAR receive a concise and focused presentation of key 
information about the clinical trial, verbally and with a written consent form. Participants (or 


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LAR) must sign the ICF prior to starting any study procedures being done specifically for this 
trial. Once signed, a copy of the ICF will be given to the participant or the LAR for their records. 
 
Many of the participants approached for participation in this research protocol will have 
impaired decision-making capacity due to critical illness and will not be able to provide informed 
consent. Accordingly, informed consent will be sought from the participant’s LAR. Regarding 
consent from the LAR, the existing federal research regulations (‘the Common Rule’) states at 
45 CFR 46.116 that “no investigator may involve a human being as a subject in research…unless 
the investigator has obtained the legally effective informed consent of the subject or the subject’s 
legally authorized representative”; and defines at 45 CFR 46 102 (c) a LAR as “an individual or 
judicial or other body authorized under applicable law to consent on behalf of a prospective 
subject to the subject’s participation in the procedures(s) involved in the research.” The Office of 
Human Research Protections (OHRP) defined examples of “applicable law” as being state 
statutes, regulations, case law, or formal opinion of a State Attorney General that addresses the 
issue of surrogate consent to medical procedures. Such “applicable law” could then be 
considered as empowering the LAR to provide consent for participant participation in the 
research. Interpretation of “applicable law” may be state specific and will be addressed by the 
sIRB and local IRB. 
 
Participants for whom consent was initially obtained from a LAR, but who subsequently regain 
decision-making capacity while in the hospital will be approached for consent for continuing 
participation, including continuance of data acquisition. The consent form signed by the LAR 
should reflect that such consent should be obtained. 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved. Due to the unique challenges of COVID-19 
infection and risk to others in close proximity several alternatives have been considered for the 
informed consent procedure. In most instances, bringing a paper consent form and pen to the 
bedside of a participant with known COVID-19 and then taking these out of the room would 
violate infection control principles and policies. Given the infectious risk from COVID-19 and 
potential shortages of PPE, there is a moral and practical imperative to minimize face-to-face 
contact between participants and non-clinical personnel. The current epidemic also presents 
unique challenges to obtaining consent from participant’s LAR. The LAR is likely to have been 
exposed to the participant and may therefore be under self-quarantine at the time of the informed 
consent discussion. Therefore, in addition to the traditional approach of an in-person consent 
discussion and signed paper informed consent, we will allow use of “no-touch” consent 
procedures. 
 


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The first preference will be to use the FDA COVID MyStudies App platform to obtain informed 
consent via iPads or smartphones securely from participants or LAR in accordance with 21 CFR 
50.27(a). Once the participant or representative has signed the form, he or she will receive an 
electronic copy. The study team will then access the signed consent in a secure manner and print 
it or transfer the file electronically.   
 
If this approach is not possible (e.g., not compatible with the existing phone or computer device), 
the next approach will be providing an unsigned consent form to the patient by a hospital staff or 
study team member with appropriate PPE who has entered the room. The study team will arrange 
a telephone call with the participant to review the informed consent document and to obtain 
verbal confirmation by the participant that their questions have been answered, that they would 
like to participate in the trial, and that they have signed and dated the informed consent 
document that is in their possession. The consent form will document the method used for 
communication with the prospective subject and the specific means by which the prospective 
subject communicated agreement to participate in the study. An impartial third party will witness 
the entire consent process and sign the consent document. If a participant is unable to provide 
consent on their own behalf, then the study team will obtain consent from a LAR and verbal 
consent with a witness will be obtained with appropriate documentation as described above. 
Finally, the participant, the hospital staff or study team takes a photograph of the signed 
informed consent document. The study team enters the photograph into the trial records and 
documents the consent process in the source document. If it is not possible to obtain a digital 
image of the signed page, the study team will document that the participant signed and dated the 
ICF, document that an imaging device was not available; and have a witness to the consent 
process. The entire consent process will be documented in the study records..   
 
Attestation of informed consent  
If none of the options outlined above (traditional signature and storage of a paper consent form, 
electronic photographs of a signed consent page, or e-consent) are available, study personnel 
may attest to completion of the informed consent process using the procedures outlined below. 
Importantly, the process of informed consent using this attestation option should not change 
compared with the traditional method of obtaining informed consent for trial participation except 
for the method of documenting the consent process in the research record. Rather than storing a 
paper document with the participant’s signature, a member of the research team and an impartial 
witness will attest to completion of the informed consent process and that the participant signed 
the informed consent document. This option of attestation of informed consent will not be 
available when obtaining consent through an LAR.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
If the study is prematurely terminated or suspended, the site investigator will promptly inform 
study participants, the sIRB, and the FDA and provide the reason(s) for the termination or 


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suspension.  Study participants will be contacted, as applicable, and be informed of changes to 
the study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sIRB, the FDA and the NIDDK. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
and their staff. This confidentiality is extended to cover testing of biological samples in addition 
to the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information 
concerning participants in the study, or the data will be released to any unauthorized third party 
without prior written approval. All research activities will be conducted in as private a setting as 
possible. Participant confidentiality will be maintained when study results are published or 
discussed in conferences. 
 
The representatives of the sIRB, and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study sites will permit access to such records. 
 
All source records including electronic data will be stored in secured systems in accordance with 
institutional policies and federal regulations. The study participant’s contact information will be 
securely stored at each clinical site for internal use during the study. At the end of the study, all 
records will continue to be kept in a secure location for as long a period as dictated by the 
reviewing IRB, institutional policies, or regulatory requirements. All collected data including 
electronic and hard copy source records and hard copies will be securely stored. Hard copy 
records will be stored in a locked cabinet in the principal investigator’s Research Office 
accessible to study coordinator and investigator or other designated research staff. The electronic 
records will be saved and stored in an institutional computing server accessible by designated 
study staff such as study coordinator and investigator using unique username and password.     


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All study data and research specimens that leave the site (including any electronic transmission 
of data) will be identified only by a coded number that is linked to a participant through a code 
key maintained at the clinical site.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be stored and analyzed at the coordinating site principal 
investigator’s laboratory. After the study is completed, the de-identified, archived data will be 
stored on the UTHSA server for the Nephrology Division in a folder specifically for this project, 
for use by study investigators and researchers included in this study. Biosamples will be made 
available to non-study investigators via NIH policy guidelines. 
 
Secondary Human Subject Research is defined as the re-use of identifiable data and/or 
identifiable biospecimens that were collected from the primary study – the NIRVANA study. 
Each specimen will be labeled only with a barcode and a unique tracking number to protect 
participant confidentiality. Secondary research with coded specimens and data may occur; 
however, participant confidentiality will be maintained. 
 
A participant’s decision can be changed at any time by notifying the study doctors in writing. If 
the participant subsequently changes his/her decision, the samples will be destroyed if the 
specimens have already not been used for research or released for a specific research project. 
 
All data collected in this study will follow NIH Data Sharing Polices. Data from this study may 
be used for secondary research. All of the individual participant data collected during the study 
will be made available after de-identification. The investigator may request removal of data on 
individual study participants from NIH data repositories in the event that a research participant 
withdraws or changes his or her consent. However, some data that have already been distributed 
for approved research use cannot be revoked or retrieved. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator/Sponsor 
Kumar Sharma, MD 
University of Texas Health San Antonio-Department of Nephrology 
7703 Floyd Curl Drive, San Antonio, Texas 78229 
210-567-4700                                       sharmak3@uthscsa.edu  
 
The Steering Committee will consist of the PI’s of each of the study sites. 
 
10.1.6 SAFETY OVERSIGHT 
 


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Safety oversight will be under the direction of the DSMB. The SAC will adjudicate all reportable 
AEs (including SAEs) using supporting documents. The unexpected AEs and SAEs will be 
reported to the SAC who will determine if the DSMB will need to evaluate for unblinding. To 
avoid bias, SAC member will be masked to the study arm of a participant. Adjudicators will 
receive training on the adjudication process.  
Once data are submitted for a participant, the database will notify SAC member that data are 
available and require AE review. SAC member will either confirm or refute the initial 
assessment reported by site investigators blinded to the treatment assignment. If discrepancies 
occur between the assessments, the disagreements will be adjudicated on a weekly adjudication 
call with the site investigator and the site SAC member. If disagreement persists, the site 
investigators and the SAC members will formally meet to discuss the event and come to a 
consensus decision. All SAEs will trigger immediate notification to the site investigator, site 
SAC member, DCC staff, and the statistician. 
 
There will not be any formal clinical site monitoring for conduct of the site activities. However, 
institutional IRB and Human Subject Protection Committee or institutional compliance may  
perform auditing according to local procedures to ensure that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
formed and appointed by the NIDDK/NIH. Details of the NIDDK policies regarding DSMBs can 
be found at the following URL https://www.niddk.nih.gov/research-funding/human-subjects-
research/policies-clinical-researchers/data-safety-monitoring-plans.  Members of the DSMB 
will remain independent from the study conduct and free of conflict of interest. The DSMB will 
provide its input to the steering committee and NIDDK, and any relevant safety findings will be 
reported to NIDDK, the FDA and to the sIRB.  
 
10.1.7 CLINICAL MONITORING 
 
There is no clinical site monitoring for this study. However, each site investigator and sub-
investigators will conduct weekly meetings to ensure that the rights and well-being of trial 
participants are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), 
with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). In these weekly meetings, site investigator will review the 
regulatory files, accountability records, eCRFs, ICFs, medical and laboratory reports, training 
records, and protocol and GCP compliance.  
 


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The local IRB may monitor and audit or otherwise supervise the study activities. Institutionally 
provided regulatory auditing by the respective site’s human protection office as well as 
applicable oversight committees may occur after enrollment of the first participant and at least 
once a year until the study is completed. In addition, respective site’s Research and Compliance 
office or equivalent (e.g., Human Research Protection Program) may conduct random or for 
cause audits of the study and report any findings to the respective IRB. These roles and 
responsibilities of the local IRB will be explicit in the authorization agreement with sIRB.  
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
  
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management. 
 
Quality control (QC) procedures will be implemented beginning with the REDCap data entry 
system and data checks for missing, out of range and logically inconsistent data values that will 
be run on the database. The Principal Investigator will be responsible for overseeing data 
management. 
 
All sites will maintain written Standard Operating Procedures (SOPs) covering study activities. 
The site principal investigator will verify that the clinical trial conduct, data generation, and 
biological specimen collection, documentation and recording, storing, and reporting are in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice 
(ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), 
Good Manufacturing Practices (GMP).  
 
All study personnel at three recruiting sites will be trained on study protocol including (i) 
participant screening methods and techniques, (ii) eligibility determination, (iii) consenting 
process, (iv) completion of each study visit procedures, (v) data collection, entry, and reporting, 
(vi) biospecimen collection and processing, and storage via Webinar and PowerPoint slides using 
Zoom or other audiovisual methods for consistency and harmonization. The DCC, in 
collaboration with two other sites, will prepare the MOP to ensure consistency in protocol 
implementation from study activation/inception until closure and data collection across 
participants and study sites. The MOP will be developed by the DCC as soon as protocol is 
finalized. All sites will strictly adhere to the MOP to maintain scientific credibility and provide 
reassurance that participant safety and scientific integrity are closely monitored. The MOP for 
the NIRVANA protocol will contain details of the study’s conduct and operations including (i) 
study’s organization, (ii) operational data definitions, (iii) recruitment, (iv) screening, (v) 
enrollment, (vi) randomization, (vii) follow-up procedures, (viii) data collection methods, data 


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flow, eCRFs, and (ix) guidelines for site-level quality control procedures. The MOP will be 
amended in a timely manner to reflect any amendment to the protocol.  
 
The DCC will determine site activation (shipment of study supplies) based on successful 
completion of training, a signed site agreement, and a successful study activation web-meeting. 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of auditing and inspection by local and regulatory authorities. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. Each local site principal investigator will maintain complete and accurate 
source documentation. All source documents will be completed in an ALCOA (Attributable, 
Legible, Contemporaneous, Original and Accurate) legible manner to ensure accurate 
interpretation of data.   
 
Sites will follow Good Documentation Practices for all study documentation. Each site will 
maintain a local (site) Trial Master File. This is sometimes referred to as site “regulatory 
documents”. The DCC will maintain a TMF for DCC trial documentation originating at the 
DCC. Each site will create and maintain source documents as defined in ICH E6 R2 for each 
participant. 
 
The DCC will draft a formal Data Management Plan that specifies all operations performed on 
data from study data acquisition through database lock when no further changes to data are 
allowed. The majority of the Data Management Plan will be accomplished through a web-based 
Electronic Data Capture (EDC) system for the study developed using REDCap. Sites will be 
trained on use of the study database including screening log completion, data entry, independent 
Source Document Verification for point estimation of the medical record abstraction error rate, 
responding to identified data discrepancies, biosample tracking, CTCAE classification and 
grading, and the SAC event review and adjudication processes. Study-specific procedural 
documentation for these processes will be provided in the MOP.  
 
REDCap Study Database: The REDCap database for the NIRVANA study will be developed 
and maintained by the DCC. Access to the REDCap data system will be granted to individuals 
upon completion of training. Accessing the REDCap study database will require a user account 
with permissions on the study. A user-maintained password will be entered to log into the 
system. All study data will be entered by sites into the REDCap study database. To the extent of 
the REDCap system capabilities, upon entry data quality checks for missing, out of range and 
logically inconsistent values will be run. These checks should be resolved by sites during data 
entry. Because REDCap has limitations with respect to rule-based identification and tracking of 
data discrepancies, comprehensive discrepancy identification and tracking will be performed 
through the Informatics Data Exchange and Acquisition System (IDEAS). Complex checks not 


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possible in REDCap will be accomplished through the IDEAS system. Where noted below, 
workflows will be automated based on data collected in the REDCap database.  Study data will 
be accessible to sites from the REDCap system. 
 
Screening Log: All potential participants for which EHR screening is performed will be entered 
in a de-identified manner on the site screening on REDCap. At the time of entry into the 
screening database the participants will be assigned a screening number. The screening log will 
capture inclusion and exclusion criteria leading to the site determination of “ineligible”. 
Additionally, the screening log will cover the period between screening and enrollment. As such, 
the screening log will also document the reason/s “eligible” potential participants were not 
enrolled. The screening log will not contain dates or other information considered identifiable 
health information. The screening log will contain de-identified data elements that may be used 
to compare enrolled and non-enrolled participants to assess generalizability. 
 
Clinical Data: Clinical data from the EHR (including AEs, concomitant medications, and 
expected adverse reactions data) and clinical laboratory data will be entered into the REDCap 
study database.  
 
Adverse Events and Serious Adverse Events: Reportable AEs will be entered into the 
REDCap study database. Reportable AEs will be entered, classified, and graded according to the 
most current versions of the CTCAE by the site investigator and independent site SAC 
Physician. Adverse events indicated as Serious Adverse Events will result in real-time alerts 
through the REDCap system to support expedited reporting. Entry of reportable Adverse Events 
will trigger notification to the independent SAC physician to initiate the independent review and 
adjudication process as described in section 8.3.7. AEs will be coded at the DCC using the 
MedDRA controlled terminology.  
Biosample Inventory and Tracking: The REDCap study database will include screens at each 
visit for sites to report samples obtained and shipped to the UTHSA COVID-19 Repository. 
Sample tracking will trigger notification to the repository. Samples received will be reconciled 
with REDCap biosample tracking on the day of receipt. Data status reports will flag expected 
and missing sample tracking data. 
 
Data Status Reports: Enrollment data will be entered into REDCap on the day of enrollment. 
Enrollment entry enables tracking and management of participant data and samples and will 
trigger notification to the site and DCC study team. Data entry will be entered every day during 
the 10-day treatment period and within one week of follow-up visits. Late data will be listed on 
an exception report by site and by participant. Similarly, data discrepancies will be resolved 
within a week of firing. Late data discrepancy resolutions will be listed on an exception report by 
site and by patient. Data will be reviewed by the DCC within 24 hours of complete entry. 
 


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The site investigator will be responsible for review of data collection tools and processes, and 
review of data and reports. 
 
 
 
10.1.8.2 STUDY RECORDS RETENTION  
 
Study related records, including the regulatory file, study product accountability records, consent 
forms, participant’s source documents and electronic records should be maintained for a period 
no shorter than 2 years following the completion of the study and may be retained longer per 
institutional policies. Consent forms with specimen retention linked to identifiable specimens 
will be maintained for as long as the specimens remain in identifiable format, and a minimum of 
three years after use of the identifiable specimens in nonexempt human subject research. Local 
institutional and applicable NIH policies will be adhered to and records will be retained 
according to whichever policy dictates a longer period in order to remain compliant with 
retention policies. 
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol.  
 
Major Deviation: Major protocol deviations are a subset of protocol deviations that might 
significantly affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a participants’ rights, safety, or well-being. Examples may include: 
 
 
• Enrolling participants who did not meet eligibility criteria  
• Performing study procedures before obtaining informed consent  
• Failure to obtain and/or document informed consent  
• Failing to follow protocol procedures that specifically relate to the primary safety or 
efficacy endpoints of the study 
 
Minor Deviation: Minor protocol deviations are a subset of protocol deviations that do not have 
a major impact on either the participant’s rights, safety or well-being, or the completeness, 
accuracy and reliability of the study data. Examples may include: 
• Follow up visits occurring outside the protocol required time frame because of the 
participant was not available or other restrictions; 
• Blood samples being obtained at times close to but not precisely at the time points 
specified in the protocol. 
 


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All protocol deviations will be entered on the Protocol Deviation Log in REDCap and submitted 
to the sIRB as well as respective site’s IRB per their policies. All major deviations will be 
promptly submitted to sIRB and local IRB.  Site will also submit all protocol deviations to 
DSMB as per DSMB guidelines. The site investigator is responsible for knowing and adhering to 
the sIRB and DSMB requirements.  
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of 
NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results 
Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and 
results from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be 
made to publish results in peer-reviewed journals.   
 
Following completion of the study, collected data will be analyzed, interpreted, and disseminated 
in the form of abstracts or posters to relevant scientific society meetings and published in 
relevant peer-reviewed journals.  In addition, results will be posted at clinicaltrials.gov. Data 
sharing will conform to NIH policies.  
 
Data from this study may be requested from other researchers with no end date after the 
completion of the primary endpoint by contacting the coordinating site principal investigator. 
Data will be available immediately following publication of study findings, with no end date, 
with data sharing at the discretion of the Sponsor NIH. Publication may occur prior to 
completion of a final clinical study report for the entire trial. 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry (ChromaDex), is critical. Therefore, any actual conflict of interest of 
persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial 
will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest 
will be required to have such conflicts managed in a way that is appropriate to their participation 
in the design and conduct of this trial. 
 
10.2 ADDITIONAL CONSIDERATIONS 
  
 
Not applicable.  
 
 
 


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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Committee 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
  
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Kim SH, Khoury CC, Herzig SJ, Trovato ME, Simon-Tillaux N, Lynch MR, Thadhani RI, 
Clish CB, Khabbaz KR, Rhee EP, Waikar SS, Berg AH, Parikh SM: De novo NAD+ 
biosynthetic impairment in acute kidney injury in humans. Nat Med 2018;24(9):1351-1359 
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[6] Funk JA, Schnellmann RG: Persistent disruption of mitochondrial homeostasis after acute 
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10.1152/ajprenal.00035.2011. 
[7] Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, 
Chonchol M, Seals DR: Chronic nicotinamide riboside supplementation is well-tolerated 
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[8] Conze D, Brenner C, Kruger CL: Safety and Metabolism of Long-term Administration of 
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