Clinical trial NCT04817111
Conditions: Friedreich Ataxia
Sponsor: Metro International Biotech, LLC
Start date: 2021-05-17; Completion date: 2022-05-19
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective is to test the safety and tolerability of short-term therapy with a nicotinamide adenine dinucleotide (NAD+) precursor (MIB-626) in adults with Friedreich's Ataxia (FA) without overt heart failure and with a left ventricular ejection fraction ≥ 40%. A key secondary objective is to test the effects of MIB-626 on cardiac and skeletal muscle bioenergetics.

Detailed description:
The primary focus for this protocol is safety and tolerability. We will systematically assess for adverse events using a safety monitoring uniform report form. We will also use cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS) to measure the Phosphocreatine(PCr)/Adenosine triphosphate (ATP)- γ ratio before and after treatment with MIB-626. In addition, if time permits we will use proton (1H)-MRS to measure skeletal muscle nicotinamide adenine dinucleotide (NAD+) before and after treatment.

Arms: arm 1: MIB-626
Interventions: intervention 1: MIB-626
Intervention descriptions: intervention 1: Two (2) 500 mg Tablets, By Mouth, Daily

Protocol documents:
ICF_000.pdf: 
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Expiration Date: 6/20/2023
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Informed Consent Form and HIPAA Authorization
Study Title: 
A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich’s 
Ataxia
Version Date:  
October 20, 2021  
Consent Name:
Main ICF
Principal Investigator:
Shana E. McCormack, M.D.
Telephone: (215) 590-3174
Emergency Contact:
Shana E. McCormack, M.D.
Telephone: (617) 596-9067
You may be eligible to take part in a research study. This form gives you important 
information about the study. It describes the purpose of this research study, and the risks 
and possible benefits of participating. 
If there is anything in this form you do not understand, please ask questions. Please take 
your time. You do not have to take part in this study if you do not want to. If you take 
part, you can leave the study at any time. 
In the sections that follow, the word “we” means the study doctor and other research 
staff. 
Study Overview
You are being asked to take part in this research study because you have a confirmed 
genetic diagnosis of Friedreich’s Ataxia (FA), but you do not have significant 
cardiovascular disease. 
The purpose of this research study is test the safety and tolerability of short-term therapy 
with a nicotinamide mononucleotide (NMN), a form of Vitamin B3, in adults with FA 
who do not have heart failure.  We will also test the effect of NMN on how the heart 
muscle uses energy. In this form, NMN may also be referred to as the “study drug.” 
In animal models, NAD+ use has shown promise for treatment of cardiac disease. 
Specifically, NR or NMN supplementation improves function in several models of heart 
failure in mice.
NMN has been well tolerated when administered to humans and other drugs in this class 
have demonstrated safety in FA, particularly when used in modest doses, therefore we 
propose to evaluate NAD+ precursor supplementation in FA with a focus on feasibility 
and safety, and obtaining preliminary data on potential effects on cardiac bioenergetics. 
The use of the study drug is considered experimental, as it has not been approved by the 
FDA for any indication. 
If you agree to take part, your participation will last for up to 15 weeks and will involve 
2-4 in person study visits. You will need to take the study drug (NMN) for 14 days (+/- 2 
days). The main study procedures are: 

Receive study drug, NMN 


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
Have 2-4  research visits; 

Have multiple research MRIs;

Have research blood tests, and ECGs
The main risks of this study are from the study drug NMN. These include: GI distress.
There is no direct benefit for participation in the study. 
If there is anything in this form you do not understand, please ask questions. Please take 
your time. You do not have to take part in this study if you do not want to. If you take 
part, you can leave the study at any time. 
Please see below for additional details about the study. 
How many people will take part?
Approximately 10 individuals will participate in this study at The Children's Hospital of 
Philadelphia.  
What is the current standard of treatment for this disease?
Currently, there is no proven treatment for FA. Supportive clinical care is recommended 
for patients, including regular neurological examinations, physical therapy, and routine 
orthopedic care. 
What is involved in the study?
What are the study procedures? 
Some of the procedures in this study will be repeated several times. Tests that are part of 
your regular, routine medical care will continue to be performed. Additional tests may be 
performed if any of your initial test results are not normal. The study involves the 
following tests and procedures. 
Experimental Procedures:
Study Drug (NMN): You will need to take the study drug, in the form of 2 tablets, by 
mouth once a day for 14 (+/- 2) days.
Routine Clinical Trial Procedures:
Medical Record Review: We will review your medical records throughout the study to 
collect information about your medical history, current health, diagnosis, 
treatments, medications, and results of clinical tests.
Medical Interviews/Questionnaires: A member of the study team will take your medical 
history, along with a listing of any medications you are taking. Throughout your 
participation you will be asked to report if you think that anything bad has 
happened as a result of the study. 
In addition, you will complete study questionnaires and surveys- they will be 
related to your overall health and quality of life.
Vital Signs: Routine exams will be conducted at each study visit including measurements 
of blood pressure, heart rate and respiratory rate, etc. 


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Physical Examination: A routine physical exam will be conducted at the baseline and 
follow up visits (i.e., listening to your heart and lungs, evaluating brain and nerve 
functions, etc.) We will also measure vital signs, including measurements of 
blood pressure, heart rate and respiratory rate. 
Anthropometrics: We will measure weight, height, and waist circumference at both the 
baseline visit and follow up visit. 
Blood Draw: Blood samples will be collected to monitor your safety and check levels of 
NMN in your blood while on the study drug, We will draw approximately 16 mL 
(~3 teaspoons) at both the baseline visit and the follow up visit.  
Fasting: You will need to not eat for at least 10 hours before the blood draw at the 
baseline visit and follow up visit. You will be reminded prior to those visits. You 
may have water during the fasting period. 
Pregnancy Test: For Female Participants: If you are pregnant or nursing, you will not be 
allowed to participate in this study. All female participants will be asked to take a 
urine pregnancy test before starting this study and during the study. The results 
will be shared with you. If you are found to be pregnant, you will not be able to 
continue participation in the study. 
Birth Control: For Female Participants: You will need to take safety measures to prevent 
pregnancy (such as not having sexual intercourse, or using a medically accepted 
form of contraception) for the duration of your participation. If you have 
questions about how to avoid pregnancy, talk to your doctor or the researcher and 
they will provide you with information on contraceptive choices. You should 
contact Dr. McCormack at once if you become pregnant during this research 
study.
For Male Participants: You should not father a baby for a minimum of 12 weeks 
after administration of NMN. You need to take safety measures to prevent 
pregnancy (such as not having sexual intercourse or using contraception) for a 
minimum of 12 weeks after administration of NMN. If you have questions about 
how to prevent pregnancy, talk to your doctor or the researcher and they will 
provide you with information on contraceptive choices.
Electrocardiogram (ECG): An ECG is a test that measures the electrical activity of the 
heart. It is used to examine the heart’s rhythm to see if it is steady or irregular. It 
can also help tell how well the heart pumps blood. Several small pads will be 
attached to your chest, shoulders and legs. They are attached to a machine that 
traces your heart activity.
Echocardiogram (Echo) (If Needed): An Echo uses sound waves to create a moving 
picture of your heart. It can find problems with heart function. You will lie on a 
padded table or a bed. A technician will glide a special device called a transducer 
across your chest to take pictures of your heart. A small amount of clear gel will 
be applied to your chest to help the transducer work better. You will need to 
complete an Echo if you have not completed one within the last year.


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Hand Grip Dynamometry: Muscle strength will be measured using a hand-grip strength                
dynamometer. You will squeeze the handle on the device with each hand and the 
strength of the “squeeze” will be measured. The measure will take approximately 
5 minutes to complete and does not involve any radiation
MRI: An MRI scan takes picture of your heart and your leg muscles. MRI uses a 
combination of a large magnet, radio waves and a computer to produce pictures. 
The MRI scan will take about 2 hours.
Visit Schedule
The table below provides a brief description of the purpose and duration of each study 
visit.  The Screening (Visit 0) and Baseline (Visit 1) procedures can be completed on the 
same day.  If Screening and Baseline are combined study procedures will be completed 
once.
Visit
Purpose
Main Procedures
Duration
Visit 0
Screening
Informed Consent, Demographics, Review 
Eligibility, Medical History, Vital Signs, 
Urine Pregnancy Test, ECG, Echo (If 
Needed)
2 hours
Visit 1, Day 1 and 2 
Baseline 
(Start Study 
Drug)
Review/Update Medical History, 
Questionnaires,  Vital Signs, Urine 
Pregnancy Test, Anthropometrics, Physical 
Exam, Blood Tests, ECG, Hand Grip, MRI, 
Dispense Study Drug 
6-8  hours
Visit 2, Day 14 and 
15 (+2)
Follow-Up 
(End Study 
Drug)
Review/Update Medical History, 
Questionnaires, Vital Signs, Urine 
Pregnancy Test, Anthropometrics, Physical 
Exam, Blood Tests, ECG, Hand Grip, MRI, 
Collect Study Drug
6-8  hours
What will be done with my data and specimens during this study?
During the study, we will collect blood and urine samples from you. By agreeing to 
participate in the study, you agree to give these samples to CHOP for research purposes. 
Will I receive any results from the tests done as part of this study?
Results that could be important for your clinical care will be shared with you. We will not 
share other results with you.
What are the risks of this study?
Participating in a research study involves inconveniences and risks. If you have any 
questions about any of the possible risks listed below, you should talk to your study 
doctor or your regular doctor. 
Like all medications, the study drug may cause side effects in some people.  NMN is a 
form of vitamin B3.  Safety data includes known adverse effects from other forms of B3 


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(including niacin, nicotinamide, and nicotinamide riboside) While in this study, you may 
experience the following side effects:
The main risks of the nicotinamide mononucleotide (NMN), are listed below. In addition, 
we have included potential risks that have been described associated with a closely 
related compound, niacin.
Common: 
(between 1 out of 10 and 1 in 
100 participants affected)

GI Distress: Nausea, Heartburn, Diarrhea, 
Constipation, Bloating
Less Common: 
(between 1 in 100 and 1 in 
1,000 people are affected)

Rash, Itching

Vasodilatory Effect (Flushing) (niacin) 

Changes in blood pressure

Muscle Pain/Soreness
Rare: 
(between 1 in 1,000 and 1 in 
10,000 participant affected)

Liver Function Abnormalities or Toxicity

Blurred Vision (niacin) 

Swelling or fluid in the eye (niacin)
While very rare, serious or life threatening reactions known as anaphylaxis can occur 
while taking the study drug. These reactions may include swelling of the throat or other 
body parts, blood pressure drops, difficulty breathing or swallowing, loss of 
consciousness, or death. A study physician will be available to treat any reactions, if one 
should occur during your study visit. 
In general, some side effects, including the risk of an allergic reaction/anaphylaxis, 
may be life-threatening
Some medications may cause unwanted effects when combined with the study drug or 
may make it difficult to tell whether or not the study drug is working. Please tell the study 
doctor about all of the medicines you are taking. This includes prescription and over-the-
counter drugs, supplements (including potassium supplements or salt substitutes), 
homeopathic, alternative, or herbal medicines, and vitamins. You should also contact the 
study doctor before starting a new medicine or stopping or changing any of your current 
medicines. It is important to maintain stable doses of the medications you take. We will 
go over which medicines you are allowed and which you are not allowed to take during 
the study.
Reproductive Risks: 
For female participants, if you are pregnant or nursing, you cannot participate in the 
study due to the study drug and exposure to radiation due to the unknown effects of the 
study drug on the fetus or infant. All female participants, will be given a pregnancy test 
before starting this study and at each study visit (2-3 times) during your participation. 
The results will be shared with you. 
You and your partner will need to practice safe methods (such as abstaining from sexual 
intercourse or using a medically accepted form of contraception) to prevent pregnancy 


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through the duration of the study. If you have questions about preventing pregnancy, the 
study doctor, Dr. Shana McCormack, will be able to discuss your choices and methods. 
Because this drug is experimental there may be other side effects we do not know about 
yet. 
Risks Associated with Study Procedures:
Interviews/Vital Signs:  There are no physical risks, but in-person and telephone 
interviews and vital sign exams may cause temporary discomfort or embarrassment. You 
do not have to answer any questions that cause you to feel uncomfortable. These will be 
performed in private.
Blood Test: Arm pain, bruising, bleeding, blood clot formation, and in rare instances, an 
infection might occur at the site where blood is drawn.  There is also the possibility of 
dizziness or fainting while your blood is drawn.
Fasting: Fasting may cause discomfort and hunger. We will schedule the study 
procedures so as to reduce the amount of fasting time. If you feel unwell fasting before 
the study, you can stop fasting at any time.
Physical Examination: Potential risks include fatigue, feelings of anxiety and frustration,
and discomfort.
Urine Pregnancy Test: Potential risks include feelings of discomfort and anxiety.
ECG: There is a small risk that redness or swelling could develop from the ECG 
electrodes (pads) that will be placed on the skin.
Echo: Echos are very safe. The gel may feel cold when it is first placed. Some people 
with sensitive skin can develop a rash from the gel.
Hand-Grip Dynamometry: The hand-grip dynamometer test may result in mild, 
temporary hand or forearm discomfort. 
MRI: There are no known physical risks associated with MRI scanning. However, MRI 
machines produce loud noises, which may cause discomfort and irritation. We will 
provide you with earplugs or earphones to quiet the noise. You may also feel 
uncomfortable lying inside the magnet due to claustrophobia or inability to lie still. If you 
become anxious, you can tell us and we will remove you from the machine. 
The MRI magnet is always activated and attracts certain metal objects. Any metal object 
on or inside of your body may heat up, move, and/or improperly function within the 
scanning room. Metal objects in the room can fly through the air toward the machine 
(magnet) and hit those in the area. However, there are many safety measures to prevent or 
reduce these risks.


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Are there any benefits to taking part in this study?
There will be no direct benefit by participating in this study. Information from this 
research may help doctors learn more about the use of this study drug in the FA 
population.
Do you need to give your consent in order to participate? 
If you decide to participate in this study, you must sign this form. A copy will be given to 
you to keep as a record. 
What are your responsibilities?
Please consider the study time commitments and responsibilities as a research participant 
when making your decision about participating in this study. You will need to follow the 
study doctor’s instructions, keep all appointments and take the study drug as directed. 
What happens if you decide not to take part in this study? 
Participation in this study is voluntary. You do not have to take part in order to receive 
care at CHOP.
If you decide not to take part or if you change your mind later there will be no penalties 
or loss of any benefits to which you are otherwise entitled. 
Can you stop your participation in the study early?
You can stop being in the study at any time. You do not have to give a reason.
Can the study doctor take you out of the study early?
The study doctor may remove you from the study if:

Your condition worsens.

The study is stopped.

The study drug is no longer available.

You cannot meet all the requirements of the study.

New information suggests taking part in the study may not be in your best 
interests.
What choices do you have other than this study?
There are options for you other than this study including:

Continuing to receive your usual clinical care.

Not participating in this study.

You may discuss other options available to you with your doctor.
What about privacy, authorization for use of Personal Health Information (PHI) and 
confidentiality? 
As part of this research, health information about you will be collected. This will include 
information from past and present medical records, study procedures/tests, and interviews 


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that are part of this research. Information related to your medical care at CHOP will go in 
your medical record. This could include physical exams, imaging studies (MRI scans), 
ECGs or tests done in the clinical lab. Medical records are available to CHOP staff. Staff 
will view your records only when required as part of their job. Staff are required to keep 
your information private. Information that could identify you will not be shared with 
anyone - unless you provide your written consent, or it is required or allowed by law. 
Laboratory test results will appear in your medical record with the exception of non-
CLIA approved test results which are performed only for this research study. We will do 
our best to keep your personal information private and confidential. However, we cannot 
guarantee absolute confidentiality. Your personal information may be disclosed if 
required by law. 
The results of this study may be shown at meetings and published in journals to inform 
other doctors and health professionals. We will keep your identity private in any 
publication or presentation.
Several people and organizations may review or receive your identifiable information. 
They will need this information to conduct the research, to assure the quality of the data, 
or to analyze the data or samples. These groups include: 

Members of the research team and other authorized staff at CHOP and UPenn;

People from agencies and organizations that perform independent accreditation 
and/or oversight of research; such as the Department of Health and Human 
Services, Office for Human Research Protections.

The Food and Drug Administration

Metro International Biotech 

Medical Monitor
By law, CHOP is required to protect your health information. The research staff will only 
allow access to your health information to the groups listed above.  By signing this 
document, you are authorizing CHOP to use and/or release your health information for 
this research. Some of the organizations listed above may not be required to protect your 
information under Federal privacy laws. If permitted by law, they may be allowed to 
share it with others without your permission.  
There is no set time for destroying the information that will be collected for this study. 
Your permission to use and share the information and data from this study will continue 
until the research study ends and will not expire. Researchers continue to analyze data for 
many years and it is not possible to know when they will be completely done. 
Can you change your mind about the use of personal information?
You may change your mind and withdraw your permission to use and disclose your 
health information at any time. To take back your permission, it is preferred that you 
inform the investigator in writing. 
Shana E. McCormack, M.D.
The Children’s Hospital of Philadelphia
The Division of Endocrinology and Diabetes


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34th Street and Civic Center Blvd.
Philadelphia, PA 19104
In the letter, state that you changed your mind and do not want any more of your health 
information collected. The personal information that has been collected already will be 
used if necessary for the research. No new information will be collected. If you withdraw 
your permission to use your personal health information, you will be withdrawn from the 
study.
You will be informed if changes to the study are needed to protect your health. You will 
be told about any new information that could affect your willingness to stay in the study, 
such as new risks, benefits or alternative treatments. 
Financial Information 
While you are in this study, the cost of your usual medical care – procedures, medications 
and doctor visits – will continue to be billed to you or your insurance.
Will there be any additional costs? 
There will be no additional costs to you by taking part in this study.
Friedrich’s Ataxia Research Alliance (FARA) and Metro International Biotech are 
providing financial support for this study.  The following research procedures, study 
drugs and study visits will be paid by study sponsor. 

Cost of study drug (Metro International Biotech);

Cost of study procedures (FARA);

Cost of travel, parking and meals (FARA, Metro International Biotech);
Will you be paid for taking part in this study? 
The compensation provided at each visit is designed to cover the cost of travel, parking, 
and meals as well as your time and effort.
Participants will receive $150.00 after completion of the Screening/Baseline Visit and 
$300.00 after completion of the Follow-Up Visit.  Total compensation will not exceed 
$450.00.
If you receive payment using a bankcard, the bank will have access to identifiable 
information. The bank will not have access to any medical information.
If your travel to CHOP (e.g. flight, hotel) is arranged and paid for by the study team, the 
agency making the reservations and their representatives will have access to identifiable 
information.
For non-local participants/families travelling from outside a 50 mile radius of CHOP, we 
will reimburse eligible travel expenses over the duration of participation in the study.  
Eligible expenses for reimbursement include mileage, tolls with receipts, and 
hotel/lodging with receipts according to reimbursement guidelines.
We may share your specimens and data with third parties (other researchers/institutions 
or for profit companies). If there are patents or products that result from the research, the 


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third parties may make money from the research. You will not receive any financial 
benefit from research done on your specimens or data.
Who is funding this research study?
The Friedreich’s Ataxia Research Alliance (FARA) will provide funding to support this 
study. 
Metro International Biotech will provide funding to support reimbursement of travel 
expenses for participants/families traveling from outside a 50 mile radius of CHOP.
Please contact Dr. McCormack if you have any questions about how this study is funded. 
What if you have questions about the study?
If you have questions about the study, call the study doctor, Dr. McCormack at (215) 
590-3174. You may also talk to your own doctor if you have questions or concerns.
The Institutional Review Board (IRB) at The Children’s Hospital of Philadelphia has 
reviewed and approved this study. The IRB looks at research studies like these and makes 
sure research subjects’ rights and welfare are protected. If you have questions about your 
rights or if you have a complaint, you can call the IRB Office at 215-590-2830. 
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. 
What happens if you are injured during the study? 
If you are hurt or get sick from something that was done as part of this study, doctors at 
the clinic or hospital can arrange for emergency care. Treatment may be billed to you or 
your insurer. If your injury is caused by a research procedure or the experimental drug, 
MetroBiotech Inc. may pay for treating the injury. This does not mean that a mistake 
happened. 
The Hospital does not offer financial compensation or payment if you are injured as a 
result of participating in this research.
If you think you have been injured from taking part in this study, call Dr. McCormack at 
(215) 590-3174. She can go over things with you, let you know of resources that may be 
available and give you information on what you need to do.
In case of injury resulting from this study, you will not lose any legal rights by signing 
this form.
What will be done with my data and specimens when this study is over? 
As part of the study, we will collect data and samples from you (including an additional 
blood sample for future analysis related to bioenergetics in FA). These blood samples 
will be given a unique code and will not include information that can identify you. Other 
types of samples (e.g. urine) will not be retained. Information that can identify you may 
be kept permanently on a secured shared drive at CHOP. Only the study doctors and 


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authorized CHOP personnel working with them on this study will have access to see 
information that can identify you. 
Results will not be disclosed to you, but they may contribute to knowledge for future 
research studies.
If you leave the study, you can ask to have the data collected about you removed or the 
samples destroyed. You can also ask us to remove information that identifies you from 
the data or samples. 
OPTIONAL Future Use of Data and Specimens for Future Research 
Please indicate whether you will allow your data and samples to be used for future 
research by putting your initials next to one of the following choices:
_____ (initials) I agree that the data and/or specimens collected may be stored and used 
for future research.
_____ (initials) I DO NOT agree that the data and/or specimens may be stored and used 
for future research. 
OPTIONAL Consent for Disclosure of Participation and results to the Participant’s 
Personal Physician for Clinical Use
Please indicate whether you grant permission to have the study team disclose your 
participation and results to your personal physician for clinical use by initialing next to 
one of the following choices:
 _____ (Initials) I agree to the disclosure of my participation and results to my personal 
physician for clinical use.
 _____ (initials) I DO NOT agree to the disclosure of my participation and results to my 
personal physician for clinical use.
OPTIONAL Consent for 7.0T MRI Scan
If you provide consent, you may participate in an additional OPTIONAL MRI scan at the 
Hospital of the University of Pennsylvania.  This MRI scan will be completed on a 7.0T 
MRI scanner.
Risks Associated: 
7.0T MRI Scanners 
While the FDA has not approved the use of 7.0T MRI scanners for diagnostic use, it does 
consider magnetic field strengths up to 8.0T to pose no more than minimal risk. No 
persistent adverse effects have been reported by facilities with magnetic field strengths at 
7.0T. However, some people have reported transient dizziness, nausea, or a metallic taste 
upon being moved into and out of the scanner. These effects typically last less than 10 


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minutes, and can be minimized by reducing the speed at which the person is moved 
inside the magnet.
Experimental Device Clause
Some of the pulse sequences and/or RF coils are not FDA approved but are considered to 
pose no more than minimal risk.
Magnetic Fields Health Risks
There is no known health risk associated with exposure to magnetic fields during an 
MRI. There are minimal risks from the loud noise associated with the MRI scanner and 
from the discomfort of lying on a hard surface. You may experience transient nausea and 
dizziness and nausea. We shall provide you with protective earplugs as necessary and 
make every attempt to ensure your comfort with blankets, etc. during your time in the 
scanner. If you wish to stop at any time, you can do so at any time by telling the 
technician, so s/he can safely stop the scanning.
Please indicate whether you with to participant in the additional OPTIONAL MRI scan 
on the 7.0T MRI scanner at The Hospital of the University of Pennsylvania by signing 
next to one of the following choices:
_____ (initials)  I agree to complete the additional optional MRI scan.
_____ (initials)  I DO NOT agree to complete the additional optional MRI scan. 
OPTIONAL Consent to be Contacted for Future Research Studies
Please indicate whether you grant permission to be contacted for future research studies 
by signing next to one of the following choices:
_____ (initials) I agree to be contacted for future research studies.
_____ (initials) I DO NOT agree to be contacted for future research studies. 


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Consent to Take Part in this Research Study and Authorization to Use and Disclose Health 
Information for the Research
The research study and consent form have been explained to you by:
Person Obtaining Consent
Signature of Person Obtaining Consent
Date
By signing this form, you are indicating that you have had your questions answered and 
you agree to take part in this research study. You are also agreeing to let CHOP use and 
share your health information as explained above. If you don’t agree to the collection, use 
and sharing of your health information, you cannot participate in this study.
Name of Subject
Signature of Subject 
Date

SAP_004.pdf: 
Title: A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich’s Ataxia 
 
 
NCT Number: NCT04817111 
Document Date: May 6, 2022 
 


STATISTICAL CONSIDERATIONS 
Primary Endpoint 
The primary focus of this protocol is safety and tolerability.  We will monitor participants using 
standardized assessment of symptoms and laboratory measurements. 
Secondary Endpoints 
Secondary endpoints will include the following: 
• The within-subject change in PCr/ATP-γ ratio (31P-MRS) before and after 14 days (+/- 2 
days) of treatment with MIB-626. 
• The within-subject change in post-exercise CrCEST recovery (CrCEST MRI) before and 
after 14 days (+/- 2 days) of treatment with MIB-626.  
• The within-subject change in skeletal muscle NAD+ (1H-MRS) before and after 14 days (+/- 
2 days) of treatment with MIB-626.  
• The within-subject change in clinical global impression (CGI-S) scale before and after 14 
days (+/- 2 days) of treatment with MIB-626. The CGI-C will be applied at the end of the 
study. 
• To assess within-subject changes in the Friedreich Ataxia Rating Scale-Activities of Daily 
Living subscale (FARS-ADL) before and after treatment with MIB-626. 
• The within subject change in hand grip strength (via dynamometry) before and after 14 days 
(+/- 2 days) of treatment with MIB-626. 
• NAD+ and its metabolites in whole blood before and after 14 days (+/- 2 days) of treatment 
with MIB-626. 
 
Statistical Methods 
Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive summaries 
(e.g. means and standard deviations for continuous variables such as age and percentages for 
categorical variables such as gender). 
Efficacy Analysis 
We will test for differences from zero of the key secondary outcome, the within-subject change 
in PCr/ATP-γ ratio, as well as other secondary outcomes of interest using paired t-tests and/or 
Wilcoxon signed rank tests, as appropriate given the variable distribution. 
 
Safety Analysis 
All participants entered into the study who receive the test article will be included in the safety 
analysis. The frequencies of AEs by type, body system, severity and relationship to study drug 
will be summarized. SAEs (if any) will be described in detail. 


AE incidence will be summarized along with the corresponding exact binomial 95% two-sided 
confidence intervals. 
Sample Size and Power 
We propose a sample size of 6 participants with complete and evaluable data (we expect that we 
will verbally consent and telephone screen up to 10 participants).  
Although the primary objective of the study is to assess safety and tolerability, we include here 
an estimate of statistical power for the key secondary endpoint of PCr/ATP-γ ratio. To estimate 
statistical power, we used data from a previous study comparing 31P-MRS in individuals with FA 
as compared to control participants.1 With an expected mean of adjusted PCr/ATP ratio of 1.42 
(SD 0.52), and assuming a short term (i.e., over 14 days) within-subject correlation of 0.6 
between measures, a sample of 6 individuals has 80% power to detect an improvement in 
PCr/ATP to 2.09 (normal = 2.20). This initial experience using this technique will generate 
estimates regarding the distribution of the cardiac 31P-MRS outcomes in FA and may provide a 
basis for a longer phase 2/3 interventional study of NAD+ precursor supplementation. 
Interim Analysis 
Due to the small sample size no interim efficacy or safety analyses is planned.  Individuals who 
experience a new Grade 3 or higher AE will be required to stop study participation. 
 

Prot_003.pdf: 
Title: A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich’s Ataxia 
 
 
NCT Number: NCT04817111 
Document Date: May 6, 2022 
 


 
 
 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
A Phase 2a Study of NAD+ Precursor Supplementation in 
Friedreich’s Ataxia 
Funder 
Friedreich’s Ataxia Research Alliance (FARA) 
Clinical Phase 
Open Label, Safety and Tolerability 
Study Rationale 
Frataxin supports the function of the mitochondrial electron 
transport chain (ETC) because it facilitates the formation of iron-
sulfur clusters, which are essential to multiple ETC components. 
Cardiac muscle has a high energy requirement, and the role of 
impaired mitochondrial oxidative phosphorylation capacity in the 
pathogenesis of FA-related cardiomyopathy is a focus of ongoing 
investigations. In animal models, there is evidence for disruption of 
the physiologic coupling between mitochondria and sarcomeres in 
cardiomyocytes, as well as iron accumulation and mitochondrial 
proliferation.16 Similar phenomena may be observable in skeletal 
muscle in humans.3,17 
 
We hypothesize that MIB-626 therapy will be feasible, well-
tolerated, and may increase cardiac mitochondrial bioenergetic 
capacity, as reflected by the phosphocreatine (PCr) to ATP ratio 
measured via cardiac 31Phosphorus magnetic resonance 
spectroscopy (31P- MRS). 
Study Objective(s) 
Primary  
 
To test the safety and tolerability of short-term MIB-626 therapy 
in adults with FA without overt heart failure. 
Secondary 
 
To use cardiac 31P-MRS to measure the within-participant 
change in PCr/ATP-γ ratio before and after treatment with MIB-
626. 
 
To assess the within-participant change in skeletal muscle post-
exercise CrCEST recovery (an index of skeletal muscle 
mitochondrial oxidative phosphorylation capacity) and the 
within-participant change skeletal muscle NAD+ via 1H-MRS 
before and after treatment with MIB-626.  
 
To assess within-participant changes in grip strength (via hand 
grip dynamometry) before and after treatment with MIB-626. 
 
To measure the concentration of NAD+ (and associated 
metabolites) in whole blood before and after treatment with 
MIB-626.  
 
To assess within-participant change in the FARS-ADL, before 
and after treatment with MIB-626. 
 
To assess within-participant change in overall well-being, 


 
 
 
 
 
 
 
 
 
 
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assessed via CGI scales (CGI-S and CGI-C), before and after 
treatment with MIB-626. 
Test Article(s) 
 
MIB-626 two (2) 500 mg tablets, po daily 
Study Design 
 
Open Label, Single Arm, Assess Safety and Tolerability 
Subject Population 
key criteria for 
Inclusion and Exclusion: 
Inclusion Criteria 
1. Molecular diagnosis of Friedreich’s Ataxia (FA). 
2. Males and females, ages 18y to < 65y. 
Exclusion Criteria 
1. Known sensitivity to nicotinamide-containing compounds. 
2. Concurrent use of vitamin B3 supplements and/or any 
medications likely to increase risk of MIB-626 toxicity. 
3. HGbA1c > 8.5% and/or DM requiring insulin or insulin 
secretagogue. 
4. Kidney disease (eGFR < 60 ml/min/1.73 m2) using serum 
creatinine and MDRD equation. The eGFR levels will be 
calculated using the MDRD (Modified Diet in Renal Disease 
study) equation, which is the equation used by the CHOP 
laboratory. 
5. Liver disease (AST/ALT > 3x ULN) 
6. Severe co-existing cardiac disease as manifest by a reduced 
LV ejection fraction to < 40%, moderate or greater valve 
disease, presence of a congenital heart defect, and/or 
evidence of pulmonary hypertension on an echocardiogram 
or cardiac MRI within 12 months of screening. 
7. History of clinically significant arrhythmias (atrial 
fibrillation, atrial flutter, or ventricular tachycardia) or an 
increased potential for arrhythmias on the screening ECG as 
evidenced by:  
 Prolonged QTc (>480 ms for females or >460 msec for 
males) 
 Any rhythm other than sinus on the baseline ECG, 
excluding sinus arrhythmia. 
 Multiple PACs (>2) or PVCs on the baseline ECG 
8. Prior history of heart failure. 
9. Any contraindication to MRI, including spinal rods (related 
to unknown safety considerations for cardiac 31P-MRS). 


 
 
 
 
 
 
 
 
 
 
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10. Use of any investigational agent within 4 weeks of 
enrollment. 
11. Females: Pregnant/lactating or planning to become pregnant 
during their participation. 
12. Any medical condition that, in the opinion of the 
investigator, will interfere with the safe completion of the 
study. 
Number Of Subjects  
 
N =10 screened at CHOP with an aim to enroll and obtain complete 
data for 6 participants. 
 
2 Sites: The Children's Hospital of Philadelphia and the Hospital of 
the University of Pennsylvania 
 
Study procedures will be completed at The Children's Hospital of 
Philadelphia and The Hospital of the University of Pennsylvania. 
Study Duration 
Each individual’s participation will last up to 15 weeks.   
 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
Participants will undergo a telephone screening to assess eligibility 
and then, within 90 days, complete an in-person screening to 
confirm eligibility. Participants with confirmed eligibility will be 
included and begin 14 (+/- 2) days of test article (MIB-626).  
Participants will complete a follow-up visit at the conclusion of 14 
(+/- 2) days of MIB-626.  
Efficacy Evaluations 
PCr/ATP-γ ratio via cardiac 31P-MRS 
Skeletal muscle CrCEST and NAD+ (1H-MRS) 
NAD+ analysis of metabolites in whole blood 
Grip strength (hand grip dynamometry)  
FARS-ADL scale 
Clinician/participant clinical global impression (CGI) scales (CGI-
S, CGI-C) 
Safety Evaluations 
Safety will be monitored through the collection of laboratory 
assessments at baseline and follow-up.  Participants will also be 
monitored using a standardized assessment of symptoms (see 
attachment).   
 
We will use the Common Terminology Criteria for Adverse Events 
(CTCAE, version 5.0, U.S. Department of Health and Human 
Services) to grade adverse events.  
 
Individuals who experience a new Grade 3 or higher AE will be 
required to stop study participation. 


 
 
 
 
 
 
 
 
 
 
x
Statistical And Analytic 
Plan 
We will focus primarily on safety and tolerability. We will note the 
number of participants who complete the protocol, monitor 
adherence, and systematically collected adverse events. We will also 
use paired t-tests and/or Wilcoxon signed rank tests to assess 
within-participant changes in cardiac and skeletal muscle 
bioenergetics, NAD+ metabolites, grip strength, FARS-ADL, and 
clinician/participant reported overall clinical status.  
 
To estimate statistical power, we used data from a previous study 
comparing cardiac 31P-MRS assessments of tissue bioenergetics in 
individuals with FA as compared to control participants.1 With an 
expected initial mean of adjusted PCr/ATP ratio in individuals with 
FA of 1.42 (SD 0.52) 1, and assuming a conservative short-term 
(i.e., over 14 (+/- 2) days) within-subject correlation of at least 0.6 
between repeated measures, a sample of 6 individuals has 80% 
power to detect an improvement in PCr/ATP to 2.09 (normal = 
2.20). This initial experience will generate estimates regarding the 
distribution of the candidate mechanistic/efficacy outcomes in FA 
and treatment responses, and may provide a basis for longer Phase 
2/3 interventional studies of MIB-626 supplementation. 
DATA AND SAFETY 
MONITORING PLAN 
The PI is responsible for data quality management and continuous 
monitoring of study participants to ensure safety.  Data will be 
reviewed at regularly scheduled team meetings. The PI and study 
team will report findings as required to the local Institutional 
Review Board and medical monitor.