NAD+ Precursor Supplementation With Exercise Training to Increase Aerobic Capacity in Friedreich's Ataxia
Phase: NA
Conditions: Friedreich Ataxia 1
Sponsor: Children's Hospital of Philadelphia

  
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
NAD+ Precursor Supplementation with Exercise Training to 
Increase Aerobic Capacity in Freidreich’s Ataxia 
Funder 
National Institutes of Health (NIH) 
Clinical Phase 
Mechanistic clinical trial (Phase II) 
Study Rationale 
Decreased aerobic capacity (VO2max on exercise testing) is 
common in FA, and may contribute to decreased insulin sensitivity 
(Si). Decreased muscle mitochondrial oxidative phosphorylation 
(OXPHOS) capacity is a potential cause of decreased VO2max in 
FA. Preclinical and clinical studies suggest that exercise training 
and NAD+ precursor supplementation may each produce increases 
in OXPHOS that translate into increased VO2max. Also, the effects 
of exercise and NAD+ precursor supplementation may be additive.   
Study Objective(s) 
Primary  
x 
To measure the effect of a combination intervention (NR + 
exercise) on VO2max in FA. 
Secondary 
x 
To measure the effect of combination administration (NR + 
exercise) on Si in FA. 
 
Supplement 
 
Tru Niagen ® Nicotinamide Riboside (NR) (300 mg capsules) 
Placebo for NR  
Study Design 
 
Randomized, placebo-controlled trial with a 2x2 factorial design 
testing the effects of an NAD+ precursor (NR) and exercise on 
VO2max and Si health in FA.   
Participants will be assigned to 1 of 4 groups: 
- 
NR Supplement, Plus Exercise 
- 
NR Supplement, NO Exercise 
- 
Placebo for NR Supplement, Plus Exercise 
- 
Placebo for NR Supplement, NO Exercise 
The 12-week in-home intervention will include recumbent cycling, 
an activity with demonstrated safety, feasibility, and appeal in this 
cohort.11 
 
 

  
 
 
 
 
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Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1) Molecular diagnosis of Friedrich’s Ataxia (FA). 
2) Males and Females, Age 10 to 40 years (inclusive).   
3) Girls t 11 years of age must have a negative urine/serum 
pregnancy test and must use an acceptable method of 
contraception, including abstinence, a barrier method 
(diaphragm or condom), Depo-Provera, or an oral 
contraceptive, for the duration of the study. 
4) Not currently meeting exercise guidelines as outlined by The 
Physical Activity Guidelines for Americans. 
- 
Children and Adolescents should do 60 minutes (1 hour) 
or more of moderate-to-vigorous physical activity daily. 
 
- 
As a part of their physical activity, children and 
adolescents should include muscle-strengthening 
physical activity on at least 3 days a week. 
 
- 
Adults should do at least 150 minutes (2 hours and 30 
minutes) to 300 minutes (5 hours) a week of moderate-
intensity, or 75 minutes (1 hour and 15 minutes) to 150 
minutes (2 hours and 30 minutes) a week of vigorous-
intensity aerobic physical activity.  
 
- 
Adults should also do muscle-strengthening activities of 
moderate or greater intensity that involve all major 
muscle groups on 2 or more days a week. 
5) Cardiac echocardiogram or cardiac MRI, performed within 1 
year of enrollment, showing a LVEF > 45% 
6) ECG, performed within 1 year of enrollment, without 
clinically significant arrhythmia. 
 
7) Weight > 24 kg 
8) Parental/guardian permission (informed consent) and if 
appropriate, child assent. 
Exclusion Criteria 
1) Known sensitivity to NR. 
2) Concurrent use of any medications, including statins, likely 
to increase risk of NR toxicity. 
3) HgbA1c > 8.5% and/or DM requiring insulin or insulin 
secretagogue. 

  
 
 
 
 
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4)  Use of supraphysiologic steroids  
5) Laboratory abnormalities that indicate clinically significant 
anemia or bleeding risk. 
Hgb < 10 g/dL or Platelets < 100K 
 
6) Laboratory abnormalities that indicate clinically significant 
kidney disease using serum creatinine and MDRD equation. 
eGFR < 60 ml/min/1.73 m2 
7) Laboratory abnormalities that indicate clinically significant 
liver disease. 
AST/SGOT 3.0 x ULN 
ALT/SGPT  3.0 x ULN 
8)  Uncontrolled and persistent arrhythmias that are felt to be 
clinically significant 
9) Known history of moderate or severe left ventricular systolic 
dysfunction (LVEF < 45%) 
10) Standard contraindications to exercise testing 
11) Inability to sit and pedal unassisted, at a cadence of at least 
55 rpm during unloaded warm up, in a cycle ergometry chair 
and complete a maximal Cardio Pulmonary Exercise Test 
(CPET) 
12) Inability to sit and pedal unassisted in a recumbent tricycle 
13) For individuals completing the MRI: Any contraindication to 
MRI Including:  
- 
ANY intra-luminal implant, filter, stent or valve 
replacement 
– ANY type of life assist device, pump, or prosthetic 
– ANY vascular clip or clamp 
– ANY surgically placed clips or clamps or bands on 
visceral organs 
– ANY intracranial implants of any type other than dental 
fillings 
– ANY non-removable piercings, jewelry, or medicinal 
patch 

 
 
 
 
 
 
 
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– ANY personal history of intraocular injury or fragment in 
or around the orbit that cannot be cleared through radiologic 
examination. 
– ANY personal history of bullet, shrapnel, or stabbing 
wounds that cannot be cleared through radiologic evaluation. 
– Inability to lie flat in the MRI scanner for 60-90 minutes. 
* participants who cannot complete the MRI will not be 
excluded from participation in the remainder of the study 
procedures if they meet those inclusion and exclusion 
criteria 
14) Use of any investigational agent within 4 weeks of 
enrollment, except open-label extension phase  
15) Females: Pregnant, lactating, or planning to become 
pregnant during their participation. 
16)  Any medical condition, in the opinion of the investigator 
that will interfere with the safe completion of the study.  
17) Parents/guardians or participants who, in the opinion of the 
Investigator, may be non-compliant with study schedules or 
procedures. 
 
 
Number Of Subjects  
 
We anticipate enrolling 80 participants (~40% pediatric, ~60% 
adult) in order to obtain complete data on 64 participants.  Pediatric 
participants (n = 32) will complete study procedures at The 
Children's Hospital of Philadelphia.  Adult participants (n = 48) will 
complete study procedures 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 36 weeks (+/- 1 
Week). 
 
Study Phases 
Screening 
Intervention 
Follow-Up   
(1) Screening: Participants will undergo a telephone screening to 
assess eligibility and then, within ~12 weeks, complete an in-person 
baseline visit to confirm eligibility. (2) Baseline Visit: Participants 
confirmed to be eligible after completion of screening procedures 
will be assigned to 1 of 4 arms and begin the 12-week intervention. 
(3) Follow-Up: Participants will return after the 12-week 
intervention to complete follow-up procedures.  
Outcomes 
VO2max (primary outcome); Si (key secondary outcome); muscle 
mass (key secondary outcome); muscle mitochondrial OXPHOS 
capacity via CrCEST MRI (key secondary outcome); NAD+ from 

 
 
 
 
 
 
 
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muscle biopsy (key secondary outcome); nutrient-specific 
mitochondrial OXPHOS capacity from muscle biopsy (key 
secondary outcome) 
Safety Evaluations 
Safety will be monitored through the collection of laboratory 
assessments at baseline, interim, and follow-up.  Participants will 
also be monitored using a standardized assessment of symptoms.  
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 may need to stop study participation at the 
discretion of the investigative team. 
Statistical And 
Analytic Plan 
Linear mixed-effects modeling will be used to evaluate effect of 
interventions over time on the primary and key secondary outcomes. 
The models incorporate subject-specific random effects to account 
for within-subject correlation due to repeated measures. Group 
averages, as well as subject-specific intercepts and slopes, will be 
estimated to capture potential variations in the baseline values and 
slopes among individuals. Linear mixed-effects models 
accommodate missing data due to dropout, such that all randomized 
participants can be included. We will compare participants who 
complete the study with those who do not, and identify potential 
factors that are associated with dropout. In the mixed-effects 
models, we will adjust for time-invariant covariates (age at 
randomization, sex) and time-varying covariates (lean mass, muscle 
OXPHOS capacity, muscle NAD+ content). By including these 
indices of “muscle quality” as covariates in the models, we will be 
able to assess whether intervention effects are explained by these 
effects. To assess other potential factors influencing outcomes, we 
will also analyze the incremental effect of adding each of the other 
measured covariates (final dose of NR achieved, final training 
intensity achieved, FA severity) to the models. 
DATA AND SAFETY 
MONITORING PLAN 
The PI will designate an independent Data Safety Monitoring Board 
(DSMB) to perform an independent review of ongoing study 
progress and safety. The DSMB will likely consist of a cardiologist, 
neurologist, and endocrinologist with expertise in FA, and also a 
statistician. The cardiologist will serve as chair, and will facilitate 
meetings as per the DSMB charter.