NAD+ Precursor Supplementation With Exercise Training to Increase Aerobic Capacity in Friedreich's Ataxia (ExRx in FA)

  • End date
    Dec 31, 2025
  • participants needed
  • sponsor
    Children's Hospital of Philadelphia
Updated on 14 October 2022


Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise on VO2max and Si in Friedreich's Ataxia (FA).

The primary objective of this research is to measure the effect of combination administration (NR + exercise) on aerobic capacity (VO2max) in FA. A key secondary objective is to measure the effect of combination administration (NR + exercise) on glucose homeostasis (Si) in FA.


Friedreich's Ataxia (FA) is a progressive neurodegenerative disease affecting 1 in 50,000 individuals in the U.S. Currently, there is no approved treatment.

There is a critical knowledge gap regarding the best ways to intervene to increase aerobic capacity (VO2max on exercise testing) in FA. Exercise is the most potent known stimulus for increasing muscle mass and mitochondrial oxidative phosphorylation (OXPHOS) capacity, increasing VO2max, and increasing insulin sensitivity (Si), however, it has not been studied in FA. One adaptation seen in exercised muscles is an increase in muscle nicotinamide adenine dinucleotide (NAD+), a cofactor required for glycolytic and mitochondrial adenosine triphosphate (ATP) production. In skeletal- and cardiac muscle-specific frataxin (FXN) knock-out animals, NAD+ precursors rescued cardiac function to near-normal, additionally highlighting its translational potential in FA. Nicotinamide riboside (NR) is a NAD+ precursor currently available as a dietary supplement (Tru Niagen ®, ChromaDex, Irvine CA) that is expected to be safe and well-tolerated in adults and children. The central hypothesis is that exercise + NR will increase skeletal muscle mitochondrial OXPHOS and increase muscle mass to increase VO2max in FA. The investigators expect that exercise + NR will also increase Si in this cohort.

Condition Friedreich Ataxia 1
Treatment Placebo, exercise intervention, Nicotinamide Riboside
Clinical Study IdentifierNCT04192136
SponsorChildren's Hospital of Philadelphia
Last Modified on14 October 2022


Yes No Not Sure

Inclusion Criteria

Molecular diagnosis of Friedrich's Ataxia (FA)
Males and Females, Age 10 to 40 years (inclusive)
Girls, 11 years of age and older, 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
Not currently meeting exercise guidelines as outlined by The Physical Activity Guidelines for Americans
ECG, performed within 1 year of enrollment, without clinically significant arrhythmia
Children and Adolescents should do 60 minutes (1 hour) or more of moderate-to-vigorous physical activity daily
Parental/guardian permission (informed consent) and if appropriate, child assent
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
Cardiac echocardiogram or cardiac MRI, performed within 1 year of enrollment, showing
an LVEF > 45%
Weight > 24 kg

Exclusion Criteria

Known sensitivity to NR
Concurrent use of any medications, including statins, likely to increase risk of NR toxicity
HgbA1c > 8.5% and/or Diabetes Mellitus (DM) requiring insulin or insulin secretagogue
Laboratory abnormalities that indicate clinically significant kidney disease using serum creatinine and Modification of Diet in Renal Disease (MDRD) equation. (Estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73 m2)
Laboratory abnormalities that indicate clinically significant liver disease. (Aspartate Aminotransferase (AST)/Serum Glutamic Oxaloacetic Transaminase (SGOT) 3.0 x Upper Limit of Normal and/or Alanine Aminotransferase (ALT)/Serum Glutamic Pyruvic Transaminase (SGPT) 3.0 x Upper Limit of Normal)
Known history of moderate or severe left ventricular systolic dysfunction (Left Ventricular Ejection Fraction (LVEF) < 45%)
Standard contraindications to exercise testing
Inability to sit and pedal unassisted in a recumbent tricycle
Use of supraphysiologic steroids
Any contraindication to MRI. Including
Laboratory abnormalities that indicate clinically significant anemia or bleeding risk. (Hemoglobin < 10 g/dL or Platelets < 100K)
Any intra-luminal implant, filter, stent or valve replacement
Any type of life assist device, pump, or prosthetic
Any vascular clip or clamp
Uncontrolled and persistent arrhythmias that are felt to be clinically significant
Any surgically placed clips or clamps or bands on visceral organs
Any intracranial implants of any type other than dental fillings
Inability to sit and pedal unassisted in a cycle ergometry chair, at a cadence of at least 55 rotations per minute (rpm) during unloaded warm up, in a cycle ergometry chair and complete a maximal Cardio Pulmonary Exercise Test (CPET)
Any non-removable piercings, jewelry, or medicinal patch
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
Females: pregnant, lactating, or planning to become pregnant during their participation
Any medical condition, in the opinion of the investigator that will interfere with the safe completion of the study
Parents/guardians or participants who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures
Use of any investigational agent within 4 weeks of enrollment, except open-label
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
extension phase
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