Overview

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.

Eligibility

Inclusion Criteria:

1. Molecular diagnosis of Friedrich's Ataxia (FA).
2. Males and Females, Age 10 to 40 years (inclusive).
3. 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.
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

   an 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 Diabetes Mellitus (DM) requiring insulin or insulin secretagogue.
4. Use of supraphysiologic steroids.
5. Laboratory abnormalities that indicate clinically significant anemia or bleeding risk. (Hemoglobin < 10 g/dL or Platelets < 100K)
6. 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)
7. 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)
8. Uncontrolled and persistent arrhythmias that are felt to be clinically significant.
9. Known history of moderate or severe left ventricular systolic dysfunction (Left Ventricular Ejection Fraction (LVEF) < 45%)
10. Standard contraindications to exercise testing.
11. 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)
12. Inability to sit and pedal unassisted in a recumbent tricycle.
13. 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
    • 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.