NAD+ and Exercise in FA

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

NCT04192136•Children's Hospital of Philadelphia

Summary

Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise on Peak VO2 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 (Peak VO2) in FA. A key secondary objective is to measure the effect of combination administration (NR + exercise) on glucose homeostasis (Si) in FA.

Detailed Description

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 (Peak VO2 on exercise testing) in FA. Exercise is the most potent known stimulus for increasing muscle mass and mitochondrial oxidative phosphorylation (OXPHOS) capacity, increasing Peak VO2, 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 Peak VO2 in FA. The investigators expect that exercise + NR will also increase Si in this cohort.

Eligibility

Age

10 - 40 years

Sex

ALL

Healthy Volunteers

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.
+2 more criteria

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.
+16 more criteria

Locations (1)

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Key Dates

Start Date

September 3, 2020

Primary Completion Date

February 7, 2025

Completion Date

October 31, 2025

Last Updated

March 11, 2026

Enrollment

ACTUAL participants

Conditions

Friedreich Ataxia 1

Interventions

Nicotinamide Riboside

DIETARY_SUPPLEMENT

Placebo

DIETARY_SUPPLEMENT

Exercise Intervention

OTHER