Exercise and Nicotinamide Riboside in Friedreich's Ataxia: Trial Results

Key Takeaways

• In patients with Friedreich's ataxia, a combination of home exercise and nicotinamide riboside was associated with a significant improvement in peak VO₂ versus control at 12 weeks.
• Nicotinamide riboside alone was not significantly different from control, exercise alone did not reach adjusted significance, and the combination did not differ from exercise alone.
• All randomized participants completed the study, and adverse events were mild or moderate, including gastrointestinal symptoms, falls, upper respiratory infections, and skin rashes.

A randomized trial in Friedreich's ataxia linked home exercise plus nicotinamide riboside to a 0.21 L/min improvement in peak VO₂ versus control.

This 12-week outpatient phase 2 trial was conducted at Children’s Hospital of Philadelphia as a single-site randomized study with a 2×2 factorial design. Researchers randomized 66 eligible participants, with all completing follow-up. Eligible participants were aged 10-40 years, had an ejection fraction of at least 45%, and were able to exercise. The cohort included 33 children and 33 adults, and randomization was stratified by age for those younger than 18 years versus those aged 18 years or older. Analyses were intention-to-treat, and the prespecified primary endpoint was change in peak VO₂ from baseline to 12 weeks.

Home exercise involved three aerobic and two resistance sessions weekly with remote exercise-physiologist oversight. Nicotinamide riboside dosing was weight based: 300 mg for weights of 24 kg up to 48 kg, 600 mg for 48 kg up to 72 kg, and 900 mg for over 72 kg. Models accounted for age, sex, and baseline peak VO₂; stage 1 compared the active groups with control, and stage 2 compared the combination with exercise alone. Versus control, the combination difference was 0.21 L/min. Exercise only differed by 0.16 L/min versus control, with a 95% CI of 0.00 to 0.31 and padjusted=0.103; nicotinamide riboside only differed by 0.10 L/min, with a 95% CI of -0.05 to 0.26 and padjusted=0.188.

In the direct comparison, the combination was not statistically different from exercise alone. Adverse events were all mild or moderate and included gastrointestinal symptoms, falls, upper respiratory infections, and skin rashes. At least one moderate adverse event of interest in these categories was reported in 7 control participants, 6 nicotinamide riboside participants, 3 exercise participants, and 4 combination participants, corresponding to 41%, 35%, 19%, and 25%. These findings were consistent with the authors’ description of the 12-week regimen as safe within this trial.

The investigators described nicotinamide riboside plus exercise as safe and associated with increased cardiopulmonary fitness over 12 weeks. They also noted that longer studies are needed to determine whether adding nicotinamide riboside to exercise belongs in a long-term comprehensive treatment approach. The reported signal was therefore limited to a 12-week change in cardiopulmonary fitness and will require longer follow-up.