Nicotinamide Riboside Plus Exercise Improves Fitness in Friedreich's Ataxia

BACKGROUND: Friedreich's ataxia is a rare, chronic, progressive, neurodegenerative condition affecting multiple organ systems, including neurological, musculoskeletal, cardiac, and endocrine systems, and is marked by low cardiopulmonary fitness. We tested the effect of exercise and NAD precursor supplementation with nicotinamide riboside, which have each shown benefits in animal and early clinical studies, on cardiopulmonary fitness in individuals with Friedreich's ataxia. METHODS: This 12-week, outpatient, phase 2, single-site (Children's Hospital of Philadelphia, Philadelphia, PA, USA), randomised, 2 × 2 factorial clinical trial recruited individuals aged 10-40 years with an ejection fraction of 45% or greater who were able to exercise. A computer-generated randomisation sequence was developed by the trial statistician. Random allocation was age-stratified (<18 years vs ≥18 years) to one of four groups: placebo and no exercise with attention control (weekly phone calls; henceforth placebo only), nicotinamide riboside and no exercise with attention control (henceforth nicotinamide riboside only), placebo and exercise (exercise only), and nicotinamide riboside and exercise (combination therapy). Individualised exercise plans were developed by the exercise physiologist (three aerobic and two resistance training sessions weekly), performed at the individual's home, and overseen remotely (telephone check-ins by the physiologist). Weight-based dosing of nicotinamide riboside or placebo was 300 mg (1 capsule) for weights of 24 kg up to 48 kg, 600 mg (2 capsules) for weight 48 kg up to 72 kg, and 900 mg (3 capsules) for weights of over 72 kg. The primary outcome was change in peak VO (L/min) during cardiopulmonary exercise testing at 12 weeks versus baseline, and the effect of treatment group was assessed in a statistical model accounting for age (stratification variable), sex, and baseline peak VO. Stage 1 analysis tested the difference between each active treatment versus the control group, and stage 2 analysis (if combination therapy was effective) tested the difference between combination treatment and exercise alone; family-wise type 1 error was maintained <0·05. Analyses were by intention-to-treat. Adverse events were recorded systematically. This trial is registered with ClinicalTrials.gov (NCT04192136) and is complete. FINDINGS: Between Sept 3, 2020, and April 23, 2025, we enrolled 74 individuals, of whom 66 met the eligibility criteria and were randomly allocated to the four study groups. All participants completed the study. 33 (50%) were children (aged 10-17 years) and 33 (50%) were adults (aged ≥18 years); 37 (56%) were male and 29 (44%) were female. Least mean squares for the change in peak VO in L/min were -0·05 (95% CI -0·16 to 0·06) for the 17 participants in the control group; 0·06 (-0·05 to 0·17) for the 17 participants in the nicotinamide riboside and no exercise group; 0·11 (0·00 to 0·22) for the 16 participants in the placebo and exercise group; and 0·16 (0·05 to 0·27) for the 16 participants in the nicotinamide riboside and exercise group. Differences between active treatment and the control group were 0·10 (95% CI -0·05 to 0·26; p=0·188) for nicotinamide riboside and no exercise; 0·16 (0·00 to 0·31; p=0·103) for placebo and exercise; and 0·21 (0·05 to 0·36; p=0·0299) for nicotinamide riboside and exercise in combination. Combination therapy was not statistically different from exercise alone (difference -0·05 ([95% CI -0·10 to 0·21]; p=0·49). 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 by seven (41%) participants in the control group; six (35%) in the nicotinamide riboside and no exercise group; three (19%) in the placebo and exercise group; and four (25%) in the nicotinamide plus exercise group. INTERPRETATION: The combination of nicotinamide riboside plus exercise for 12 weeks was safe and increased cardiopulmonary fitness in children and adults with Friedreich's ataxia. Longer studies are needed to establish whether adding nicotinamide riboside to exercise could be considered as part of a long-term, comprehensive treatment approach. FUNDING: US National Institutes of Health and Friedreich's Ataxia Research Alliance.