Lin KY; Department of Paediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Bucha A; McSweeney K; Wade KL; Karaj A; Tamaroff J; O’Malley S;
Chung NM; Cilenti NA; Wanner J; Adzika GK; Mesaros C; Blair IA;
Rojsajjakul T; Serai S; Farmer J; Bryant K; Lu Y; Harhay MO; Weber DR;
Paridon SM; Seifert EL; Putt ME; Zamani P; Baur JA; Lynch DR; McCormack SE

Lancet Neurology. 25(5):469-481, 2026 May.

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 x 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 VO2 (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 VO2. 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 VO2 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;
padjusted=0.188) for nicotinamide riboside and no exercise; 0.16 (0.00 to
0.31; padjusted=0.103) for placebo and exercise; and 0.21 (0.05 to 0.36;
padjusted=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.