Highlights
In this single-centre, 2 × 2 factorial, randomised phase 2 trial, the combination of nicotinamide riboside and individualized home-based exercise improved peak oxygen consumption over 12 weeks in patients with Friedreich’s ataxia compared with placebo and no exercise.
The adjusted between-group difference in change in peak VO2 for combination therapy versus control was 0.21 L/min (95% CI 0.05 to 0.36; padjusted=0.0299), meeting the study’s prespecified efficacy threshold in stage 1 analysis.
Exercise alone and nicotinamide riboside alone each showed numerically favorable changes, but neither comparison versus control reached statistical significance after multiplicity adjustment.
Safety was reassuring: all adverse events were mild or moderate, and no excess burden of moderate adverse events was seen with the combination regimen.
Background and Clinical Context
Friedreich’s ataxia is a rare, autosomal recessive, multisystem neurodegenerative disease caused in most cases by GAA trinucleotide repeat expansions in FXN, resulting in reduced frataxin expression. Clinically, the disorder is characterized by progressive gait and limb ataxia, dysarthria, sensory neuropathy, weakness, scoliosis, hypertrophic cardiomyopathy, and metabolic complications including diabetes. Functional decline is often substantial, and cardiopulmonary fitness is typically reduced even in ambulatory patients.
Low exercise capacity in Friedreich’s ataxia is clinically important. It may reflect impaired skeletal muscle oxidative metabolism, deconditioning, neuromuscular inefficiency, and cardiac involvement. Reduced peak VO2 is not simply a physiological curiosity; in many chronic diseases it tracks with functional limitation, quality of life, and prognosis. Yet therapeutic options that specifically target physical capacity in Friedreich’s ataxia remain limited.
Two interventions have been of interest. The first is structured exercise training, which has shown promise in small studies and is biologically plausible given its effects on mitochondrial function, endurance, strength, and functional reserve. The second is augmentation of cellular NAD+ metabolism through nicotinamide riboside, a precursor that has drawn attention in preclinical models of mitochondrial dysfunction and aging biology. Because frataxin deficiency is associated with mitochondrial abnormalities and impaired bioenergetics, NAD+ precursor therapy has been hypothesized to support metabolic resilience. The present trial directly tested whether either strategy, alone or together, could improve cardiopulmonary fitness in Friedreich’s ataxia.
Study Design
Trial overview
This was a 12-week, outpatient, phase 2, single-site, randomised controlled trial conducted at Children’s Hospital of Philadelphia, Philadelphia, PA, USA. The study used a 2 × 2 factorial design, allowing simultaneous evaluation of nicotinamide riboside and exercise while also examining the combination strategy.
Participants
Eligible participants were aged 10-40 years, had Friedreich’s ataxia, an ejection fraction of 45% or greater, and were able to exercise. These inclusion criteria selected a group with sufficient cardiac reserve and practical capacity to undertake the intervention, while still representing a clinically meaningful cross-section of ambulatory or exercise-capable patients.
Between Sept 3, 2020, and April 23, 2025, 74 individuals were enrolled, 66 met eligibility criteria, and all 66 were randomly assigned and completed the study. The cohort included 33 children aged 10-17 years and 33 adults aged 18 years or older; 37 participants were male and 29 were female.
Randomisation and treatment groups
Randomisation was computer generated by the trial statistician and stratified by age, using a prespecified cutoff of younger than 18 years versus 18 years or older. Participants were assigned to one of four groups:
1) placebo and no exercise with attention control, referred to as placebo only;
2) nicotinamide riboside and no exercise with attention control, referred to as nicotinamide riboside only;
3) placebo and exercise, referred to as exercise only; and
4) nicotinamide riboside and exercise, referred to as combination therapy.
Interventions
The exercise intervention was individualized by an exercise physiologist and consisted of three aerobic sessions and two resistance sessions per week, performed at home with remote oversight through telephone check-ins. This pragmatic design is notable because it tested a program that could plausibly be implemented outside a tertiary centre.
Nicotinamide riboside or placebo was dosed by weight: 300 mg daily for body weight 24 kg to less than 48 kg, 600 mg daily for 48 kg to less than 72 kg, and 900 mg daily for more than 72 kg.
Endpoints and statistical approach
The primary endpoint was change in peak VO2 in L/min during cardiopulmonary exercise testing at 12 weeks compared with baseline. The analysis adjusted for age stratum, sex, and baseline peak VO2, and followed the intention-to-treat principle.
The statistical plan used a staged testing strategy. Stage 1 compared each active treatment group against the control group, while controlling the family-wise type 1 error rate below 0.05. Stage 2, to be performed if combination therapy was effective, compared combination therapy with exercise alone to explore whether nicotinamide riboside added benefit beyond exercise.
Key Results
Primary efficacy outcome
The least mean squares change in peak VO2 at 12 weeks was:
-0.05 L/min (95% CI -0.16 to 0.06) in the control group (n=17);
0.06 L/min (-0.05 to 0.17) in the nicotinamide riboside only group (n=17);
0.11 L/min (0.00 to 0.22) in the exercise only group (n=16);
0.16 L/min (0.05 to 0.27) in the combination therapy group (n=16).
Compared with control, adjusted differences were:
0.10 L/min (95% CI -0.05 to 0.26; padjusted=0.188) for nicotinamide riboside only;
0.16 L/min (0.00 to 0.31; padjusted=0.103) for exercise only;
0.21 L/min (0.05 to 0.36; padjusted=0.0299) for combination therapy.
Thus, only the combined intervention met the prespecified threshold for statistical significance against the control condition after multiplicity adjustment. The signal is clinically plausible and directionally consistent across groups: control worsened slightly, nicotinamide riboside alone improved modestly, exercise alone improved somewhat more, and the combination showed the largest gain.
Did nicotinamide riboside add to exercise?
The stage 2 comparison between combination therapy and exercise alone was not statistically significant: difference -0.05 (95% CI -0.10 to 0.21; p=0.49). This result deserves careful interpretation. It does not prove absence of additive biological effect; rather, it indicates that in this modestly sized phase 2 sample, the trial did not demonstrate a statistically reliable increment from adding nicotinamide riboside to exercise alone.
In practical terms, the overall outcome pattern suggests that the combined regimen was effective compared with control, but the study was not able to clearly separate the contribution of nicotinamide riboside beyond the exercise effect. This is a common issue in factorial phase 2 studies, especially in rare diseases where sample sizes are necessarily limited.
Safety and tolerability
Adverse events were all mild or moderate. Reported categories included gastrointestinal symptoms, falls, upper respiratory infections, and skin rashes. At least one moderate adverse event of interest in these categories occurred in seven participants (41%) in the control group, six (35%) in the nicotinamide riboside only group, three (19%) in the exercise only group, and four (25%) in the combination group.
Several points are clinically relevant. First, there was no obvious excess of moderate adverse events in the active treatment arms. Second, a home-based exercise strategy in a neurologically impaired population did not appear to generate a prohibitive safety burden. Third, nicotinamide riboside at the doses used here was not associated with a major tolerability signal over 12 weeks.
Clinical Interpretation
This trial offers one of the more practical intervention models tested in Friedreich’s ataxia: a home-based, individualized exercise prescription paired with a low-burden oral metabolic therapy. The finding that combination therapy improved peak VO2 is important because cardiopulmonary fitness is a meaningful intermediate outcome in this disease, linking neurological disability, physical endurance, and multisystem health.
However, clinicians should be cautious not to overstate the result. The primary endpoint was physiological rather than directly patient-reported or disability-based. We do not yet know whether the observed gain in peak VO2 translates into better walking endurance, reduced fatigue, slower decline, fewer cardiometabolic complications, or improved quality of life over the long term. A 12-week improvement in fitness is encouraging, but durability matters greatly in a chronic progressive disorder.
The nonsignificant comparison between combination therapy and exercise alone also limits immediate conclusions about nicotinamide riboside as an independent disease-management addition. Exercise remains the more established biological and rehabilitative intervention. What this study shows most clearly is that the combined package is feasible, safe, and superior to placebo plus attention control for improving peak VO2 over 12 weeks.
Mechanistic Perspective
The biological rationale for both interventions is strong. Exercise training can enhance mitochondrial biogenesis, oxidative capacity, autonomic conditioning, peripheral muscle efficiency, and cardiovascular performance. In Friedreich’s ataxia, these effects may partly offset the downstream consequences of frataxin deficiency, even if they do not correct the primary molecular lesion.
Nicotinamide riboside enters NAD+ biosynthesis pathways and may support cellular redox balance, sirtuin signaling, and mitochondrial function. In principle, combining a metabolic substrate-support strategy with an activity-based rehabilitation program could create a synergistic response: exercise increases energetic demand and adaptive signaling, while NAD+ precursor availability may facilitate mitochondrial adaptation. The present trial’s pattern is compatible with that hypothesis, but not definitive proof of synergy.
Strengths of the Trial
This study has several notable strengths. It was randomised, prospectively registered, and analyzed by intention to treat. The factorial design was efficient and especially appropriate in a rare disease setting. The population included both children and adults, increasing clinical relevance across the age spectrum of Friedreich’s ataxia care. Adherence was likely aided by individualized planning and remote follow-up, which also improves real-world applicability.
The endpoint, peak VO2 measured by cardiopulmonary exercise testing, is objective and less vulnerable to expectation bias than many functional endpoints. The complete retention of all 66 randomised participants is another major strength and reduces concern about attrition bias.
Limitations and Generalizability
The trial also has important limitations. It was single-centre, which may limit external validity. The sample size was necessarily small, and the confidence intervals around treatment effects remain fairly wide. The intervention period lasted only 12 weeks, too short to assess sustained benefits, progression-modifying effects, or uncommon adverse events.
Eligibility required participants to be capable of exercise and to have an ejection fraction of at least 45%. Therefore, the results may not generalize to more advanced Friedreich’s ataxia, nonambulatory patients, or those with more significant cardiomyopathy. The home-based exercise design is pragmatic, but it can also introduce variability in implementation despite remote oversight.
Another limitation is endpoint scope. Peak VO2 is valuable, but clinicians and patients will also want data on fatigue, falls, daily function, neurological scales, cardiac structure and rhythm, metabolic outcomes, and quality of life. Finally, although the combination arm succeeded against control, the absence of a significant difference versus exercise alone means that the evidence for nicotinamide riboside as a necessary adjunct remains preliminary.
Implications for Practice and Research
For clinicians caring for patients with Friedreich’s ataxia, this trial supports structured exercise as a serious therapeutic component rather than merely a supportive suggestion. The intervention was individualized, mixed aerobic and resistance training, and delivered largely at home. That model is attractive for neuromuscular practice, where travel burden and specialist access often limit participation.
Whether nicotinamide riboside should be incorporated into routine care is less settled. The data justify further study and may support discussion in specialized centres or research contexts, but they are not yet sufficient to establish standard-of-care use. Longer multicentre trials should test durability, dose-response, subgroup effects by age and disease severity, and whether gains in peak VO2 are accompanied by improvements in patient-centered outcomes and cardiac endpoints.
Future studies should also examine biomarkers of NAD+ metabolism, mitochondrial adaptation, and frataxin-related pathobiology to help determine who is most likely to benefit and whether treatment response can be predicted early.
Conclusion
This phase 2 randomised trial provides encouraging evidence that 12 weeks of individualized home-based exercise combined with nicotinamide riboside can safely improve cardiopulmonary fitness in children and adults with Friedreich’s ataxia. The result is clinically meaningful because reduced exercise capacity is a central and undertreated feature of the disease. At the same time, the findings should be viewed as an important step rather than a definitive practice-changing endpoint. Exercise appears promising and feasible; nicotinamide riboside remains biologically compelling but still requires confirmation in larger and longer trials designed to assess additive benefit, durability, and real-world functional impact.
Funding and Trial Registration
This study was funded by the US National Institutes of Health and the Friedreich’s Ataxia Research Alliance. The trial was registered at ClinicalTrials.gov, NCT04192136.
References
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