Safety and efficacy of individualised exercise and NAD(+) precursor supplementation in patients with Friedreich's ataxia in the USA: a single-centre, 2 × 2 factorial, randomised controlled trial.

1. Lancet Neurol. 2026 May;25(5):469-481. doi: 10.1016/S1474-4422(26)00082-7. Safety and efficacy of individualised exercise and NAD(+) precursor supplementation in patients with Friedreich's ataxia in the USA: a single-centre, 2 × 2 factorial, randomised controlled trial. Lin KY(1), Bucha A(1), McSweeney K(1), Wade KL(2), Karaj A(3), Tamaroff J(4), O'Malley S(1), Chung NM(2), Cilenti NA(2), Wanner J(1), Adzika GK(5), Mesaros C(6), Blair IA(6), Rojsajjakul T(6), Serai S(7), Farmer J(8), Bryant K(8), Lu Y(9), Harhay MO(3), Weber DR(2), Paridon SM(1), Seifert EL(10), Putt ME(3), Zamani P(11), Baur JA(5), Lynch DR(12), McCormack SE(13). Author information: (1)Division of Cardiology, Department of Paediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (2)Division of Endocrinology and Diabetes, Department of Paediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (3)Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (4)Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, Vanderbilt University Medical Center, Nashville, TN, USA. (5)Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (6)Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (7)Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (8)Friedreich Ataxia Research Alliance, Downingtown, PA, USA. (9)Palliative and Advanced Illness Research Centre, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (10)MitoCare Center, Department of Pathology & Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA. (11)Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (12)Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (13)Division of Endocrinology and Diabetes, Department of Paediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: mccormacks1@chop.edu. 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 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. FUNDING: US National Institutes of Health and Friedreich's Ataxia Research Alliance. Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved. DOI: 10.1016/S1474-4422(26)00082-7 PMCID: PMC13162205 PMID: 42009009 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests KYL and SEM report support from the US National Institutes of Health (NIH) grant R01CA254955 supporting separate research on NAD(+) precursor supplementation and exercise in cancer survivors, and KYL serves on a Data Monitoring Committee for Cytokinetics. JF and KB are employees of Friedreich Ataxia Research Alliance, which receives grants, sponsorships, and consultancy fees from Biogen, PTC Therapeutics, Larimar Therapeutics, Design Therapeutics, Solid Biosciences, Lexeo Therapeutics, and Neurocrine. KB reports sponsorship for a podcast from Real Chemistry, the creative agency of Biogen. MOH reports support from NIH grants R01-HL168202 and U01HL168419 and consulting fees from Elsevier and the American Thoracic Society for statistical analyses. DW has received consulting fees for Ascendis, Catalyst, and Santhera; compensation for presenting from Inozyme; and is on a Data and Safety Monitoring Board (DSMB) for Merck. SMP reports consulting fees from Mezzion Pharmaceuticals. PZ reports consulting support from Tenax Therapeutics and grant support from Amgen, the University of Pennsylvania, and NIH grants (R01HL174691, R01 HL149722, R01 HL155599, R01 HL157264, UH3 DK128298, and U01 HL160277). JAB reports support from Metro Biotech including a Sponsored Research Agreement and license to one patent; consulting fees from Altimmune; participation on the Scientific Advisory Board for Cytokinetics, and a DSMB for two clinical trials (NCT04913805 and NCT05138575); and receipt of materials from Elysium Health. DRL reports grant support from the US Department of Defence, Reata Biogen, PTC Therapeutics, and Larimar Therapeutics; and royalties from Neurimmune. SEM also reports an NIH grant (R01DK135211); serving as site primary investigator for industry trials (Rhythm Pharmaceuticals and Amryt Pharmaceuticals); and receipt of materials from Metro Biotech for a separate study of nicotinamide riboside. All other authors declare no competing interests.