{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T02:47:47Z","timestamp":1790304467155,"version":"4.1.0"},"reference-count":32,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the safety and efficacy of orally administered tetramethylpyrazine nitrone in patients with ALS.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This phase 2, multicenter, double-masked, placebo-controlled, randomized clinical trial was conducted from December 24, 2020, through July 14, 2023, in 11 centers in China, with a 180-day follow-up. Patients aged 45 to 70 years, with ALS onset within 2 years, ALS Functional Rating Scale\u2013Revised (ALSFRS-R) scores of at least 2 points on each item, and forced vital capacity (FVC) of at least 80% were included. Patients experienced a 1- to 4-point decrease in ALSFRS-R score during a 3-month screening period.<\/jats:p><\/jats:sec>Interventions<\/jats:title>Patients were randomly assigned 1:1:1 to receive low-dose tetramethylpyrazine nitrone (600 mg twice daily), high-dose tetramethylpyrazine nitrone (1200 mg twice daily), or placebo (twice daily) for 180 days.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The primary outcome was change in ALSFRS-R score (range of 0-48, with lower scores indicating worse function) from baseline to 180 days. The secondary outcomes were changes in FVC, grip strength, ALS Assessment Questionnaire-40 (ALSAQ-40) score, and end point events. Safety outcomes included adverse events.<\/jats:p><\/jats:sec>Results<\/jats:title>A total of 155 patients (mean [SD] age, 55.0 [6.5] years; 115 men [74.2%]) were randomized (51 [32.9%] to the low-dose tetramethylpyrazine nitrone group, 52 [33.6%] to the high-dose tetramethylpyrazine nitrone group, and 52 [33.6%] to the placebo group). No significant differences were observed in ALSFRS-R score changes between low-dose tetramethylpyrazine nitrone (least squares [LS] mean difference, \u22120.89 points; 95% CI \u22123.25 to 1.48 points) and high-dose tetramethylpyrazine nitrone (LS mean difference, \u22120.20 points; 95% CI \u22122.48 to 2.07 points) compared with placebo. High-dose tetramethylpyrazine nitrone showed a significantly slower decline in grip strength at day 180 (LS mean difference, 2.46 kg; 95% CI, 0.15-4.76 kg). In a subgroup of patients younger than 65 years with slower disease progression, tetramethylpyrazine nitrone significantly attenuated the decline in grip strength (LS mean difference, 3.63 kg; 95% CI, 0.84-6.41 kg), bulbar scores (LS mean difference, 0.66 points; 95% CI, 0.03-1.29 points), and respiratory scores (LS mean difference, 0.54 points; 95% CI, 0.03-1.06 points). Adverse events were mostly mild or moderate, with no severe treatment-related adverse events or deaths.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>This randomized clinical trial demonstrates that tetramethylpyrazine nitrone is safe and well-tolerated in patients with ALS. There was no difference in the primary end point across the low-dose, high-dose, and placebo groups, with significant benefits in a subgroup of younger patients with slower disease progression.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ChiCTR Identifier: ChiCTR2000039689<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.61055","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T16:34:27Z","timestamp":1740414867000},"page":"e2461055","source":"Crossref","is-referenced-by-count":9,"title":["Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis"],"prefix":"10.1001","volume":"8","author":[{"given":"Xiaolu","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology, Peking University Third Hospital, Beijing, China"},{"name":"Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China"},{"name":"Key Laboratory for Neuroscience, National 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