Tetramethylpyrazine Nitrone in Amyotrophic Lateral Sclerosis
Authors: Xiaolu Liu, Huifang Shang, Qianqian Wei, Xiaoli Yao, Ling Lian, Jingxia Dang, Rui Jia, Zhiying Wu, Hongfu Li, Qi Niu, Xi Cheng, Zhangyu Zou, Sheng Chen, Min Zhang, Yang Liu, Yaling Liu, Qi Liu, Xusheng Huang, Hongfen Wang, Honglin Feng, Shuyu Wang, Dongsheng Fan, Yuqiang Wang, Zaijun Zhang, Gaoxiao Zhang, Yewei Sun, Mei Jing, Dilip Dhakal
Journal: JAMA Network Open (2025)

Importance Tetramethylpyrazine nitrone has exhibited promising results in improving motor dysfunction in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Objective To evaluate the safety and efficacy of orally administered tetramethylpyrazine nitrone in patients with ALS. Design, Setting, and Participants 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–Revised (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. Interventions 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. Main Outcomes and Measures 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. Results 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, −0.89 points; 95% CI −3.25 to 1.48 points) and high-dose tetramethylpyrazine nitrone (LS mean difference, −0.20 points; 95% CI −2.48 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. Conclusions and Relevance 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. Trial Registration ChiCTR Identifier: ChiCTR2000039689